g proteins and their cell type specific functions

Mammalian G Proteins and Their Cell Type Specific Functions

NINA WETTSCHURECK AND STEFAN OFFERMANNS

Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany

I. Introduction 1160A. Basic principles of G protein-mediated signaling 1160B. G protein �-subunits and ��-complexes 1163

II. Cardiovascular System 1167A. Autonomic control of heart function 1167B. Myocardial hypertrophy 1168C. Smooth muscle tone 1169D. Platelet activation 1171

III. Endocrine System and Metabolism 1173A. Hypothalamo-pituitary system 1173B. Pancreatic �-cells 1174C. Thyroid gland/parathyroid gland 1175D. Regulation of carbohydrate and lipid metabolism 1175

IV. Immune System 1177A. Leukocyte migration/homing 1177B. Immune cell effector functions 1178

V. Nervous System 1179A. Inhibitory modulation of synaptic transmission 1179B. Modulation of synaptic transmission by the Gq/G11-mediated signaling pathway 1179C. Roles of Gz and Golf in the nervous system 1180

VI. Sensory Systems 1180A. Visual system 1181B. Olfactory/pheromone system 1181C. Gustatory system 1182

VII. Development 1182A. G13-mediated signaling in embryonic angiogenesis 1183B. Gq/G11-mediated signaling during embryonic myocardial growth 1183C. Neural crest development 1183

VIII. Cell Growth and Transformation 1184A. Constitutively active mutants of G�q/G�11 family members 1184B. The oncogenic potential of G�s 1184C. Gi-mediated cell transformation 1185D. Cellular growth induced by G�12/G�13 1185

IX. Concluding Remarks 1185

Wettschureck, Nina, and Stefan Offermanns. Mammalian G Proteins and Their Cell Type Specific Functions.Physiol Rev 85: 1159–1204, 2005; doi:10.1152/physrev.00003.2005.—Heterotrimeric G proteins are key players intransmembrane signaling by coupling a huge variety of receptors to channel proteins, enzymes, and other effectormolecules. Multiple subforms of G proteins together with receptors, effectors, and various regulatory proteinsrepresent the components of a highly versatile signal transduction system. G protein-mediated signaling is employedby virtually all cells in the mammalian organism and is centrally involved in diverse physiological functions such asperception of sensory information, modulation of synaptic transmission, hormone release and actions, regulation ofcell contraction and migration, or cell growth and differentiation. In this review, some of the functions ofheterotrimeric G proteins in defined cells and tissues are described.

Physiol Rev 85: 1159–1204, 2005;doi:10.1152/physrev.00003.2005.

www.prv.org 11590031-9333/05 $18.00 Copyright © 2005 the American Physiological Society

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I. INTRODUCTION

All cells possess transmembrane signaling systemsthat allow them to receive information from extracellularstimuli like hormones, neurotransmitters, or sensorystimuli. This fundamental process allows cells to commu-nicate with each other. All transmembrane signaling sys-tems share two basic elements, a receptor which is able torecognize an extracellular stimulus as well as an effectorwhich is controlled by the receptor and which can gener-ate an intracellular signal. Many transmembrane signalingsystems like receptor tyrosine kinases incorporate thesetwo elements in one molecule. In contrast, the G protein-mediated signaling system is relatively complex consist-ing of a receptor, a heterotrimeric G protein, and aneffector. This modular design of the G protein-mediatedsignaling system allows convergence and divergence atthe interfaces of receptor and G protein as well as of Gprotein and effector. In addition, each component, thereceptor, the G protein as well as the effector can beregulated independently by additional proteins, solublemediators, or on the transcriptional level. The relativelycomplex organization of the G protein-mediated trans-membrane signaling system provides the basis for a hugevariety of transmembrane signaling pathways that aretailored to serve particular functions in distinct cell types.It is probably this versatility of the G protein-mediatedsignaling system that has made it by far the most oftenemployed transmembrane signaling mechanism. In thisreview we summarize some of the biological roles of Gprotein-mediated signaling processes in the mammalianorganism which are based on their cell type-specific func-tion. Although we have tried to cover a wide variety ofcellular systems and functions, the plethora of availabledata forced us to restrict this review. Particular emphasisis placed on cellular G protein functions that have beenstudied in primary cells or in the context of the wholeorganism using genetic approaches.

A. Basic Principles

of G Protein-Mediated Signaling

More than 1,000 G protein-coupled receptors (GPCRs)are encoded in mammalian genomes. While most of themcode for sensory receptors like taste or olfactory recep-tors, �400–500 of them recognize nonsensory ligands likehormones, neurotransmitters, or paracrine factors (53,185, 519, 534, 649). For more than 200 GPCRs, the phys-iological ligands are known (Table 1). GPCRs for whichno endogenous ligand has been found are “orphan”GPCRs (376, 389, 688).

Upon activation of a receptor by, e.g., its endogenousligand, coupling of the activated receptor to the hetero-trimeric G protein is facilitated. Multiple site-directed mu-

tagenesis experiments have been performed on G protein-coupled receptors, and they have revealed various cyto-plasmic domains of the receptors that are involved in thespecific interaction between the receptors and the G pro-tein. However, despite the determination of the structureof rhodopsin at atomic resolution (504), it is still not clearhow specificity of the receptor-G protein interaction isachieved and how a ligand-induced conformationalchange in the receptor molecule results in G proteinactivation (177, 212, 213, 565, 674).

The heterotrimeric G protein consists of an �-subunitthat binds and hydrolyzes GTP as well as of a �- and a�-subunit that form an undissociable complex (233, 255,475). Several subtypes of �-, �-, and �-subunits have beendescribed (Table 2). To dynamically couple activated re-ceptors to effectors, the heterotrimeric G protein under-goes an activation-inactivation cycle (Fig. 1). In the basalstate, the ��-complex and the GDP-bound �-subunit areassociated, and the heterotrimer can be recognized by anappropriate activated receptor. Coupling of the activatedreceptor to the heterotrimer promotes the exchange ofGDP for GTP on the G protein �-subunit. The GTP-bound�-subunit dissociates from the activated receptor as wellas from the ��-complex, and both the �-subunit and the��-complex are now free to modulate the activity of avariety of effectors like ion channels or enzymes. Signal-ing is terminated by the hydrolysis of GTP by the GTPaseactivity, which is inherent to the G protein �-subunit. Theresulting GDP-bound �-subunit reassociates with the ��-complex to enter a new cycle if activated receptors arepresent. For recent excellent reviews on basic structuraland functional aspects of G proteins, see References 49,83, 361, and 526.

While the kinetics of G protein activation throughGPCRs has been well described for quite a while, onlyrecently has the regulation of the deactivation processbeen understood in more detail. Based on the observationthat the GTPase activity of isolated G proteins is muchlower than that observed under physiological conditions,the existence of mechanisms that accelerate the GTPaseactivity had been postulated. Various effectors have in-deed been found to enhance GTPase activity of the Gprotein �-subunit, thereby contributing to the deactiva-tion and allowing for rapid modulation of G protein-me-diated signaling (23, 45, 348, 571). More recently, a familyof proteins called “regulators of G protein signaling” (RGSproteins) has been identified, which is also able to in-crease the GTPase activity of G protein �-subunits (272,481, 550). There are �30 RGS proteins currently known,which have selectivities for G protein �-subfamilies. Thephysiological role of RGS proteins is currently under in-vestigation. Besides their role in the modulation of Gprotein-mediated signaling kinetics, they also influencethe specificity of the signaling process and in some casesmay have effector functions.

1160 NINA WETTSCHURECK AND STEFAN OFFERMANNS

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TABLE 1. Physiological ligands of G protein-coupled receptors

Endogenous Ligand(s) ReceptorCoupling to G Protein

Subclass(es) Reference Nos.

Amino acids, dicarboxylic acidsGlutamate mGluR1,5 Gq/11 117

mGluR2,3,4,6,7,8 Gi/o 117�-Aminobutyric acid (GABA) GABAB1 (binding), GABAB2 (signaling) Gi/o 64�-Ketoglutarate GPR99 Gq/11 248Succinate GPR91 Gq/11, Gi/o 248L-Arginine, L-lysine GPRC6A Gq/11 ? 673

Biogenic AminesAcetylcholine M1,M3,M5 Gq/11 675

M2, M4 Gi/o 675Epinephrine, norepinephrine �1A,�1B,�1D Gq/11 252

�2A,�2B,�2C Gi/o 252�1,�2,�3 Gs 399

Dopamine D1,D5 Gs 487D2,D3,D4 Gi/o 487

Histamine H1 Gq/11 262H2 Gs 262H3,H4 Gi/o 262

Melatonin MT1,MT2,MT3 Gi/o 151Serotonin 5-HT1A/B/D/E/F Gi/o 281

5-HT2A/B/C Gq/11 2815-HT4,5-HT6,5-HT7 Gs 281, 466, 4675-HT5A/B Gi/o, Gs 281

Trace amines TA1, TA2 Gs 57, 80Ions

Ca2� CaSR Gq/11, Gi/o 218H� SPC1, G2A Gq/11, G12/13 403, 465

GPR4, TDAG-8 Gs 403, 658Nucleotides/nucleosides

Adenosine A1, A3 Gi/o 184A2A, A2B Gs 184

ADP P2Y12, P2Y13 Gi/o 273, 422ADP/ATP P2Y1 Gq/11 183ATP P2Y11 Gq/11, Gs 183UDP P2Y6 Gq/11 183UDP-glucose P2Y14 Gi/o 1UTP/ATP P2Y2, P2Y4 Gq/11 183

LipidsAnandamide, 2-arachidonoyl glycerol CB1, CB2 Gi/o 28011-Cis-retinal (covalently bound for

light-dependent receptor activation;see below)

Rhodopsin Gt-r 717Opsins (green, blue, red) Gt-c 471Melanopsin Gq/11 ? 436, 505, 530

Fatty acids (C2–C5) GPR41, GPR43 Gi/o, Gq/11 72(C12–C20) GPR40 Gq/11 70(C14–C22) GPR120 Gq/11 265

5-Oxo-ETE TG1019, GPR170 Gi/o 69Leukotrinene B4 (LTB4) BLT Gi/o 68LTC4, LTD4 CysLT1, CysLT2 Gq/11 68LXA4 FPRL1 (ALXR) Gi/o 68Lysophosphatidic acid (LPA) LPA1/2/3 (Edg2/4/7) Gi, Gq/11, G12/13 110Platelet-activating factor (PAF) PAF Gq/11 528Prostacyclin (PGI2) IP Gs 238, 470Prostaglandin D2 (PGD2) DP Gs 238, 470

CRTH2 Gi 238, 470Prostaglandin F2� (PGF) FP Gq/11 238, 470Prostaglandin E2 (PGE2) EP1 Gq/11 238, 470

EP2, EP4 Gs 238, 470EP3 Gs, Gq/11, Gi 238, 470

Spingosine-1-phosphate (S1P) S1P1/2/3/4/5 (Edg1/5/3/6/8) Gi, Gq/11, G12/13 293Spingosylphosphorylcholine (SPC) SPC1 (OGR1), SPC2 (GPR4) Gi 706, 735Thromboxane A2 (TxA2) TP Gq/11, G12/13 238, 470

Peptides/proteinsAdrenocorticotrophin (ACTH) MC2 Gs 682Adrenomedullin AM1 (CL�RAMP2), AM2 (CL�RAMP3) Gs 525

CELLULAR FUNCTIONS OF G PROTEINS 1161


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TABLE 1—Continued

Endogenous Ligand(s) ReceptorCoupling to G Protein


Amylin AMY1 (CT�RAMP1), AMY2

(CT�RAMP2), AMY3 (CT�RAMP3)Gs 525

Angiotensin II AT1 Gq/11, G12/13, Gi/o 134AT2 ?

Apelin APJ Gi/o 627Bradykinin B1, B2 Gq/11 378Calcitonin CT Gs, Gq/11 525Calcitonin gene-related peptide (CGRP) CGRP1 (CL�RAMP1) Gs, Gq/11 525CC chemokines CCR1,2,3,4,5,6,7,8,9,10 Gi/o 466, 467CXC chemokines CXCR1,2,3,4,5,6 Gi/o 466, 467CX3C chemokines XCL1, XCL2, CX3L1 Gi/o 466, 467Cholecyctokinin (CCK-8) CCK1, CCK2 Gq/11, Gs 582Complement C3a/C5a C3a, C5a Gi/o 208Corticitropin-releasing factor (CRF),

urocortinCRF1, CRF2 Gs 239

Endothelin-1, -2, -3 ETA (ET-1, ET-2), ETB (ET-1, -2, -3) Gq/11, G12/13, Gs 131Follicle-stimulating hormone (FSH) FSH Gs 648Formyl-Met-Leu-Phe (fMLP) FPR Gi/o 373Galanin, galanin-like peptide GAL1, GAL3 Gi/o 657

GAL2 Gi/o, Gq/11, G12/13 657Gastric inhibitory peptide GIP Gs 332, 431Gastrin CCK2 Gq/11 582Gastrin-releasing peptide (GRP),

bombesinBB2 Gq/11 36

Ghrelin GHS-R Gq/11 342Glucagon Glucagon Gs 431Glucagon-like peptide GLP1, GLP2 Gs 431Gonadotropin-releasing hormone GnRH Gq/11 445Growth hormone-releasing hormone GHRH Gs 206, 431Kisspeptins, metastin GPR54 Gq/11 137, 575Luteinizing hormone,

choriogonadotropinLSH Gs, Gi 648

Melanin-concentrating hormone MCH1 Gi/o? 63MCH2 Gq/11

Melanocortins MC1, MC3, MC4, MC5 Gs 682Motilin GPR38 Gq/11 173Neurokinin-A/-B (NK-A/-B) NK2 (NK-A), NK3 (NK-B) Gq/11 513Neuromedin-B, bombesin BB1 Gq/11 496Neuromedin U NMU1 (FM-3), NMU2 (FM-4) Gq/11 67Neuropeptide FF & AF NPFF1, NPFF2 Gi/o 54Neuropeptide W-23, W-30 GRP7, GPR8 Gi/o 580Neuropeptide Y (NPY) etc. Y1, Y2, Y4, Y5, Y6 Gi/o 440Neurotensin NTS1, NTS2 Gq/11 654Opioids (�-endorphin, Met/Leu-

enkephalin, dynorphin A, nociceptin/orphanin FQ)

�, �, �, ORL1 Gi/o 370

Orexin A/B OX1, OX2 Gs, Gq/11 442Oxytocin OT Gq/11, Gi/o 256Parathyroid hormone (related peptide) PTH/PTHrP Gs, Gq/11 203Prokineticin-1,2 PK-R1, PK-R2 Gq/11 591Prolactin-releasing peptide PrRP (GPR10) Gq/11 613Relaxin, insulin-like 3 LGR7, LGR8 Gs 35Secretin Secretin Gs 431Somatostatin SST1, SST2, SST3, SST4, SST5 Gi/o 511Substance P (SP) NK1 Gq/11 513Thyrotropin (TSH) TSH Gs, Gq/11, Gi, G12/13 648Thyrotropin-releasing hormone (TRH) TRH-1, TRH-2 Gq/11 614Urotensin II UT-II (GPR14) Gq/11 150Vasoactive intestinal polypeptide (VIP),

PACAPVPAC1, VPAC2, PAC1 Gs 651

Vasopressin V1a, V1b Gq/11 256V2 Gs 256

Proteases (the new NH2-terminal domainproduced by proteolytic cleavageserves as a tethered ligand)

Thrombin and others PAR-1, PAR-3, PAR-4 Gq/11, G12/13, Gi/o 271Trypsin and others PAR-2 Gq/11 271



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The interaction of G proteins with the inner side ofthe plasma membrane is facilitated by lipid modificationsof both the �-subunit as well as of the �-subunit of the��-complex (97, 448, 589, 728). Recent data provide evi-dence that heterotrimeric G proteins of the Gi family arealso involved in receptor-independent processes (52,413), which appear to be critically involved in the posi-tioning of the mitotic spindle and the attachment of mi-crotubules to the cell cortex (234). These processes alsoinvolve a group of proteins that carry a so-called GoLocomotif which functions as a guanine nucleotide dissocia-tion inhibitor (684).

B. G Protein �-Subunits and ��-Complexes

The functional versatility of the G protein-mediatedsignaling system is based on its modular architecture andon the fact that there are numerous subtypes of G pro-teins. The �-subunits that define the basic properties of aheterotrimeric G protein can be divided into four families,G�s, G�i/G�o, G�q/G�11, and G�12/G�13 (Table 2). Eachfamily consists of various members that often show veryspecific expression patterns. Members of one family arestructurally similar and often share some of their func-tional properties. The ��-complex of mammalian G pro-teins is assembled from a repertoire of 5 G protein �-sub-units and 12 �-subunits (Table 2). While �1- to �4-subunitsform a tight complex with �-subunits which can only beseparated under denaturing conditions, the �5-subunitinteraction with �-subunits is comparably weak (347,543). The �5-subunit is an exception in that it can also befound in a complex with a subgroup of RGS proteins(689). The ��-complex was initially regarded as a more

passive partner of the G protein �-subunit. However, ithas become clear that ��-complexes freed from the Gprotein �-subunit can regulate various effectors (112).These ��-mediated signaling events include the regula-tion of ion channels (488), of particular isoforms of ad-enylyl cyclase and phospholipase C (169, 615), as well asof phosphoinositide-3-kinase isoforms (641). With a fewexceptions, the ability of different ��-combinations toregulate effector functions does not dramatically differ(112).

Most receptors are able to activate more than one Gprotein subtype. The activation of a G protein-coupledreceptor therefore usually results in the activation ofseveral signal transduction cascades via G protein �-sub-units as well as through the freed ��-complex. The pat-tern of G proteins activated by a given receptor deter-mines the cellular and biological response, and activatedreceptors that lead to functionally similar or identicalcellular effects usually activate the same G protein sub-types. The G protein receptor interaction in general doesnot occur in an absolutely specific or in a completelypromiscuous manner. Some receptors appear to interactonly with certain G protein subforms, and in some cellularsystems, the compositions of defined G protein-mediatedsignaling pathways can be very specific. However, thereare some characteristic patterns of receptor-G proteincoupling that have been described for the majority ofreceptors (Fig. 2).

The G proteins of the Gi/Go family are widely ex-pressed and especially the �-subunits of Gi1, Gi2 and Gi3

have been shown to mediate receptor-dependent inhi-bition of various types of adenylyl cyclases (615). Be-cause the expression levels of Gi and Go are relatively

TABLE 1—Continued

Sensory Stimuli ReceptorCoupling to G Protein


Light�500 nm (max. absorption) Rhodopsin (11-cis-retinal) Gt-r 717�426 nm (max. absorption) Blue-opsin (11-cis-retinal) Gt-c 471�530 nm (max. absorption) Green-opsin (11-cis-retinal) Gt-c 471�560 nm (max. absorption) Red-opsin (11-cis-retinal) Gt-c 471�425–480 nm (max. absorption) Melanopsin (11-cis-retinal) Gq/11? 436, 505, 530

TasteUmami T1R1 � T1R3 Ggust? 457, 477, 730

mGluR4 Gi/o 95Sweet T1R2 � T1R3 Ggust? 457, 477, 730Bitter T2 receptor group (many; �25 in

human, �36 in mouse)Ggust? 94, 457, 463

Odorants many (�350 in human, �1,000 inmouse)

Golf 77, 457

Pheromones V1 group (few in human, �150 inmouse)

Gi2 ? 428, 457

V2 group (none in human, �150 inmouse)

Go ? 428, 457

In the reference column, reviews are cited whenever possible to limit the number of references.



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high, their receptor-dependent activation results in therelease of relatively high amounts of ��-complexes.Activation of Gi/Go is therefore believed to be the majorcoupling mechanism that results in the activation of��-mediated signaling processes (112, 543). The func-tion of members of the Gi/Go family has often beenstudied using a toxin from Clostridium botulinum

(pertussis toxin; PTX) which is able to ADP-ribosylatemost of the members of the G�i/G�o family close totheir COOH termini. COOH-terminally ADP-ribosylatedG�i/G�o is unable to interact with the receptor. ThusPTX treatment results in the uncoupling of the receptorand Gi/Go. The structural similarity between the 3 G�i

subforms suggests that they may have partially over-lapping functions. In contrast to other G proteins, theeffects of Go, which is particularly abundant in the

nervous system, appears to be primarily mediated by its��-complex. Whether G�o can regulate effectors di-rectly is currently not clear. A less widely expressedmember of the G�i/G�o family is G�z (438), which incontrast to Gi and Go is not a substrate for PTX. G�z isexpressed in various tissues including the nervous sys-tem and platelets. It shares some functional similaritieswith Gi-type G proteins but has recently been shown tointeract specifically with various other proteins includ-ing Rap1GAP and certain RGS proteins (438). Several�-subunits like gustducin and transducins belong to theG�i/G�o family and are involved in specific sensoryfunctions (24, 126).

The Gq/G11 family of G proteins couples receptors to�-isoforms of phospholipase C (169, 538). The �-subunitsof Gq and G11 are almost ubiquitously expressed while the

TABLE 2. Heterotrimeric G proteins

Name Gene Expression Effector(s)

�-SubunitsG�s class

G�s GNAS Ubiquitous AC (all types) 1G�sXL (GNASXL) Neuroendocrine AC 1G�olf GNAL Olfactory epithelium, brain AC 1

G�i/o classG�i1 GNAI1 Widely distributed AC (types I,III,V,VI,VIII,IX) 2 (directly regulated)

various other effectots are regulated via G��released from activated Gi1-3 (see below)

G�i2 GNAI2 UbiquitousG�i3 GNAI3 Widely distributedG�o GNAO Neuronal, neuroendocrine VDCC2, GIRK1 (via G��; see below)G�z GNAZ Neuronal, platelets AC (e.g., V,VI) 2 (directly regulated); Rap1GAPG�gust GNAT3 Taste cells, brush cells PDE 1?; other effectors via G��?G�t-r GNAT1 Retinal rods, taste cells PDE 6 (�-subunit rod) 1G�t-c GNAT2 Retinal cones PDE 6 (�-subunit cone) 1

G�q/11 classG�q GNAQ Ubiquitous PLC-�1-4 1G�11 GNA11 Almost ubiquitous PLC-�1-4 1G�14 GNA14 Kidney, lung, spleen PLC-�1-4 1G�15/16 GNA16 (Gna15) Hematopoietic cells PLC-�1-4 1

G�12/13 classG�12 GNA12 Ubiquitous PDZ-RhoGEF/LARG, Btk, Gap1m, cadherinG�13 GNA13 Ubiquitous p115RhoGEF, PDZ-RhoGEF/LARG, radixin

�-Subunits�1 GNB1 Widely, retinal rods AC type I 2 AC types II,IV,VII 1 PLC-�

(�3��2��1) 1 GIRK1–4 (Kir3.1–3.4) 1 receptorkinases (GRK 2 and 3) 1 PI-3-K, �, � 1 T typeVDCC (Cav3.2) 2 (G�2�2) N-,P/Q-,R-type VDCC(Cav2.1–2.3) 2

�2 GNB2 Widely distributed�3 GNB3 Widely, retinal cones�4 GNB4 Widely distributed�5 GNB5 Mainly brain

�-Subunits�1, �rod GNGT1 Retinal rods, brain,�14, �cone GNGT2 Retinal cones, brain�2, �6 GNG2 Widely�3 GNG3 Brain, blood�4 GNG4 Brain and other tissues�5 GNG5 Widely�7 GNG7 Widely�8, �9 GNG8 Olfactory/vomeronasal epithelium�10 GNG10 Widely�11 GNG11 Widely�12 GNG12 Widely�13 GNG13 Brain, taste buds

AC, adenylyl cyclase; PDE, phosphodiesterase; PLC, phospholipase C; GIRK, G protein-regulated inward rectifier potassium channel; VDCC,voltage-dependent Ca2� channel; PI-3-K, phosphatidylinositol 3-kinase; GRK, G protein-regulated kinase; RhoGEF, Rho guanine nucleotide exchangefactor.



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other members of this family like G�14 and G�15/16 (G�15

being the murine, G�16 the human ortholog) show a ratherrestricted expression pattern. Receptors that are able tocouple to the Gq/G11 family do not appear to discriminatebetween Gq and G11 (490, 660, 696, 705). Similarly, there isobviously no difference between the abilities of both Gprotein �-subunits to regulate phospholipase C �-iso-forms. While G�q and G�11 both are good activators of�1-, �3-, and �4-isoforms of phospholipase C (PLC), thePLC �2-isoform is a poor effector for both (538). Thebiological significance of the diversity among the G�q

gene family is currently not clear. While the importance ofGq and G11 in various biological processes has been wellestablished, the roles of G�14 and G�15/16, which showvery specific expression patterns, are not clear. Mice car-rying inactivating mutations of the G�14 and G�15 geneshave no or very minor phenotypical changes (132; H. Jiangand M. I. Simon, personal communication). In contrast,mice lacking G�q or both G�q and G�11 have multipledefects (489, 494, 495) (see below).

The G proteins G12 and G13, which are often activatedby receptors coupling to Gq/G11, constitute the G12/G13

family and are expressed ubiquitously (139, 607). Theanalysis of cellular signaling processes regulated throughG12 and G13 has been difficult since specific inhibitors ofthese G proteins are not available. In addition, G12/G13-

coupled receptors usually also activate other G proteins.Most information on the cellular functions regulated byG12/G13 therefore came from indirect experiments em-ploying constitutively active mutants of G�12/G�13. Thesestudies showed that G12/G13 can induce a variety of sig-naling pathways leading to the activation of variousdownstream effectors including phospholipase A2,Na�/H� exchanger, or c-jun NH2-terminal kinase (139,193, 276, 523, 607). Another important cellular function ofG12/G13 is their ability to regulate the formation of acto-myosin-based structures and to modulate their contractil-ity by increasing the activity of the small GTPase RhoA(79). Activation of RhoA by G�12 and G�13 is mediated bya subgroup of guanine nucleotide exchange factors(GEFs) for Rho which include p115-RhoGEF, PDZ-Rho-GEF, and LARG (194, 236, 618). While the RhoGEF activ-ity of PDZ-RhoGEF and LARG appears to be activated byboth G�12 and G�13, p115-RhoGEF activity is stimulatedonly by G�13. Recently, an interesting link between G12/G13 and cadherin-mediated signaling was described, bothG�12 and G�13 interact with the cytoplasmic domain ofsome type I and type II class cadherins, causing therelease of �-catenin from cadherins (434, 435). Variousother proteins including Bruton’s tyrosine kinase, the RasGTPase-activating protein Gap1m, radixin, heat shockprotein 90, AKAP110, protein phosphatase type 5, orHax-1 have also been shown to interact with G�12 and/orG�13 (309, 359, 485, 532, 638, 709).

The ubiquitously expressed G protein Gs couplesmany receptors to adenylyl cyclase and mediates recep-tor-dependent adenylyl cyclase activation resulting in in-creases in the intracellular cAMP concentration. The�-subunit of Gs, G�s, is encoded by GNAS, a compleximprinted gene that gives rise to several gene productsdue to the presence of various promoters and splice vari-ants (Fig. 3). In addition to G�s, two transcripts encodingXL�s and Nesp55 are generated by promoters upstream ofthe G�s promoter. While the chromogranin-like proteinNesp55 is structurally and functionally not related to G�s,XL�s is structurally identical to G�s but has an extra longNH2-terminal extension that is encoded by a specific firstexon (329). In contrast to G�s, XL�s has a limited expres-sion pattern being mainly expressed in the adrenal gland,heart, pancreatic islets, brain, and the pars intermedia ofthe pituitary (509). However, XL�s shares with G�s theability to bind to ��-subunits and to mediate receptor-dependent stimulation of cAMP production (33, 339). In-terestingly, the first exon of the Gnasxl gene encodesanother protein termed ALEX (338), which is able tointeract with the XL domain of XL�s and to inhibit itsactivity (188, 338). Interestingly, Nesp55 and XL�s aredifferentially imprinted. While the promoter of Nesp55 isDNA-methylated on the paternally inherited allele result-ing in the expression only from the maternally inheritedallele, the promoter driving XL�s expression is methyl-

FIG. 1. Functional cycle of G protein activity. The complex of a7-transmembrane domain receptor and an agonist (Ag) promotes therelease of GDP from the �-subunit of the heterotrimeric G proteinresulting in the formation of GTP-bound G�. GTP-G� and G�� dissociateand are able to modulate effector functions. The spontaneous hydrolysisof GTP to GDP can be accelerated by various effectors as well as byregulators of G protein signaling (RGS) proteins. GDP-bound G� thenreassociates with G��.



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ated on the maternal allele, and XL�s is only expressedfrom the paternal allele (244, 245, 515). Several othertranscripts like Nespas of which some are believed to be

untranslated show ubiquitous expression and are derivedfrom the paternal allele due to differentially methylatedpromoter regions (243, 294, 396, 619). In contrast, the

FIG. 2. Typical patterns of receptor/G protein coupling. Although there are many exceptions, three basic patterns of receptor-G protein couplinghave been found which critically define the cellular response after ligand-dependent receptor activation. �2, �2-adrenergic receptor; D1–5, dopaminereceptor subtypes 1 to 5; GIRK, G protein-regulated inward rectifier potassium channel; 5-HT1,2, serotonin receptor subtypes 1 and 2; M1–5,muscarinic acetylcholine receptor subtypes 1 to 5; mGluR1–7, metabotropic glutamate receptor subtypes 1 to 7; PLC-�, phospholipase C-�; PI-3-K,phosphoinositide-3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; IP3, inositol 1,4,5-trisphosphate; DAG, diacylglycerol; PKC, protein kinase C;Rho-GEF, Rho-guanine nucleotide exchange factor; TP, thromboxane A2 receptor; IP, prostacyclin receptor.

FIG. 3. Model of the GNAS gene complex withsome of its transcripts. Some of the transcripts gen-erated from the maternal and paternal allele areshown on the top and bottom, respectively. Openboxes indicate noncoding sequences; closed boxesindicate coding sequences. Exon 3 of the GNAS gene(hatched box) is alternatively spliced out giving riseto long and short forms of G�s. Promoters active onthe maternal and paternal allele are indicated by ar-rows. While Nesp is only expressed from the maternalallele, XL�s and Nespas are expressed from the pa-ternal allele. The GNAS promoter is biallelically ac-tive; however, in a few tissues only the maternal alleleis expressed (see text). Several other transcripts ofthe GNAS gene complex have been described; how-ever, their function is unclear. Exon sequences areshown in black and white for coding and noncodingsequences, while transcripts are shown in gray andwhite for coding and noncoding sequences.



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promoter driving the expression of G�s has been shownto be biallelically active and to lack differential methyl-ation (85, 244, 245, 733). However, in a few tissues such asthe renal proximal tubules, the thyroid, pituitary, andovaries, the paternal G�s expression is silenced by an asyet undefined mechanism (209, 242, 394, 414, 723).

II. CARDIOVASCULAR SYSTEM

A. Autonomic Control of Heart Function

Cardiac regulation by the sympathetic system is me-diated by �-adrenergic receptors that are coupled primar-ily to Gs (Fig. 4). cAMP produced in response to Gs

activation directly modulates the gating of hyperpolariza-tion-activated, cyclic nucleotide-gated channels and acti-vates protein kinase A (PKA) which in turn phosphory-lates several proteins involved in excitation-contractioncoupling including L-type Ca2� channels, phospholam-ban, or troponin I (44). These cellular changes are be-lieved to underlie the well-known effects of sympatheticcardiac activation including positive chronotropic,dromotropic, lusitropic, and inotropic effects (545).Transgenic overexpression of the short form of G�s

(G�s-S) in the murine heart had no effect on the basalcardiac function but resulted in an enhanced efficacy of�-adrenoceptor Gs signaling, and chronotropic and ino-tropic responses to catecholamines were increased (299).Once G�s-overexpressing mice become older, they de-velop clinical and pathological signs of cardiomyopathy(300). These pathological processes are accompanied by alack of normal heart rate variability as well as of protec-tive desensitization mechanisms (635, 650). The develop-ment of cardiomyopathy after prolonged overexpressionof G�s is in line with the current concept of the patho-physiological mechanisms underlying the development ofchronic heart failure. The insufficient cardiac output char-

acteristic for heart failure typically goes along with anincreased sympathetic tone resulting in chronic catechol-amine stimulation of cardiomyocytes, which is believed tobe deleterious (71). Although the �1-adrenoceptor is thepredominant subtype expressed in cardiomyocytes, also�2-adrenoceptors are expressed in the heart (545). Inter-estingly, there is increasing evidence that �1- and �2-adrenoceptors play different roles in catecholamine-in-duced cardiomyopathy. Mice overexpressing human �2-adrenoceptors have only slightly altered cardiac functionand appear to have normal life expectancy (259, 260, 443,544) while mice overexpressing �1-adrenoceptors developsevere hypertrophy and die of heart failure (162). The �1-and �2-adrenoceptors also differ with regard to their sig-nal transduction. While �1-adrenergic receptors are Gs

coupled, �2-adrenoceptors are also able to couple to Gi-type G proteins (700, 701) (Fig. 4). The additional activa-tion of Gi via �2-adrenergic receptors may explain theobserved differences in signaling induced via �1- and�2-adrenergic receptors (116, 125, 232, 405, 725, 736). Thisled to the hypothesis that �2-adrenoceptor stimulationexerts some sort of protection against cardiac hypertro-phy and failure, especially under conditions of chronicactivation of the �-adrenergic system and that this is dueto signaling via Gi. The well-documented upregulation ofGi in human heart failure (174, 482) may be a mechanismto counteract deleterious Gs-mediated signaling. The po-tential cardioprotective role of Gi is also supported bystudies in mice. While the overexpression of �2-adrener-gic receptors in normal cardiomyocytes is well tolerated,mice which lack in addition the major Gi �-subunit, G�i2,die within a few days after birth (180). Mice that overex-press �2-adrenoceptors in cardiomyocytes and whichcarry only one intact G�i2 gene allele develop more pro-nounced cardiac hypertrophy and earlier heart failurecompared with �2-adrenoceptor transgenic animals withnormal G�i2 levels.

FIG. 4. Role of heterotrimeric G proteins in mediating autonomic control of heart function by the sympathetic and parasympathetic system.�1/�2, �1- and �2-adrenergic receptor; M2, muscarinic receptor; If, pacemaker channel; GIRK, G protein-regulated inward rectifier potassium channel;VDCC, voltage-dependent calcium channel; PKA, protein kinase A.



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The muscarinic acetylcholine (M2) receptor that iscoupled to Gi/Go G proteins mediates the parasympa-thetic regulation of the heart (Fig. 4). The negative chro-notropic and dromotropic effects of the parasympatheticsystem are believed to result from the Gi-mediated inhi-bition of adenylyl cyclase, resulting in an inhibition of thecAMP production as well as by the activation of G protein-regulated inward rectifier potassium channels (GIRK) by��-subunits released from activated Gi/Go (601). Theatrial GIRK consists of Kir3.1 and Kir3.4 subunits. Micelacking either of the two channel subunits have normalbasal heart rates but show reduced vagal and adenosine-mediated slowing of heart rate and markedly reducedheart rate variability, which is thought to be determinedby the vagal tone (47, 680). The involvement of G��complexes in regulation of GIRK channels has been wellestablished using electrophysiological and biochemicalapproaches (349, 398, 679). Mice in which the amount offunctional G�� protein was reduced by more than 50% incardiomyocytes also show an impaired parasympatheticheart rate control (207). The central role of G�i in inhib-itory regulation of heart rate and atrioventricular conduc-tance has led to attempts to treat cardiac arrhythmias byatrioventricular nodal gene transfer of G�i2 in a model ofpersistent atrial fibrillation in swine (146). While wild-typeG�i2 did not change basal heart rate, a constitutivelyactive mutant of G�i2 resulted in a significant decrease inheart rate. When tested for their effects in a model fortachycardia-induced cardiomyopathy, the condition wassignificantly improved by wild-type G�i2 and even moreby constitutively active G�i2 (37). In addition to the stim-ulatory regulation of potassium channels, muscarinic reg-ulation of heart function also involves inhibition of volt-age-dependent L-type Ca2� channels via an unknownmechanism. In mice lacking the �-subunit of Go, inhibi-tory muscarinic regulation of cardiac L-type Ca2� chan-nels was abrogated, although G�o represents only a minorfraction of all G proteins in the heart (639). Interestingly,mice which lack the �-subunit of Gi2 (G�i2) also show aseverely affected inhibitory regulation of L-type Ca2�

channels via muscarinic M2 receptors (101, 468). Thissuggests that both G proteins, Go and Gi2, are involved inthe regulation of cardiac L-type Ca2� channels.

B. Myocardial Hypertrophy

Myocardial hypertrophy is the chronic adaptive re-sponse of the heart to injury or increased hemodynamicload. It is characterized by increased cardiomyocyte sizeand protein content, as well as altered gene expression,recapitulating an embryonic phenotype (109, 301). Suchpathological myocardial hypertrophy was shown to beassociated with increased cardiac mortality (191, 285,535), raising the question whether prevention of patho-

logical hypertrophy is beneficial or not (191). Severalmechanosensitive mechanisms involving stretch-acti-vated ion channels, integrins or Z-disc proteins were sug-gested to mediate myocardial hypertrophy in response topressure overload (191, 285, 535). In addition, GPCR ago-nists like norepinephrine/phenylephrine, angiotensin II,or endothelin-1 were shown to induce a hypertrophicphenotype in cultured rat embryonic cardiomyocytes (4,341, 560, 581). These ligands are known to activate Gq/G11-coupled receptors, such as the �1-adrenergic recep-tor, the angiotensin AT1 receptor, or the endothelin ETA

receptor (362, 561, 592). Activation of G�q by Pasteurella

multocida toxin (559) or expression of wild-type G�q (5,362) induces the hypertrophic phenotype in cultured car-diomyocytes, while inhibition of Gq/G11 by the RGS do-main of GRK2 inhibited agonist-induced hypertrophy(423). In vivo, cardiac-restricted expression of wild-type(128) or constitutively active G�q (437) results in cardiachypertrophy. In addition, in vivo overexpression of typi-cally Gq/G11-coupled receptors (444, 474) or their down-stream effectors (65, 454, 656) induces hypertrophy. Con-versely, in vivo inhibition of Gq/G11 by overexpression ofRGS4, a GTPase-activating G protein for Gq/G11 and Gi/Go

(547), or by overexpression of the COOH terminus of G�q

(10) results in a reduced hypertrophic response, and car-diomyocyte-specific inactivation of the genes encodingG�q/G�11 completely abrogates the hypertrophic re-sponse elicited by pressure overload (677). Interestingly,an impaired hypertrophic response due to inhibition ofGq/G11-mediated signaling does not negatively influencelong-term cardiac function (166), suggesting that hyper-trophy in response to pressure overload is not necessarilyrequired to maintain cardiac function. In addition to pres-sure overload-induced myocardial hypertrophy, the Gq/G11-mediated signaling pathway was also implicated inthe pathogenesis of diabetic cardiomyopathy. G�q levelsand PKC activity were shown to be enhanced in thestreptozotocin-induced diabetic rat heart (714), and heartspecific overexpression of RGS4 protected mice againstdifferent models of diabetic cardiomyopathy. In contrast,heart-specific expression of a RGS-resistant G�q causedsensitization towards diabetic cardiomyopathy (235). Thedownstream signaling processes in Gq/G11-mediated hy-pertrophy are complex and not fully understood (Fig. 5).Intracellular Ca2� mobilization in response to activationof Gq/G11-coupled receptors promotes Ca2�/calmodulin(CaM)-dependent activation of calcineurin, which in turnmediates dephosphorylation and nuclear translocation oftranscription factors of the NFAT (nuclear factor of acti-vated T cells) family. Although activation of the cal-cineurin/NFAT signaling pathway is clearly sufficient toinduce myocardial hypertrophy, it is not completely clearwhether inhibition of this signaling pathway prevents hy-pertrophy (for review, see Refs. 190, 191). In addition, avariety of other effectors have been implicated in myo-



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cardial hypertrophy, such as protein kinase C (PKC) iso-forms, mitogen-activated protein (MAP) kinases, thephosphatidylinositol (PI) 3-kinase/Akt/GSK-3 pathway orsmall GTPases (for review, see Refs. 148, 191, 285, 535).

GPCRs known to mediate myocardial hypertrophycan also activate G12/G13 family G proteins, resulting inthe activation of RhoA (215, 257). RhoA was suggested tobe involved in the hypertrophic responses to phenyleph-rine, endothelin, chronic hypertension, or overexpressionof G�q (128, 264, 278, 360, 562, 567). Expression of inhib-itory COOH-terminal peptides of G�12 and G�13, as wellas expression of the G12/G13 specific RGS domain ofp115RhoGEF, inhibited phenylephrine-mediated JNK ac-tivation in neonatal cardiomyocytes (423). In addition,overexpression of a constitutively active mutant of G�13

induced a hypertrophic response in neonatal cardiomyo-cytes, with increased expression of the hypertrophy-asso-

ciated embryonic gene program (179). However, no invivo data on the role of G12/G13 in myocardial hypertrophyare available.

C. Smooth Muscle Tone

Smooth muscle tone is controlled by the phosphory-lation state of the regulatory light chain (MLC20) of myo-sin II (for review, see Refs. 269, 593, 594). MLC20 isphosphorylated by the Ca2�/CaM-dependent myosin lightchain kinase (MLCK), leading to enhanced velocity andforce of actomyosin cross-bridging. Dephosphorylation ofMLC20 is mediated by myosin phosphatase, an enzymethat is negatively regulated by the Rho/Rho-kinase path-way. Thus increased contractility can be achievedthrough Ca2�-mediated MLCK activation and throughRho-dependent inhibition of MLC20 dephosphorylation. Avariety of transmitters and hormones regulate smoothmuscle tone through GPCRs (Fig. 6). Typical vasocon-strictor receptors, such as the angiotensin AT1 receptor,the endothelin ETA receptor, or the �1-adrenergic recep-tor, act on Gq/G11-coupled receptors (159, 215, 724) toenhance intracellular Ca2� concentration, leading toMLCK activation. Increased intracellular Ca2� levels arenot only due to IP3-mediated Ca2� release from the sar-coplasmic reticulum, but also to Ca2� influx through cat-ion channels or voltage-gated Ca2� channels (for review,see Refs. 269, 593). In addition, many Gq/G11-coupledreceptors have been shown to activate RhoA, therebycontributing to Ca2�-independent smooth muscle con-traction (593, 594). Smooth muscle specific overexpres-sion of a COOH-terminal G�q peptide, which is believed toinhibit the receptor/G protein interaction, ameliorates hy-pertension induced by long-term treatment with phenyl-ephrine, serotonin, or angiotensin II (331). Mice lackingRGS2, a GTPase activating G protein which acceleratesthe inactivation of Gq/G11, suffer from hypertension (261).Interestingly, it was recently shown that the nitric oxide/cGMP cascade, which constitutes the main relaxant path-way in smooth muscle cells, negatively regulates Gq/G11

signaling by cGMP kinase-mediated phosphorylation andactivation of RGS2 (625). However, in addition to thisperipheral vascular mechanism, an increased sympathetictone might contribute to elevated arterial blood pressurein RGS2-deficient mice (227).

In vitro, most Gq/G11-coupled vasoconstrictor recep-tors also activate G12/G13 family G proteins, like the re-ceptors for endothelin-1, vasopressin, angiotensin II (215,257), thrombin (411), or thromboxane A2 (491, 492). Con-stitutively active forms of G�12 and G�13 induced a pro-nounced, RhoA-dependent contraction in cultured vascu-lar smooth muscle cells, and receptor-mediated contrac-tions were strongly inhibited by dominant negative formsof G�12 and G�13 (215). These data suggest that also the

FIG. 5. Gq/G11 family G proteins are centrally involved in myocar-dial hypertrophy. G protein-coupled receptors like the �1-adrenergicreceptor (�1), the angiotensin AT1 receptor, or the endothelin ETA

receptor act through Gq/G11 to induce hypertrophy via activation ofdownstream effectors including the calcineurin/NFAT pathway, PKCisoforms, MAP kinases, the PI-3-kinase/Akt/GSK-3 pathway or smallGTPases. CaM, calmodulin; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; MAPK, mitogen-activated protein kinases; NFAT, nuclearfactor of activated T cells; PI-3-K, phosphoinositide-3-kinase; PIP2, phos-phatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC-�, phos-pholipase C-�.



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G12/G13-mediated signaling pathway is involved in theregulation of smooth muscle tone, most likely by modu-lating the activity of myosin phosphatase via Rho/Rho-kinase. In accordance with this, inhibition of Rho-kinasewas shown to normalize blood pressure in humans andexperimental animals (426, 636). The relative contributionof Gq/11/Ca2�-mediated and G12/13/Rho/Rho-kinase-medi-ated signaling to regulation of vascular smooth muscletone is not clear. However, data obtained in visceralsmooth muscle suggested that Gq/G11 conveys a fast, tran-sient response, while G12/G13 mediates a sustained, toniccontraction (257).

Vascular smooth muscle relaxation is mediated by avariety of mechanisms, one of them being the activationof Gs-coupled receptors like the adenosine A2 receptors,�2-adrenergic receptors, or prostaglandin receptor sub-types IP, DP, and EP2. How the subsequent increase incAMP levels reduces smooth muscle tone is not under-stood. In vitro data suggest that the relaxant effect ispartially due to a PKA-mediated MLCK phosphorylation,which decreases the enzyme’s affinity for the Ca2�/CaMcomplex, but the physiological relevance of this signalingpathway is unclear. Possible other substrates for PKA areheat shock protein 20, RhoA, or myosin phosphatase (forreview, see Ref. 269). cAMP has also been suggested tocross-activate cGMP kinase I in vascular or airwaysmooth muscle (32, 390), but this hypothesis has been

questioned by the finding that vessels from cGKI-deficientmice relax normally in response to cAMP (518). In addi-tion, cAMP-independent mechanisms of Gs-mediated re-laxation involving large-conductance, Ca2�-activated K�

(MaxiK, BK) channels have been proposed (624).The role of Gi-mediated signaling in vascular smooth

muscle tone seems to differ between different vesseltypes. An inhibitory effect of PTX on norepinephrine-induced contractility was reported in rat tail artery (516,600) but was absent in aorta (517). High blood pressure inspontaneously hypertensive rats is preceded by increasedexpression of Gi proteins (18, 19), and PTX treatmentdelayed the onset of hypertension (387), suggesting thatdecreased cAMP levels play a role in the pathogenesis ofthis model of hypertension. Enhanced signaling via aPTX-sensitive G protein was reported in immortalized Blymphoblasts from patients with essential hypertension(520), and this was attributed to a C825T polymorphism inthe gene coding for G�3, a constituent of the Gi hetero-trimer (586). The C825T polymorphism was suggested tobe associated with an increased risk of hypertension,obesity, and arteriosclerosis in some (for review, see Ref.585) but not in all studies (283, 616, 617). However, thesignificance of genetic association studies in general re-mains controversial (20, 199, 291).

Very similar to vascular smooth muscle, also airwaysmooth muscle tone is mainly regulated by Gq/G11 family

FIG. 6. Heterotrimeric G proteins involvedin the regulation of smooth muscle tone. Gq/G11-coupled receptors increase the intracellu-lar Ca2� concentration, leading to Ca2�/cal-modulin (CaM)-dependent MLCK activationand MLC20 phosphorylation. Especially G12/G13-coupled receptors mediate RhoA activa-tion, thereby contributing to Ca2�-independentsmooth muscle contraction. Relaxation is in-duced by activation of Gs-coupled receptors,but the mechanisms underlying cAMP-medi-ated relaxation are not clear. Gi-mediated sig-naling might contribute to contraction by inhib-iting Gs-mediated relaxation. cGKI, cGMP-de-pendent protein kinase I; DAG, diacylglycerol;IP3, inositol 1,4,5-trisphosphate; MLC20, regula-tory chain of myosin II; MLCK, myosin light-chain kinase; MPP, myosin phosphatase; PIP2,phosphatidylinositol 4,5-bisphosphate; PKA,cAMP-dependent kinase; PLC-�, phospholipaseC-�; RhoGEF, Rho specific guanine nucleotideexchange factor; ROCK, Rho kinase; TRP, tran-sient receptor potential channel.



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G proteins, which mediate bronchoconstriction, and Gs

family G proteins, which mediate bronchorelaxation. Ace-tylcholine released from postganglionic parasympatheticnerves controls resting tone mainly via the Gq/G11-cou-pled M3 receptor subtype (90), but also other Gq/G11-coupled receptors are expressed in airway smooth mus-cles, like the H1 histamine receptor (133, 222), the leuko-triene CysLT1 receptor (314), the B2 bradykinin receptor(421, 630), the ETB endothelin receptor (216, 241, 441),and others. Airway hyperreactivity in the A/J mouse strainwas suggested to be due to enhanced agonist affinity andincreased G protein coupling efficiency of the M3 musca-rinic receptor (205), and Gq protein was shown to beupregulated in antigen-induced airway hyperresponsiverats (106). Mice lacking the �-subunit of Gq showed im-paired metacholine-induced airway responses and lackedthe typical increase in metacholine sensitivity after aller-gen sensitization and reexposition (55). Not much isknown about the role of G�12 and G�13 in airway smoothmuscle tone regulation. The fact that repetitive antigenchallenge significantly increases the expression of theseproteins in airway smooth muscle suggests a role in aller-gic asthma (105, 108), but direct evidence for an involve-ment of G12/G13 is still lacking. Gs-coupled receptors playan important role in the relaxation of contracted airwaysmooth muscle, most prominently the �2-adrenergic re-ceptor, but also the prostaglandin E2 receptor EP2 (512)or the prostacyclin IP receptor (41) (for review, see Ref.628). The Gi family of G proteins contributes to the reg-ulation of airway smooth muscle contractility mainly byinhibiting the relaxant effects of Gs. The inhibitory effectof PTX on acetylcholine-induced bronchoconstriction isnegligible in normal rats, but significant in rats sufferingfrom antigen-induced airway hyperresponsiveness (107).In these mice, G�i3 protein is upregulated in bronchialsmooth muscle cells, suggesting that the relative contri-

bution of Gi-mediated constriction is increased in antigen-challenged airway smooth muscle (107).

D. Platelet Activation

Platelets are small cell fragments that circulate in theblood and adhere at places of vascular injury to the vesselwall where they become activated resulting in the forma-tion of a platelet plug that is responsible for primaryhemostasis. Platelets can also become activated underpathological conditions, e.g., on ruptured atheroscleroticplaques leading to arterial thrombosis. Platelet adhesionand activation is initiated by their interaction with adhe-sive macromolecules like collagen and von Willebrandfactor (vWF) at the subendothelial surface (303, 554).While collagen is able to induce firm adhesion of plateletsto the subendothelium (666), the recruitment of addi-tional platelets to the growing platelet plaque requires thelocal accumulation of diffusible mediators that are pro-duced or released once platelet adhesion has been initi-ated, and some level of activation through platelet adhe-sion receptors has occurred (3). These mediators includeADP/ATP and thromboxane A2 (TxA2), which are se-creted or released from activated platelets as well asthrombin, which is produced on the surface of activatedplatelets. These platelet stimuli have in common theiraction through G protein-coupled receptors. While ADPinduces the activation of Gq and Gi via P2Y1 and P2Y12

receptors (197, 354), the activated TxA2 receptor (TP)couples to Gq and G12/G13 (337, 492) (Fig. 7). G protein-coupled protease-activated receptors (PARs) that are ac-tivated by thrombin are functionally coupled to Gq, G12/G13, and in some cases to Gi (121). In response to thesesecondary mediators of platelet activation, platelets im-mediately undergo a shape change reaction during whichthey become spherical and extrude pseudopodia-like

FIG. 7. Role of heterotrimeric G pro-teins in mediating platelet activation bysoluble mediators like ADP, thrombox-ane A2 (TxA2), thrombin, and epineph-rine. Major roles are played by the G pro-teins Gq, G13, and Gi which couple recep-tors to the indicated effector molecules.The subsequent signaling processes even-tually lead to platelet responses likeshape change, degranulation, and aggre-gation (for details, see text). TP, TxA2

receptor; PAR, protease-activated recep-tor; P2Y1/P2Y12, purinergic receptors;�2A, �2A-adrenergic receptor; RhoGEF,Rho guanine nucleotide exchange factor;PLC-�2/3, phospholipase C-�2/3; PI-3-K,phosphoinositide-3-kinase; PIP2, phos-phatidylinositol 4,5-bisphosphate; IP3,inositol 1,4,5-trisphosphate; DAG, diacyl-glycerol; PKC, protein kinase C; PIP3,phosphatidylinositol 3,4,5-trisphosphate.



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structures. In addition, the glycoprotein IIb/IIIa (integrin�IIb�3) undergoes a conformational change resulting inbinding of fibrinogen/vWF and subsequent platelet aggre-gation. Finally, the formation and release of TxA2, throm-bin, and ADP is further stimulated. Thus secondary me-diators increase through G protein-coupled receptorstheir own formation resulting in an amplification of theireffects, and eventually all G protein-mediated signalingpathways induced via these receptors become activated.The multiple positive feedback mechanisms operatingduring platelet activation have obscured the exact analy-sis of the roles individual G protein-mediated signalingpathways play during the platelet activation process.Progress has recently been made using genetic mousemodels in understanding the role of individual G protein-mediated signaling pathways during platelet activation.

The requirement of Gq-mediated signaling for ago-nist-induced platelet activation has been demonstrated bythe phenotype of G�q-deficient platelets, which fail toaggregate and to secrete in response to thrombin, ADP,and TxA2 due to a lack of agonist-induced phospholipaseC activation. This dramatic phenotype found in G�q-defi-cient platelets is due to the fact that platelets lack G�11

(313), which is in most other cells coexpressed with G�q

and can compensate G�q deficiency. Mice lacking G�q

have increased bleeding times and are protected againstcollagen/epinephrine-induced thromboembolism (494).Although Gq-mediated signaling appears to be absolutelyrequired for platelet activation, there is clear evidencethat also Gi type G proteins need to be activated to inducefull activation of integrin �IIb�3. In mice lacking the�-subunit of Gi2, the response of ADP that acts throughthe Gi-coupled P2Y12 receptor is reduced (304). However,also the effects of mediators like thrombin and TxA2,which primarily signal through Gq and G12/G13 were foundto be inhibited in platelets lacking G�i2 (304, 712). Thissupports the view that platelet activation by thrombin andthromboxane A2 requires in part the action of secondarymediators like ADP, which are released after activation ofGq-mediated signaling pathways through TxA2 and throm-bin receptors. An important role of the Gi-mediated sig-naling pathway in platelet activation is also suggested bystudies in platelets lacking the Gq-coupled P2Y1 receptoror after pharmacological blockade of P2Y1 (170, 251, 310,379, 568). These platelets do not aggregate in response tolow and intermediate concentrations of ADP unless Gq-mediated signaling is induced via activation of anotherreceptor. Similarly, platelets lacking P2Y12 or in whichP2Y12 was pharmacologically blocked did not aggregate inresponse to ADP unless the Gi-mediated pathway wasactivated via a different receptor (181, 568). Thus there isclear evidence that Gq and Gi synergize to induce plateletactivation. It is currently not clear how Gi contributes tointegrin �IIb�3 activation in platelets, but a decrease incAMP levels is unlikely to be involved (129, 529, 569, 712).

Another member of the Gi family of heterotrimeric Gproteins, Gz, has been implicated in platelet activationinduced by epinephrine acting on �2-adrenergic recep-tors. In contrast to ADP, TxA2, and thrombin, epinephrineis alone not able to fully activate mouse platelets. How-ever, it is able to potentiate the effect of other plateletstimuli. In G�z-deficient platelets, the inhibitory effect ofepinephrine on adenylyl cyclase and epinephrine-potenti-ating effects were strongly impaired while the effects ofother platelet activators appear to be unaffected (713).

Despite the central role of Gq in platelet activation, itwas recently demonstrated that induction of Gi- and G12/G13-mediated signaling pathways is sufficient to induceintegrin �IIb�3 activation (149, 483). Interestingly, inG�13-deficient platelets, but not in G�12-deficient plate-lets, the potency of various stimuli including TxA2, throm-bin, and collagen to induce platelet shape change andaggregation is markedly reduced (455). These defects areaccompanied by a defect in the activation of RhoA and adelayed phosphorylation of the myosin light chain as wellas by an inability to form stable platelet thrombi underhigh sheer stress conditions (455). In addition, mice car-rying platelets that lack G�13 have an increased bleedingtime and are protected against the formation of arterialthrombi induced in a carotid artery thrombosis model(455). These data indicate that in addition to Gq and Gi

also G13 is crucially involved in the signaling processesmediating platelet activation via G protein-coupled recep-tors both in hemostasis and thrombosis. These findingsalso indicated that G13-mediated signaling is not onlyinvolved in the response of platelets to relatively lowstimulus concentrations that induce platelet shapechange but is also required for normal responsiveness ofplatelets at higher stimulus concentrations. A reducedpotency of platelet activators in the absence of G13-medi-ated signaling becomes in particular limiting under highflow conditions that lead to a rapid clearance of solublestimuli from the site of platelet activation and formationof mediators. In addition, the defective activation ofRhoA-mediated signaling in the absence of G13 appears tocontribute to the observed defect in the stabilization ofplatelet aggregates under high sheer stress ex vivo as wellas in vivo. In fact, RhoA-mediated signaling has beensuggested to be required for platelet aggregation underhigh sheer conditions as well as for the irreversible ag-gregation of platelets in suspension (450, 570).

These studies have clearly shown that three G pro-teins are major mediators of platelet activation via Gprotein-coupled receptors: Gq, Gi2, and G13. However,even in the absence of either Gq, Gi2, or G13 some plateletactivation can still be induced, while in the absence ofboth G�q and G�13, platelets are unresponsive to throm-bin, TxA2, or ADP. This indicates that the activation ofGi-mediated signaling alone is not sufficient to induce anyplatelet activation (456). The optimal activation of plate-



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lets under physiological and pathological conditions ob-viously requires the parallel signaling through several het-erotrimeric G proteins.

III. ENDOCRINE SYSTEM AND METABOLISM

The endocrine system consists of a variety of glandsand other structures that produce, store, and secrete hor-mones directly into the systemic circulation, thereby con-trolling electrolyte and water homeostasis, metabolism,growth, reproduction, etc. GPCRs contribute to endocrinefunctions in a twofold way: 1) by mediating hormonal endorgan effects and 2) by controlling hormone secretionitself. Hormone secretion, as well as secretion from neu-ronal or exocrine cells, typically involves elevation ofcytosolic Ca2� and/or cAMP (for review, see Refs. 160,738). In most secretory cells, Ca2� influx through voltage-operated Ca2� channels is the dominant mode of regula-tion, like in adrenal chromaffin cells (160), while in othercells, such as anterior pituitary gonadotropes, Ca2� mo-bilization from internal stores is the critical step (633). Inyet another endocrine cell, such as lactotroph cells, bothincreased intracellular Ca2� levels and cAMP productioncontribute to secretion (130, 186, 620). Accordingly, withrare exceptions, activation of Gs and/or Gq/G11 family Gproteins enhances secretion regardless of the endocrinecell type involved.

A. Hypothalamo-Pituitary System

Hormone release from the anterior pituitary is tightlycontrolled by hypothalamic releasing hormones and re-lease inhibiting factors, all of which act through GPCRs.The receptors for corticotropin-releasing hormone (263)and growth hormone-releasing hormone (GHRH) (588)primarily act through Gs, while receptors for gonado-tropin-releasing hormone (445), thyrotropin-releasinghormone (211, 720), and the many prolactin-releasing fac-tors (186) mainly act through Gq/G11 family G proteins,and only partly through Gs. In addition to their secreta-gogue effects, hypothalamic releasing hormones regulatehormone synthesis and cell proliferation (81, 430, 531,583, 587, 647). Anterior pituitary secretion and prolifera-tion is not only stimulated by the classical hypothalamicreleasing hormones, but also by a variety of other factors,such as the gastrointestinal peptide hormone ghrelin,which enhances growth hormone (GH) secretion viathe predominantly Gq/G11-coupled growth hormonesecretagogue receptor GHS-R (343, 588), or members ofthe pituitary adenylate cyclase-activating polypeptide(PACAP)/glucagon superfamily, which exert secreta-gogue effects on a variety of pituitary cell types via theirGs-coupled receptors (579). The in vivo relevance of Gs

family G proteins in anterior pituitary function was stud-

ied in mice and in patients with inactivating or activatingGs mutants. Somatotroph-specific overexpression of chol-era toxin, which irreversibly activates Gs by ADP ribosy-lation, caused somatotroph hyperplasia, increased GHlevels and gigantism in mice (82). In humans, activatingmutations of GNAS can be found in �40% of GH produc-ing pituitary tumors (363, 406), as well as in 10% ofnonfunctioning pituitary adenomas (406, 632, 685). Theseactivating mutations of GNAS encode substitutions ofeither Arg-201 or Gln-227, two residues that are critical forthe GTPase reaction (187, 223, 363, 406). In GH-secretingtumors, the mutation is almost always in the maternalallele, presumably because G�s is mainly expressed fromthe maternal allele (“paternally imprinted”) in pituitarycells (242). Activating GNAS mutations were also, thoughrarely, found in corticotroph (541, 686), but not in thyro-troph tumors (147, 406). Such activating somatic GNAS

mutations are not necessarily restricted to the pituitary,but are often part of the McCune-Albright syndrome,which is defined by the trias fibrous dysplasia of bone,cafe-au-lait skin pigmentation, and endocrine hyperfunc-tions of variable degree (for review, see Refs. 599, 669).Endocrine hyperfunction is due to constitutive activationof Gs signaling in other endocrine glands, leading to ad-renal hyperplasia with Cushing syndrome (60, 182), pre-cocious puberty (138, 574), or hyperthyroidism (see sect.IIIC). In melanocytes, increased Gs activity mimics theactivity of melanocyte stimulating hormone, leading totypical cafe-au-lait hyperpigmentation (334).

Heterozygous inactivating GNAS mutations result inAlbright hereditary osteodystrophy (AHO), a congenitaldisorder characterized by obesity, short stature, brachy-dactyly, subcutaneous ossifications, and neurobehavioraldeficits of variable severity (for review, see Refs. 13, 366,599, 669). In addition to these defects, patients with ma-ternally inherited mutations show multihormone resis-tance (termed pseudohypoparathyroidism type Ia,PHP1a) in tissues with a paternally imprinted GNAS al-lele, such as proximal tubules of the kidney, thyroid, orovaries (209, 242, 414, 723). In these tissues, the effects ofGs-coupled hormone receptors, like those for parathyroidhormone, thyroid stimulating hormones, or the gonado-tropins, are impaired. Clinically, this results in variabledegrees of hypocalcemia and hyperphosphatemia, hypo-thyroidism (see also sect. IIIC), and delayed or incompletesexual development and reproductive dysfunction inwomen (13, 366, 599, 669). These abnormalities of thereproductive system are easily explained by malfunctionof receptors for follicle-stimulating hormone and luteiniz-ing hormone. In addition, at least in mice, the Gs-coupledorphan receptor GPR3 is crucially involved in the main-tenance of meiotic arrest in oocytes (432, 433).

The phenotype of humans heterozygous for an in-activating GNAS mutation is partly reproduced in micecarrying a targeted disruption of Gnas exon 2. In these



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animals, PTH resistance was only found if the mutationwas maternally inherited, and only these animalsshowed reduced G�s expression in the renal cortex(723). In humans, renal PTH resistance without Al-bright hereditary osteodystrophy (PHPIb) can also bedue to other GNAS mutations, such as a mutant whichresults in a biallelic paternal imprinting phenotype(395), or a mutant unable to interact with the PTHreceptor (697). Yet another GNAS mutation causes im-paired signaling via the PTH and TSH receptors, butenhanced signaling via the likewise Gs-coupled recep-tor for luteinizing hormone, leading to enhanced tes-tosterone production. This paradoxical combination ofgain and loss of function is explained by the fact thatthe underlying GNAS mutation results in a constitu-tively active form of G�s which, however, is tempera-ture sensitive. The mutant is stable only at the rela-tively low temperature in the testis, but rapidly de-graded at 37°C, leading to G�s deficiency (287). Withrespect to pituitary function, patients with inactivatingGNAS mutations show variable degrees of GHRH resis-tance (415), GH deficiency (210), or hypoprolactinemia(88). In accordance with the important role of Gs familyG proteins in lactotrophs and somatotrophs, hypotha-lamic inhibiting hormones, like dopamine or somatosta-tin, act through Gi-coupled receptors (311, 536).

Releasing hormone secretion itself is influenced byGPCRs, and several former orphan receptors were re-cently shown to positively regulate releasing hormonesecretion. Kisspeptins for example, a family of peptidesderived from the metastasis suppressor gene Kiss-1, wereshown to enhance hypothalamic gonadotropin-releasinghormone secretion via the GPR54 receptor (137, 220, 472),and genetic inactivation of GPR54 in mice or mutation inhumans causes hypogonadotropic hypogonadism (137,196, 220, 575). The peptide hormone ghrelin induces pitu-itary growth hormone release not only directly via activa-tion of GHS-R on somatotroph cells, but also acts as areleasing factor for hypothalamic GHRH (343). BothGPR54 and GHS-R are known to activate Gq/G11 family Gproteins (343, 345), suggesting that releasing hormonerelease is controlled by the same mechanisms as pituitaryhormone release. In line with this notion, mice lackingboth G�q alleles and one G�11 allele selectively in thenervous system show severe somatotroph hypoplasiawith dwarfism due to reduced hypothalamic GHRH pro-duction, which is probably secondary to impaired GHS-Rsignaling (676).

B. Pancreatic �-Cells

The tight regulation of blood glucose levels is mainlyachieved by the on-demand release of insulin from pan-creatic �-cells. High glucose levels result in enhanced

intracellular glucose metabolism with ATP accumulationand consecutive closure of ATP-sensitive K� channels,leading to the opening of voltage-operated Ca2� channelsand Ca2�-mediated insulin exocytosis (27, 119). In addi-tion to the ATP-dependent mechanism of insulin release,several GPCRs have been shown to either amplify or toinhibit glucose-induced insulin release (for review, seeRefs. 161, 364, 558), and these receptors and their respec-tive ligands play an important role in the regulation ofislet function by, e.g., the autonomous system (for review,see Ref. 7). Neuropeptides and hormones that potentiateinsulin secretion mainly act though Gs-coupled receptors,like glucose-dependent insulinotropic polypeptide, secre-tin, cholecystokinin, PACAP, glucagon, vasoactive intes-tinal polypeptide, or glucagon-like peptide-1 (GLP-1) (forreview, see Refs. 161, 418, 542). The potentiating effect ofGs on glucose-induced insulin release (576, 608, 609)might either be mediated by phosphorylation of voltage-operated Ca2� channels (295) or through the opening ofnonselective cation channels (275). Transgenic expres-sion of a constitutively active G�s mutant in mouse �-cellscaused increased islet cAMP production and insulin se-cretion, but these changes were only detectable in thepresence of phosphodiesterase inhibitors, suggesting thatincreased G�s activity is normally compensated by up-regulation of cAMP degrading enzymes like phosphodies-terases (408). Conversely, activation of receptors coupledto Gi or Go, like the �2-adrenergic receptor or receptorsfor somatostatin, neuropeptide Y, prostaglandin E2, orgalanin, inhibits insulin secretion in a PTX-sensitive man-ner (319, 328, 365, 514, 542).

Not only Gs family members, but also Gq/G11 family Gproteins, can mediate potentiation of glucose-induced in-sulin release. Acetylcholine released from postganglionicparasympathetic nerves or muscarinic agonists actthrough the Gq/G11-coupled M3 receptor (58, 157) to en-hance insulin release during the cephalic phase of insulinsecretion (8, 447, 691). This effect was shown to dependon PLC activation and consecutive inositol 1,4,5-trisphos-phate (IP3)-mediated intracellular Ca2� elevation (46, 469,726) and PKC activation (22). The exact pathways leadingto increased insulin secretion are not clear, but activationof L-type Ca2� channels (58), modulation of ATP-sensitiveK� channels (469), activation of CaM-kinase II (427, 537),or enhanced plasma membrane Na� permeability (254)have been suggested. In addition to acetylcholine, a vari-ety of other local mediators act through Gq/G11-coupledreceptors to enhance insulin release, like cholecystokininvia the CCK1 receptor (652), bombesin via the BB2 recep-tor (521, 646), arginine vasopressin via the V1b receptor(375, 501, 539), or endothelin via the ETA receptor (224).Fatty acids such as palmitate potentiate insulin secretionat high glucose levels independently of ATP formation(527, 663), and Ca2� influx via voltage-operated Ca2�

channels or intracellular Ca2� mobilization was suggested



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to mediate these effects. The former orphan GPCR GPR40was shown to mediate the effects of saturated and unsat-urated fatty acids (C�6) on intracellular Ca2� mobiliza-tion in pancreatic �-cells (70, 296, 346). These effectswere not PTX sensitive, suggesting that Gq/G11-mediatedintracellular Ca2� mobilization was involved (70, 296).Another recently deorphanized GPCR probably coupledto Gq/G11 is GPR120, which was suggested to be involvedin fatty acid-induced release of GLP-1 from intestinalcells, thereby contributing to GLP-1-mediated insulin re-lease (265).

C. Thyroid Gland/Parathyroid Gland

Thyroid stimulating hormone (TSH) regulates thy-roid cell proliferation as well as thyroid hormone synthe-sis and release through the G protein-coupled TSH recep-tor (508). In vitro, the TSH receptor was shown to coupleto all four G protein families (15, 16, 368), but the majorsignal transduction pathway in vivo seems to be the Gs/cAMP cascade, which was shown to activate iodide or-ganification, thyroid hormone production, secretion, andthyroid cell mitogenesis (153–155, 546). In TSH receptor-deficient mice, direct stimulation of adenylyl cyclase re-stores the ability to concentrate and organify iodide, sug-gesting that expression of the sodium-iodide symporter iscontrolled by G�s (417). In vitro, overexpression of con-stitutive active G�s in a thyroid cell line (462) or activa-tion of Gs by transgenic expression of cholera toxin in themouse thyroid (727) caused hyperplasia and increasedhormone secretion. In line with this, spontaneous activat-ing mutations of GNAS can cause thyroid cell hyperfunc-tion in humans, leading to hyperthyroidism, goiter, andbenign adenoma (175, 406, 424, 502). Malignant transfor-mation of thyroid cells has also been observed (165, 611,711), but seems to require additional mutational or epige-netic events (115). Much more frequent than activatingGNAS mutations are the activating mutations of the TSHreceptor itself (508), which mainly lead to constitutiveactivation of the Gs/cAMP cascade, or, in some cases, toactivation of both Gs- and Gq/G11-coupled pathways (48,643). Since the paternal GNAS allele is partly imprinted inthyroid cells (209, 394), inactivating GNAS mutants inher-ited from the maternal side cause TSH resistance withmoderately elevated TSH levels and low thyroid hormonelevels (171, 381, 382, 670, 719). Mild TSH resistance canalso be observed in patients with PHP1B due to a GNAS

mutation with paternal specific epigenotype of both exon1A regions (34, 394, 395). In addition to adenylyl cyclaseactivation, TSH stimulates PLC activity (344, 369, 644),but the TSH concentrations needed for PLC stimulationare 100-fold higher than those needed for adenylyl cyclasestimulation (643).

The parathyroid gland controls Ca2� homeostasisthrough parathyroid hormone (PTH), which enhances

Ca2� (re)absorption in gut and kidney, as well as Ca2�

release from bone. High extracellular Ca2� concentra-tions activate the G protein-coupled extracellular Ca2�

sensing receptor (CaR), leading to inhibition of PTH pro-duction and secretion in parathyroid cells (for review, seeRefs. 74, 268, 661). Activation of the CaR causes a PTX-insensitive (240) stimulation of PLC-� isoforms, with con-secutive increments in inositol phosphates, DAG, andintracellular Ca2� levels (73, 75, 478). In addition, anactivation of phospholipases A2 and D (333) as well as aPTX-sensitive suppression of cAMP formation was ob-served (98). These studies suggested that the CaR couplesboth to Gq/G11 and Gi/Go family G proteins, and thisnotion was supported by the finding that CaR activationinduced incorporation of radiolabeled GTP into G�q andG�i in Madin-Darby kidney (MDCK) cells, which endog-enously express low levels of the CaR (25). The fact thatincreased intracellular Ca2� levels result in decreased,not increased, hormone release is quite exceptional, andparathyroid cells are, besides renin-secreting juxtaglo-merular cells (572), the only endocrine cells showing suchinverse coupling. However, the molecular mechanism un-derlying Ca2�-mediated inhibition of PTH secretion is notunderstood (for review, see Refs. 74, 86, 268, 661).

D. Regulation of Carbohydrate and

Lipid Metabolism

Normal blood glucose levels are maintained both byregulating the activity of enzymes involved in carbohy-drate metabolism and by controlling glucose uptake intoperipheral tissues. Insulin is a major regulator of bothprocesses, but also a variety of GPCR agonists, like cat-echolamines and glucagon, contribute to glucose ho-meostasis. In hepatocytes, activation of Gs-coupled recep-tors like the �2-adrenergic receptor or glucagon receptorscauses PKA-mediated phosphorylation of key enzymeswhich regulate glycogen synthesis, glycogen breakdown,glycolysis, or gluconeogenesis (167, 168). Together, thesechanges lead to enhanced hepatic glucose release. Com-parable changes can be induced by activation of Gq/G11-coupled receptors like the �1-adrenergic receptor or re-ceptors for vasopressin and angiotensin, and these effectsare probably mediated by Ca2�/calmodulin-dependent al-teration of enzymatic activity (167, 168). In the periphery,glucose uptake into skeletal muscle and adipocytes ismediated by translocation of glucose transporter subtype4 (GLUT4) from intracellular vesicles to the plasma mem-brane (665). A variety of GPCRs have been demonstratedto modify insulin-induced GLUT4 translocation, and evena direct interaction between the insulin receptor and het-erotrimeric G proteins was suggested (412). HeterozygousGNAS-deficient mice show, in addition to other metabolicabnormalities (for effects on lipolysis, see below), an



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increased sensitivity towards insulin, which was attrib-uted to enhanced insulin-dependent glucose uptake intothe skeletal muscle (104, 721). In line with this, transgenicexpression of a constitutively active mutant of G�s

(G�sQ227L) in fat, liver, and skeletal muscle decreasedglucose tolerance (284), suggesting that G�s-mediated sig-naling negatively regulates insulin-induced GLUT4 trans-location. In contrast, Gi family G proteins seem to facili-tate insulin effects. Pretreatment of isolated adipocytesand soleus muscle with PTX results in reduced insulin-stimulated glucose uptake (111, 325), and mice in whichG�i2 was downregulated in liver and adipose tissue usingan antisense RNA approach show insulin resistance withhyperinsulinemia, decreased glucose tolerance, and insu-lin resistance (459–461). In the latter mice, both insulin-induced GLUT4 translocation to the plasma membraneand activation of glycogen synthase and antilipolytic me-diators were impaired (461). The decrease in G�i2 levelswas accompanied by an increase in protein tyrosine phos-phatase-1B (PTP-1B) activity, an enzyme known to de-phosphorylate phosphorylated tyrosine residues on theinsulin receptor and on insulin receptor substrate-1. Thissuggests that the inhibition of insulin signaling in micewith reduced G�i2 levels is due to disinhibition of PTP-1B(461). Mice expressing a constitutively active mutant ofG�i2 (G�i2Q205L) in fat, liver, and skeletal muscle dis-played reduced fasting blood glucose levels and increasedglucose tolerance (103). Adipocytes from these miceshowed enhanced insulin-induced glucose uptake andGLUT4 translocation, as well as increased PI 3-kinase andAkt activities (596). In addition, PTP-1B is suppressed inG�i2 overexpressing mice (626), and streptozotocin-in-duced diabetic changes are ameliorated (732). Up to nowit is not clear at which levels the insulin receptor-medi-ated pathway interacts with the Gi-mediated pathway. Itwas suggested that Gi/Go family G proteins physicallyinteract and are phosphorylated by the activated insulinreceptor (for review, see Ref. 510). In addition, Gi/Go

might be involved in insulin-mediated autophosphoryla-tion of the insulin receptor (351).

Data from 3T3 L1 adipocytes strongly point to aninvolvement of Gq/G11 family G proteins in basal andinsulin-induced GLUT4 translocation. Overexpression ofwild-type or constitutively active G�q increased basalGLUT4 translocation (290, 326), while microinjection ofG�q/G�11 antibodies or RGS2 protein inhibited insulin-induced GLUT4 translocation (290, 326). In line with thesefindings, inhibition of GRK2, a negative regulator of Gq/G11 signaling, increased insulin-stimulated GLUT4 trans-location, while adenovirus-mediated overexpression ofGRK2 reduced translocation as well as 2-deoxyglucoseuptake (637). The exact mechanisms underlying Gq/G11-mediated GLUT4 translocation are not fully understood.Several Gq/G11-coupled receptors are able to stimulateglucose uptake via GLUT4 translocation, such as recep-

tors for endothelin-1 (ET-1), norepinephrine, platelet-ac-tivating factor, or bradykinin (335, 336, 698). Microinjec-tion of an anti-G�q/G�11 antibody or of RGS2 proteincauses inhibition of ET-1-induced GLUT4 translocation(289). Of note, chronic ET-1 treatment inhibits insulin-stimulated glucose uptake and GLUT4 translocation in3T3-L1 adipocytes, and decreased tyrosine phosphoryla-tion of insulin receptor substrates was suggested to me-diate this heterologous desensitization (292). The Gq/G11-mediated effect on GLUT4 translocation was shown to bePI 3-kinase dependent in some (289, 290) but not in allstudies (59, 326). Recently, a role for the ADP ribosylationfactor 6 and the Ca2�-activated tyrosine kinase Pyk2 wassuggested (59, 371, 506).

Other examples for G protein-regulated metabolicprocesses are adipocyte lipolysis and lipogenesis. Activa-tion of Gs-coupled receptors like those for cat-echolamines, ACTH, glucagons, TSH, or PTH enhanceslipolysis via PKA-dependent phosphorylation of hormone-sensitive lipase (274, 401, 606). In adipocytes from pa-tients heterozygous for an inactivating GNAS mutation,the lipolytic effect in response to epinephrine is impaired,and this was suggested to contribute to obesity observedin AHO patients (87). Heterozygous disruption of Gnas

exon 2 in mice causes not only enhanced insulin sensitiv-ity (721), but also a variety of other metabolic defects thatdepend on the parental origin of the inherited mutation(722). While mice with a maternally inherited inactivatingmutation of the Gnas gene are obese and hypometabolic,paternally inherited Gnas mutations cause abnormal lean-ness with decreased serum, liver, and muscle triglycer-ides, and lipid oxidation in adipocytes is enhanced (104,722). Since these mice have increased urine norepineph-rine excretion, it was suggested that increased sympa-thetic stimulation of adipocytes caused the changes inlipid metabolism (104, 722). The reason for the restrictionto paternally inherited mutations is not completely clear.Deletion of Gnas exon 2 does not only affect the expres-sion of G�s, but also of alternative gene products likeXL�s (Fig. 3) (245, 667). An involvement of XL�s in thehypermetabolic phenotype seems likely for three reasons.First, XL�s is only expressed from the paternal allele(104) and is therefore well suited to explain a paternallyinherited phenotype. Second, XL�s-deficient mice show aphenotype similar to paternally exon 2-deficient mice(522). Third, mice with paternal inheritance of a Gnas

exon 1 deletion, which does not affect XL�s expression,do not show the respective phenotype (668). Interest-ingly, studies in XL�s-deficient mice suggest that G�s andXL�s can exert opposing effects on whole body metabo-lism (522, 668). In addition to Gs family G proteins, alsothe Gq/G11 family was implicated in the regulation oflipolysis. Expression of antisense RNA to G�q in liver andwhite fat caused hyperadiposity, which was suggested to



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be attributed to an impaired lipolytic response towards�1-adrenergic agonists (198).

Inhibition of adipocyte lipolysis is mediated by theinsulin receptor or by activation of Gi-coupled receptorslike the �2-adrenergic receptor, receptors for adenosineor prostaglandin (401) or the recently deorphanized re-ceptor for nicotinic acid, GPR109A (HM74a/PUMA-G)(634). G�i was suggested to be directly involved in theantilipolytic effect of insulin, since insulin-dependent in-hibition of lipolysis and activation of glucose oxidation inadipocytes were shown to be PTX sensitive (219).

IV. IMMUNE SYSTEM

A. Leukocyte Migration/Homing

Directed cell movement in response to an increasedconcentration of chemoattractant underlies the correcttargeting of leukocytes to lymphatic organs during anti-gen surveillance and also allows them to migrate to sitesof infection and/or inflammation (for review, see Refs.653, 694). Known lymphocyte chemoattractants either be-long to the large family of chemokines (355, 500) or to thelysophospholipid family, like sphingosine-1-phosphate(S1P) or lysophosphatidic acid (LPA) (123, 221, 282). Bothchemokine and lysophospholipid receptors are GPCRs.While chemokine receptors primarily act through Gi fam-ily G proteins (355), lysophospholipid receptors activateGi, G12/G13, and Gq/G11 family G proteins depending ontype and activation state of the respective cell (377, 584,612).

Inactivation of Gi family G proteins by PTX pretreat-ment strongly impairs lymphocyte migration in vitro (28,598) and causes defective homing to spleen, lymph nodes,and Peyer’s patches in vivo (31, 124, 597, 662), suggestingthat Gi family G proteins are involved in these processes. Inline with this, inactivation of Gi by transgenic expression ofthe S1 subunit of PTX in murine thymocytes resulted inaccumulation of mature T cells in the thymus, with greatlyreduced levels of T cells in peripheral lymphatic organs (91,92). To investigate the role of Gi-mediated signaling in moredetail, mouse lines carrying inactivating mutations of G�i

subtypes were generated. Both G�i2 and G�i3 are expressedin the murine thymus (91), but only inactivation of G�i2

mimicked the phenotype of PTX expressing mice with re-spect to thymic accumulation of mature T cells. NeitherG�i2- nor G�i3-deficient mice showed defects in T cell hom-ing to the periphery (552), suggesting that the homing de-fects induced by PTX probably result from the combinedinactivation of Gi2 and Gi3.

Despite the predominant role of Gi signaling in che-mokine-induced lymphocyte migration, an involvement ofGq/G11 family G proteins was suggested by a variety of invitro studies (11, 21, 353, 590, 716). In contrast to other

tissues, hematopoietic cells do not only express the�-subunits G�q and G�11, but also G�15, which corre-sponds to human G�16 (17, 683). Mice deficient for G�11,G�15, or both G�q and G�15 were normal under basalconditions and after antigenic challenge, and only a minorsignaling defect in response to complement C5a wasfound in G�15-deficient macrophages (132).

The G12/G13 effector RhoA was repeatedly shownto be involved in the regulation of lymphocyte adhesionand migration (367, 631), but direct evidence for aninvolvement of the G12/G13 family is still lacking. Indi-rect evidence for a role of G13 in lymphocyte migrationcomes from studies in Lsc-deficient mice. The murineRho-specific guanine nucleotide exchange factor Lsc(p115RhoGEF in humans) is expressed exclusively in he-matopoietic cells and couples G�13 to the activation ofRhoA (236). Lsc-deficient mice show impaired agonist-induced actin polymerization and motility, as well as ab-normal B-cell homing and altered T- and B-cell prolifera-tion (214). Defective migration was also observed in micelacking the proton-sensing receptor G2A (465), which wasshown to couple to G�13 (316). G2A-deficient macro-phages (659) and T cells (533) showed reduced migrationtowards lysophosphatidylcholine (LPC), while G2A over-expression in a macrophage cell line enhanced migrationtowards LPC (533, 715). How LPC effects are affected bythe absence of G2A is currently not clear (690). In thelatter cells, LPC-induced chemotaxis was inhibited byoverexpression of dominant negative mutants of G�q/G�11 or G�12/G�13, as well as expression of RGS domainsor GRK2 (specific for Gq/G11) or of p115RhoGEF (specificfor G12/G13), while PTX treatment was without effect(715).

Also neutrophils respond to a variety of chemoattrac-tants, such as N-formyl-Met-Leu-Phe (fMLP), C5a, plateletactivating factor (PAF), or the chemokine interleukin(IL)-8, with polarization and directed migration. This ef-fect was shown to be PTX sensitive (43, 217, 577, 598) andto be mainly mediated via ��-subunits (479, 480) (Fig. 8).Lentiviral-mediated knockdown of different G proteinsubunits in a macrophage cell line revealed that comple-ment C5a-induced migration critically depends on G�2,but not on G�1, G�i2, or G�i3 (286). Intracellular effectorsof G�� in neutrophils are the �-isoform of PI 3-kinase(PI3K�) and the �2- and �3-isoforms of phospholipase C(PLC-�2, -�3). While neutrophils from mice lackingPLC-�2 and -�3 show normal, or even enhanced, chemo-tactic responses (388), migration of PI3K�-deficient neu-trophils was severely impaired (266, 388, 566). Moreover,PI3K�-deficient neutrophils failed to accumulate at sitesof inflammation in a septic peritonitis model (266), sug-gesting that PI3K� mediates chemotactic responses bothin vitro and in vivo. In addition to PI3K�, RhoA activityseems to be required for fMLP-induced neutrophil chemo-kinesis and chemotaxis (review in Ref. 484), and espe-



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cially the deadhesion of the uropod was attributed toRhoA (12, 397). Interestingly, fMLP receptor-mediatedchemotaxis of HL60 cells was recently suggested to in-volve not only Gi, but also G12/G13 (702). In these cells,activation of Gi defined “frontness” by activating PI3K andRac, whereas activation of G12/G13 defined “backness” byinducing RhoA-dependent actomyosin interaction (702).

B. Immune Cell Effector Functions

Activation of immune cells by antigen contact ini-tiates complex signaling cascades leading to proliferation,differentiation, or initiation of effector functions like cy-tokine production, mediator release, phagocytosis, etc.Although these functions are not directly G protein me-diated, G proteins might have important modulatory roles(312, 400).

In neutrophils, chemoattractant-induced O2� forma-

tion is mediated via Gi-coupled receptors (39) and isstrongly impaired both in neutrophils from mice lackingPLC-�2 and -�3 (388, 695, 699) and in PI3K�-deficientneutrophils (266, 388, 566). PI3K-mediated formation ofphosphatidylinositol 3,4,5-trisphosphate (PIP3) was shownto activate the small GTPase Rac, which contributes toneutrophil migration by actin polymer formation in theleading edge (540, 653) and to O2

� formation by NADPH

oxidase activation (144). Recently, a new Rac GEF termedP-Rex1 was shown to mediate Rac activation in responseto PIP3 and G�� in neutrophils (672).

In lymphocytes, the balance between the TH1-drivencellular immunity and TH2-driven humoral response ismainly shaped by the cytokine pattern present during Thelper cell activation. PTX has long been known to pro-mote TH1 responses (246, 270, 464), and this was sug-gested to be due to a negative regulation of IL-12 produc-tion by Gi, especially in dendritic cells (246, 279). Micelacking G�i2 develop a diffuse inflammatory colitis resem-bling ulcerative colitis in humans (277, 552), and adeno-carcinomas secondary to chronic inflammation were of-ten observed (552). In these mice, levels of proinflamma-tory TH1-type cytokines and of IL-12 were increased (277),and these changes clearly preceded the onset of bowelinflammation (497, 498). In addition, antigen presentingcells like CD8a� dendritic cells showed a highly increasedbasal production of IL-12 (246), suggesting that colitis inthese mice is a TH1-driven disease and that production ofproinflammatory TH1 cytokines is constitutively sup-pressed through a Gi-mediated pathway. Accordingly, ac-tivation of Gs-mediated signaling opposes these effects.Cholera toxin, which activates Gs by ADP-ribosylation,can be used as an adjuvant to promote TH2 responses(419, 687, 707), and systemic administration of choleratoxin during induction of TH1-based autoimmune diseasescan shift the immune response to the nonpathogenic TH2phenotype (610). In general, the Gs family was suggestedto attenuate proinflammatory signaling, but direct evi-dence is lacking. In vitro, application of cAMP (62, 321,671) or activation of typically Gs-coupled receptors, likethose for vasoactive intestinal polypeptide or PACAP(135, 201), was shown to inhibit immune cell functions.Immune cells from mice lacking the Gs-coupled adeno-sine A2A receptor respond with enhanced cytokine tran-scription and NF�B activation to activation of Toll-likereceptors (404), and activation of Gs by cholera toxininhibits signaling in T cells (476, 595) or natural killer cells(678).

The relevance of Gq/G11 and G12/G13 family G pro-teins in lymphocyte activation and proliferation is un-clear. In vitro studies suggested an involvement of bothfamilies in the activation of Bruton’s tyrosine kinase, aprotein that is required for normal B-cell development andactivation (42, 309, 402). The Gq/G11 family, especiallyhuman G�16, has been implicated in T-cell activation in avariety of in vitro studies (392, 603, 734), but the physio-logical relevance of these findings is unclear. In vivo, noobvious immunological defects were observed inG�11

�/�, G�15�/�, or G�15

�/�;G�q�/� mice (132). How-

ever, after antigenic challenge, G�q-deficient mice showedimpaired eosinophil recruitment to the lung, probably dueto an impaired production of granulocyte macrophagecolony stimulating factor GM-CSF by resident airway leu-

FIG. 8. Gi family G proteins are centrally involved in neutrophilmigration and activation and mediate their effects via the �2- and�3-isoforms of phospholipase C (PLC-�2/�3), phosphoinositide 3-ki-nases (PI-3-K), or the RacGEF P-Rex1. Btk, Bruton’s kinase; DAG,diacylglycerol; IP3, inositol 1,4,5-trisphosphate; PIP2, phosphatidylinosi-tol 4,5-bisphosphate; PI(3,4,5)P3, phosphatidylinositol 3,4,5-trisphos-phate; PKC, protein kinase C.



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kocytes (56). Indirect evidence for a role of Gq/G11 and/orG12/G13 in T-cell activation comes from RGS2-deficientmice, which show impaired T-cell proliferation and IL-2production after T-cell receptor stimulation, as well asdefective antiviral immunity in vivo (499). Inactivation ofthe murine TxA2 receptor, which is typically coupled toGq/G11 and/or G12/G13 family G proteins (337, 492), causeda lymphoproliferative syndrome due to prolongedT-cell/DC interaction (317). Genetic inactivation of theproton-sensitive G2A receptor (465), which was shown toactivate G12/G13, causes a late-onset autoimmune syn-drome in mice (372), suggesting that these G proteins maybe involved in the regulation of lymphocyte activation.

V. NERVOUS SYSTEM

G proteins play multiple roles in the nervous systemas most neurotransmitters also activate G protein-cou-pled metabotropic receptors to modulate neuronal activ-ity. In contrast to ionotropic receptors, GPCRs that arepresent pre- and postsynaptically mediate comparativelyslow responses. Only a few well-studied examples aredescribed below.

A. Inhibitory Modulation of Synaptic Transmission

The regulation of neurotransmitter release at presyn-aptic terminals is an important mechanism underlying themodulation of synaptic transmission in the nervous sys-tem. Inhibitory regulation of neurotransmitter release ismediated by various GPCRs like �2-adrenoceptors, �- and�-opioid receptors, GABAB receptors, adenosine A1, orendocannabinoid CB1-receptors. These receptors have incommon that they couple to G proteins of the Gi/Go

family. A major mechanism by which these G proteinsmediate the inhibition of transmitter release is the inhib-itory modulation of the action potential-evoked Ca2� en-try to the presynaptic terminal which is required to triggerneurotransmitter release. N- and P/Q-type calcium chan-nels that are concentrated at nerve terminals as well asR-type calcium channels have been shown to be inhibitedvia Gi/Go-coupled receptors (145). This inhibition is due tothe interaction of the G protein ��-complex with the�1-subunit of Cav2.1–2.3 (89, 420). The �-subunit of thechannel as well as strong depolarization can reduce thisinhibition (61, 439). Most G�� combinations are similarlyeffective in inhibiting channels of the Cav2 family (202,288, 557). There is some evidence that ��-mediated inhi-bition of Cav2 channels is not the only mechanismthrough which GPCRs mediate inhibition of neurotrans-mitter release (449). Also, G protein-coupled inwardlyrectifying K� channels (GIRKs) are localized at presynap-tic terminals; however, their physiological role in regula-tion of transmitter release from presynaptic terminals is

less clear (156, 524). GIRKs are well-established effectorsfor G protein ��-subunits (113, 356, 398, 718), and mostG�� combinations appear to be similarly effective in ac-tivating GIRKs (681, 708). There is also increasing evi-dence that the G��-mediated inhibition of neurotransmit-ter release at the presynaptic terminus involves mecha-nisms downstream of the regulation of Ca2� (51). Thismay involve the direct interaction between G�� and thecore vesicle fusion machinery as suggested by the obser-vation that G�� can directly bind to SNARE proteins likesyntaxin and SNAP25 as well as cysteine string protein(CSP) (50, 51, 305, 410). Evidence exists that presynapticCa2� channels, syntaxin1, and the �-subunit of Go arecomponents of a functional complex at the presynapticnerve terminal release site (384, 602).

Both Gi-type G proteins as well as Go are highlyabundant in the nervous system. Mice lacking the �-sub-unit of Go are smaller and weaker than their littermatesand have a greatly reduced life expectancy (308, 639). Inaddition, these animals have tremors and occasional sei-zures, and they show an increased motor activity with anextreme turning behavior. G�o-deficient mice have alsobeen shown to be hyperalgesic (308). When neuronal cellsfrom G�o-deficient mice were analyzed by electrophysio-logical methods for the regulation of GIRKs and voltage-dependent Ca2� channels through GPCRs, it was foundthat the recovery kinetics after agonist washout weremuch slower in the absence of G�o. However, currentmodulation via various receptors was as effectively as inwild-type cells (225, 308). This indicates that other Gproteins especially Gi-type G proteins that are activatedby the same receptors can compensate for Go deficiency.

B. Modulation of Synaptic Transmission by the

Gq/G11-Mediated Signaling Pathway

In the nervous system, the G proteins Gq and G11 arewidely expressed (622), and they are involved in multiplepathways that modulate neuronal function. The modula-tion of synaptic transmission has best been described atthe parallel fiber (PF)-Purkinje cell (PC) synapse in thecerebellum. At the PF-PC synapse, Gq/G11 mediate theeffects of metabotropic glutamate group 1 receptors(mGluR1). The Gq/G11-mediated IP3-dependent transientincrease in the dendritic Ca2� concentration, which doesnot require changes in the membrane potential (178, 621),is important for the induction of long-term depression(LTD) at the PF-PC synapse (452). LTD in turn is believedto be one of the cellular mechanisms underlying cerebel-lar motor learning (66). Interestingly, while G�q-deficientmice develop an ataxia with clear signs of motor coordi-nation deficits, G�11-deficient animals show only verysubtle defects in motor coordination (237, 489). A detailedcomparison of both mouse lines showed that Ca2� re-



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sponses to mGluR1 activation were absent in G�q-defi-cient mice, whereas they are indistinguishable betweenwild-type and G�11-deficient animals (237). However, syn-aptically evoked LTD was decreased in G�11-deficientanimals, but to a lesser extent than in G�q-deficient mice.The predominant role of Gq in Purkinje cells can beexplained by the higher expression compared with G�q

(489). In fact, quantitative single-cell RT-PCR analysisshowed that Purkinje cells express at least 10-fold moreG�q than G�11 (237).

Lack of G�q also results in a defect in the regressionof supernumerary climbing fibers innervating Purkinjecells in the third postnatal week. This process is believedto be due to a defect in the modulation of the PF-PCsynapse. Similar cerebellar phenotypes as in G�q-deficientmice have been described in mice lacking the mGluR1 (9,323) as well as in mice lacking the �4-isoform of PLC,which is predominantly expressed in the rostral cerebel-lum (324, 453). Interestingly mGluR1, G�q, and PLC-�4can be found colocalized in dendritic spines of PCs (324,622, 664), suggesting that they are components of a sig-naling cascade involved in the modulation of the PF-PCsynapse.

Interestingly, hippocampal synaptic plasticity isequally impaired in G�q- and G�11-deficient mice (451).However, mGluR-dependent long-term depression in thehippocampal CA1-region was absent in G�q-deficient micebut appeared to be unaffected in mice lacking G�11 (340).Similarly, suppression of slow afterhyperpolarizations viamuscarinic and metabotropic glutamate receptors wasnearly abolished in G�q-deficient mice but was unchangedin mice lacking G�11 (350).

Besides the voltage-dependent, G protein-mediatedinhibition of calcium channels via G�� (see above), func-tional studies in calyx-type nerve terminals and in sym-pathetic neurons have identified a voltage-insensitive in-hibition of calcium currents via metabotropic receptorsthat is believed to involve Gq/G11 (322, 449). How Gq/G11

activation can lead to inhibition of voltage-dependent cal-cium channels is not clear. However, recent evidence sug-gests that the depletion of phosphatidylinositol 4,5-bisphos-phate (PIP2), the substrate of PLC plays a role (200).

There is also evidence that activation of Gq/G11-mediated signaling on the postsynaptic site is involvedin the induction of retrograde signaling via the endo-cannabinoid system. Gq/G11-coupled receptors likegroup I mGluRs as well as muscarinic M1 receptors canlead to the activation of the retrogradely acting canna-binoid system by stimulating the formation of endocan-nabinoids (136, 189, 380, 409).

C. Roles of Gz and Golf in the Nervous System

Gs is the ubiquitous G protein that couples recep-tors in a stimulatory fashion to adenylyl cyclases. How-

ever, in a few tissues the G protein Golf is the predom-inant G protein that couples receptors to adenylyl cy-clase. Apart from the olfactory system (see below),G�olf expression levels exceed those of G�s also in afew other defined brain regions like the nucleus accum-bens, the olfactory tubercle, and the striatum (40, 120,737). In the striatum, Golf appears to be critically in-volved in dopamine (D1) and adenosine (A2) receptor-mediated effects (258, 737). Data from various labora-tories show that in the striatum, the dopamine D1 re-ceptor, G�olf and adenylyl cyclase type V as well as theG protein �7-subunit are coexpressed. Strikingly, micelacking either of these signaling components showclear signs of motor abnormalities (40, 298, 573, 703).Mice lacking adenylyl cyclase V show an attenuatedD1-receptor/Golf-mediated adenylyl cyclase activationin the striatum (298). G�7-deficient mice have stronglyreduced levels of striatal G�olf, and activation of adeny-lyl cyclase via dopamine receptors is abolished in thestriatal cells (573). Thus, in rodents, striatal D1 recep-tors appear to activate adenylyl cyclase V through a Gprotein containing G�olf and �7. In humans, it has re-cently been shown that G�olf expression is markedlydiminished in the putamen of patients with Huntingtondisease, while the putamen of patients with Parkinsondisease showed significantly increased levels of G�olf

and G�7 (120).The G protein Gz is a member of the Gi/Go family. It

shares with other Gi/Go family members the ability toinhibit adenylyl cyclase (176, 267). It is expressed primar-ily in brain, retina, adrenal medulla, and platelets. G�z-deficient mice are viable and have no major phenotypicalabnormalities. However, G�z deficiency results in an ab-normal response to certain psychoactive drugs (253, 713).This includes a considerably pronounced cocaine-in-duced increase in locomotor activity as well as a reduc-tion in the short-term antinociceptive effects of morphine(713). In addition, G�z-deficient animals develop signifi-cantly increased tolerance to morphine (374). Interest-ingly, the behavioral effects of catecholamine reuptakeinhibitors that are used as antidepressant drugs wereabolished in mice lacking G�z (713). While mice lackingG�z clearly indicate that Gz plays a role in the nervoussystem and is involved in various drug responses, thefunction of Gz on a cellular level in the nervous systemremains unclear.

VI. SENSORY SYSTEMS

G protein-mediated signal transduction processesmediate the perception of many sensory stimuli. Odors,light, and especially sweet and bitter taste substances actdirectly on GPCRs that modulate the activity of primarysensory cells via often very specialized heterotrimeric Gproteins.



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A. Visual System

The human retina contains two types of photorecep-tor cells, rods and cones. While rods mediate mainlyachromatic night vision and contain one type of GPCR,rhodopsin, cones are responsible for chromatic day visionand contain three GPCRs (opsins), which are sensitive todifferent parts of the visible light spectrum. Rhodopsinand opsins are coupled to different but closely relatedheterotrimeric G proteins. Rod-transducin (Gt-r) andcone-transducin (Gt-c), which mediate the effects of rho-dopsins and opsins, respectively, couple these receptorsin a stimulatory manner to cGMP-phosphodiesterase(PDE) by binding and sequestering the inhibitory �-sub-unit of the retinal type 6 PDE (PDE6). Activation of PDElowers cytosolic cGMP levels leading to a decreased openprobability of cGMP-regulated cation channels in theplasma membrane, which eventually results in hyperpo-larization of the photoreceptor cells (24). In mice lackingG�t-r, the majority of retinal rods does not respond to lightany more, and these animals develop mild retinal degen-eration with increasing age (84). To ensure an adequatetime resolution of the light signal, the transducin-medi-ated signaling process initiated by light-induced receptoractivation requires an efficient termination mechanism. Atleast three proteins contribute to the rapid deactivation oftransducin by increasing its GTPase activity: RGS9 andG�5L, which form a complex, and the �-subunit of thetransducin effector cGMP-PDE (24). In mice lacking G�5,the levels of RGS9 and other G protein �-like (GGL)domain RGS proteins in various tissues including retinaare drastically reduced, suggesting that the formation ofthe RGS9 G�5 complex is required for expression andfunction of RGS9 (100). Animals lacking G�5 or RGS9show a strongly impaired termination of transducin-me-diated signaling (99, 352, 407).

The light-induced hyperpolarization of photoreceptorcells results in a decreased release of glutamate. Gluta-mate released from photoreceptor cells acts on twoclasses of second-order neurons in the retina, one thatdepolarizes in response to glutamate most likely via iono-tropic glutamate receptors (OFF bipolar cells) and an-other that hyperpolarizes (ON bipolar cells). ON bipolarcells are in the absence of light inhibited by glutamatereleased from rods and cones, and this effect is mediatedby the metabotropic glutamate receptor mGluR6. Light-induced hyperpolarization of rods results in decreasedglutamate release and disinhibition of ON bipolar cellsdue to a decreased activation of mGluR6. In mice lackingmGluR6 or the G�o splice variant G�o1, the modulation ofON bipolar cells in response to light is abolished (142, 143,425), indicating that Go is the principle mediator of glu-tamate-induced inhibition of ON bipolar cells, which oc-curs especially in the absence of light. The retina-specificRGS protein Ret-RGS1 is localized in the dendritic tips of

ON bipolar cells together with mGluR6 and G�o1 and mayplay a critical role in increasing the deactivation of Go1

resulting in an acceleration in the rising phase of the lightresponse of the ON bipolar cells. This mechanism hasbeen suggested to match the kinetics of ON bipolar cellactivation to that of the OFF bipolar cells that arisesdirectly from ligand-gated channel activation by gluta-mate (141).

B. Olfactory/Pheromone System

Chemosensation by the olfactory system is based onthe expression of a huge variety of GPCRs specifically inthe olfactory epithelium. Individual olfactory sensory neu-rons appear to often express only one olfactory receptor,and olfactory sensory neurons expressing one receptortype converge to the same subgroup of glomeruli in theolfactory bulb (457, 548). Rodents have �1,000 differentolfactory receptors, whereas the number in humans isconsiderably smaller and has been estimated to be �350(457). Despite this remarkable diversity on the level of thereceptor, the olfactory GPCRs appear to employ the sameG protein-mediated signal transduction pathway in olfac-tory sensory neurons. The G protein Golf is centrallyinvolved in signaling by olfactory receptors in response toodorant stimuli, and G�olf-deficient mice are anosmic ex-hibiting dramatically reduced electrophysiological re-sponses to all odors tested (40). Golf, a G protein relatedto Gs, couples olfactory receptors in the cilia to adenylylcyclase III, resulting in the increased formation of cAMP.cAMP then activates a cyclic nucleotide-gated (CNG) cat-ion channel consisting of three different subunits,CNGA2, CNGA4, and CNGB1. The increase in cellularCa2� activates a Ca2�-activated Cl� channel that furtherdepolarizes the cell membrane (457, 548). Most G�olf-deficient pups die a few days after birth due to insufficientfeeding. Rare surviving animals exhibit inadequate mater-nal behavior resulting in the death of all pups born toG�olf-deficient mothers. This indicates that normal nurs-ing and mothering behavior in rodents is greatly depen-dent on an intact olfactory system (40). The fundamentalrole of this signaling pathway is underscored by the anos-mic phenotype found not only in mice lacking G�olf, butalso adenylyl cyclase (693) as well as in mice lacking thesubunits of the olfactory CNG channel (30, 76, 731).

A second olfactory system called the accessory ol-factory system or the vomeronasal system exists in mostmammals (152, 330). The peripheral sensory structure ofthis system, the vomeronasal organ, is localized at thebottom of the nasal cavity. The vomeronasal system re-sponds to pheromones that mediate defined effects onindividuals of the same species and modulate social, ag-gressive, reproductive, and sexual behaviors. In the vome-ronasal organ, two families of GPCRs, which in mice



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consist of �150 members each, have been identified. TheV1 receptor family is expressed in vomeronasal sensoryneurons together with the G protein Gi2, whereas the V2receptor family is expressed in a different population ofneurons that coexpresses the G protein Go (428). In hu-mans, no intact genes coding for V2 family receptors havebeen found, and most V1 receptor genes are pseudogenes,suggesting that the function of the vomeronasal organ ofrodents is not fully preserved in humans and higher pri-mates. Similar to the olfactory receptors, individual mem-bers of the V1 and V2 receptor families appear to bespecifically expressed in individual sensory neurons thatproject to a small group of glomeruli in defined regions ofthe accessory olfactory bulb. The striking coexpression ofV1 receptor family members and Gi2 and of V2 receptorfamily members and Go suggests that these G proteinsmediate the cellular effects induced by activation of therespective pheromone receptors. Consistent with this,G�i2-deficient mice have a reduced number of vomerona-sal sensory neurons that normally express G�i2 and showalterations in the behaviors for which an intact vomero-nasal organ is believed to be required like maternal ag-gressive behavior as well as aggressive behavior in malesexposed to an intruder (486). In mice lacking G�o apo-ptotic death of vomeronasal sensory cells which usuallyexpress G�o has been observed (623). Despite these be-havioral and anatomical abnormalities in G�i2- and G�o-deficient mice, a direct involvement of G�i2 in signaling ofV1 receptor-expressing cells and of G�o in V2 receptor-expressing cells has not been demonstrated so far. Thetransient receptor potential channel TRP2, which is ex-pressed in vomeronasal sensory neurons, has been iden-tified as a critical downstream mediator of the signaltransduction pathway in vomeronasal sensory neurons(383, 605).

C. Gustatory System

Unlike the olfactory system, chemosensation bythe gustatory system involves only in part G protein-mediated signal transduction mechanisms. The tastequalities sweet, bitter, and amino acid (umami) signalthrough GPCRs, whereas salty and sour tastants actdirectly on ion channels (391). During recent years, twofamilies of candidate mammalian taste receptors, T1receptors and T2 receptors, have been implicated insweet, umami, and bitter detection. The T2 receptorsare a group of �30 GPCRs that are specifically ex-pressed in taste buds of the tongue and that are linkedto bitter taste in mice and humans (6, 78, 94, 429). TheT1 receptor family consists of only three GPCRs andhas been shown to form heterodimers. T1R1 and T1R3form a receptor that responds to amino acids carryingthe umami taste (477), and T1R2 forms heterodimers

with T1R3 that functions as a sweet receptor (386, 477).Studies in knockout mice support a role of T1R2/T1R3as a sweet receptor and of T1R1/T1R3 as an umamireceptor. In addition, T1R3 may form homodimers thatcan also mediate some sweet tastes, and there is evi-dence that also a splice variant of the mGluR4 gluta-mate receptor may be involved in umami sensation (95,96, 127, 730). The signal transduction mechanisms usedby different G protein-coupled taste receptors are lessclear. Gustducin, a G protein mainly expressed in tastecells, is believed to be able to couple receptors tophosphodiesterase resulting in a decrease of cyclic nu-cleotide levels. Mice lacking the �-subunit of gustducinshow impaired responses to bitter, sweet, as well asumami tastes (247, 555, 692). However, the residualbitter and sweet taste responses in G�gust-deficientmice and the finding that expression of a dominantnegative mutant of �-gustducin reduces this respon-siveness even further indicates that �-gustducin is notthe only �-subunit involved in sweet, bitter, and umamisignal transduction (416, 556). In addition, �-gustducin-deficient mice expressing the �-subunit of rod-transdu-cin as a transgene driven by the �-gustducin promoterpartially recovered responses to sweet and bitter com-pounds (247). However, in mice lacking the �-subunitof rod-transducin, responses to bitter and sweet com-pounds were normal, whereas the responses to variousumami compounds were impaired (249). Thus gustdu-cin is involved in sweet, bitter, and umami taste detec-tion, whereas rod-transducin mediates part of umamitaste sensation. Both gustducin and transducin are ableto activate phosphodiesterase, thereby leading to de-creased cGMP levels, disinhibition of cyclic nucleotide-inhibited channels, and calcium influx. In addition, bit-ter tastants have also been shown to activate PLC-�2

through G�� subunits (probably G�3�13) released fromgustducin or other G proteins (416), and PLC�2 hasrecently been shown to be involved in the activation oftransient receptor potential M5 (TRPM5) cation chan-nels, which cause depolarization of the cells (729).Interestingly, mice lacking PLC-�2 or TRPM5 are com-pletely insensitive not only to bitter tastants but also tosweet and umami (729), indicating that the G protein/PLC-�2/TRPM5 signaling cascade is centrally involvedin the sensation of these three taste qualities. However,other signal transduction pathways have been sug-gested, and it is not clear how gustducin or transducinfunctions are related to those of PLC�2 and TRPM5.

VII. DEVELOPMENT

Although heterotrimeric G proteins are expressedthroughout the prenatal development of the mammalianorganism, only a limited number of studies have so far



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addressed the role of G proteins in development. Mostinsights into the developmental role of G protein-medi-ated signaling pathways came from studies on mousemutants lacking individual G protein �-subunits. Somenull mutations like those of the genes encoding G�s, G�13,or G�q/G�11 are embryonic lethal (493, 495, 723) andclearly indicate an essential role during development.

A. G13-Mediated Signaling in

Embryonic Angiogenesis

Both G12 and G13 have been shown to induce cy-toskeletal rearrangements in a Rho-dependent manner(79, 563). Lack of G�13 in mice results in embryoniclethality at midgestation. At this stage, mouse embryosexpress both G�12 and G�13. G�13-deficient mouse em-bryos show a defective organization of the vascular sys-tem, which is most prominent in the yolk sac and in thehead mesenchyme (493). Vasculogenic blood vessel for-mation through the differentiation of progenitor cells intoendothelial cells was not affected by the loss of G�13.However, angiogenesis which includes sprouting, growth,migration, and remodeling of existing endothelial cells,was severely disturbed, and the maintenance of the integ-rity of newly developed vessels appeared to be defectivein G�13-deficient embryos. Chemokinetic effects ofthrombin, which acts through protease-activated recep-tors (PARs), were completely abrogated in fibroblastslacking G�13, indicating that G�13 is required for fullmigratory responses of cells to certain stimuli. Interest-ingly, approximately one-half of the embryos that lack theprotease-activated receptor 1 (PAR-1) also die at midges-tation with bleeding from multiple sites (118). This phe-notype of embryos lacking PAR-1 which is expressed inendothelial cells, can be rescued by a PAR-1 transgenewhose expression is driven by an endothelial-specific pro-moter (226). This clearly indicates that PAR-1 function isrequired for proper vascular development. The more se-vere embryonic defect of G�13 compared with PAR-1-deficient embryos suggests that G�13 function is not re-stricted to protease-activated receptor signaling.

The defects observed in G�13-deficient embryos andcells occurred in the presence of G�12, and loss of G�12

did not result in any obvious defects during development.Interestingly, G�12-deficient mice that carry only one intactG�13 allele also die in utero (228). This genetic evidenceindicates that G�13 and its closest relative, G�12, fulfill atleast partially nonoverlapping cellular and biologic func-tions, which are required for proper development.

B. Gq/G11-Mediated Signaling During Embryonic

Myocardial Growth

The G�q/G�11-mediated signaling pathway appears toplay a pivotal role in the regulation of the physiological

myocardial growth during embryogenesis. This is demon-strated by the phenotype of mice lacking both G�q andG�11. These mice die at embryonic day 11 due to a severethinning of the myocardial layer of the heart (495). Boththe trabecular ventricular myocardium as well as thesubepicardial layer appeared to be underdeveloped.There are several Gq/G11-coupled receptors that may beinvolved in the regulation of cardiac growth at midgesta-tion. Inactivation of the gene encoding the Gq/G11-coupledserotonin 5-HT2B receptors in mice resulted in cardiomy-opathy with a loss of ventricular mass due to a reductionin the number and size of cardiomyocytes (473), and lackof both endothelin A (ETA) and endothelin B (ETB) re-ceptors, which can signal through Gq/G11, resulted inmidgestational cardiac failure (710). Most likely there issome degree of signaling redundancy with several inputsinto the Gq/G11-mediated signaling pathway, and only de-letion of both the G�q and the G�11 gene results in severephenotypic defects during early heart development. Inter-estingly, one intact allele of the G�q or the G�11 gene wassufficient to overcome the early developmental block inheart development. However, newborn mice that haveonly one intact G�q or G�11 allele show an increasedincidence of cardiac defects ranging from septal defectsto univentricular hearts (495).

C. Neural Crest Development

Signaling through Gq/G11 has been implicated in theproliferation and/or migration of neural crest cells. ET-1and the Gq/G11-coupled endothelin A (ETA) receptor areessential for normal function of craniofacial and cardiacneural crest. ET-1 and ETA receptor-deficient mice dieshortly after birth due to respiratory failure (114, 357,358). Severe skeletal abnormalities could be observed intheir craniofacial region, including a homeotic transfor-mation of mandibular arch-derived structures into maxil-lary-like structures as well as absence of auditory ossiclesand tympanic ring (503, 553). A hypomorphic phenotypesimilar to, but less severe than ETA or ET-1 null micecould be observed in G�q (�/�);G�11 (�/�) mice (495).In G�q/G�11 double-deficient mice studied at embryonicday 9.5, a expression of ET-1-dependent transcriptionfactors like Dlx3, Dlx6, dHAND, and eHAND was ablated(297), a finding similar to those made in mice lacking ETA

or ET-1 (114, 629). This suggests that in the neural crest-derived pharyngeal arch mesenchyme, a signaling path-way involving ET-1, ETA receptors, and G�q/G�11 is oper-ating. ET-1, which is expressed in the pharyngealendoderm binds to ETA receptors in neural crest cells ofthe pharyngeal archs of embryonic day 9.5 embryos(114). Gq/G11 then couples ETA receptors via phospho-lipase C-� activation to the activation of the expression ofgenes encoding transcription factors including Dlx3,



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Dlx6, dHAND and eHAND (297). In contrast, G�q (�/�);G�11 (�/�) mice did not show any craniofacial abnormal-ities indicating that ETA receptor-mediated neural crestdevelopment requires a certain amount of G�q/G�11. It isalso possible that G�11 is expressed at lower levels thanG�q in the neural crest-derived mesenchyme of the pha-ryngeal archs, or that the ETA receptor couples preferen-tially to G�q.

The ET-3 and ETB receptor system has been shownto be involved in the development of neural crest cellstaking part in the formation of epidermal melanocytes aswell as the myenteric ganglia of the distal colon. In micelacking ET-3 or the ETB receptor, this results in white-spotted hair and skin color as well as a dilation of theproximal colon (38, 710). These defects are very similar tothose present in humans suffering from multigenicHirschsprung disease, which in various cases has beenshown to be caused by mutations in ETB or ET-3 genes(158, 204). Whether Gq/G11-mediated signaling is involvedin ET-3-induced differentiation of cutaneous and entericneural crest cells has not been studied directly so far.However, several hypermorphic alleles of the G�q andG�11 genes have recently been found in mouse mutantswith an aberrant accumulation of pigment-producing me-lanocytes (302, 642). Genetic evidence was provided thatthe action of G�q/G�11 depended on the ETB receptor.

VIII. CELL GROWTH AND TRANSFORMATION

During recent years it has become obvious thatGPCRs and heterotrimeric G proteins play importantroles in the regulation of cell growth and that some Gproteins can induce cellular transformation (140, 229,549). Many G protein �-subunits are able to transformcells under certain conditions when rendered constitu-tively active by inducing GTPase inactivating mutations.In some cases, activated G protein �-subunits have beenfound in human tumors.

A. Constitutively Active Mutants of G�q/G�11

Family Members

Transforming mutants of G�q/G�11 have not beenfound in human tumors. However, their potential onco-genic function has been studied in cell lines by expres-sion of constitutively active forms like G�qQ209L orG�11Q209L. These studies indicated that activated G�q/11

can lead to transformation of fibroblasts when expressedat low levels (318) but induces growth inhibition andapoptosis when expressed at higher levels (140). Interest-ingly, various Gq/G11-coupled receptors have been shownto possess highly transforming activity. This has veryearly been shown for the 5-HT2C serotonin receptor aswell as for the M1, M3, and M5 muscarinic receptors,

which are able to transform fibroblasts in the presence ofa receptor agonist (231, 315). It is well known that variousGq/G11-coupled neuropeptide receptors like those for gas-trin-releasing peptides, galanin, neuromedin B, vasopres-sin, and others are involved in the autocrine and paracrinestimulation of proliferation in small cell lung cancer cells(250). This suggests that endogenous Gq/G11-coupled re-ceptors can be tumorigenic in the presence of excessligands. In vitro experiments indicate that constitutivelyactive Gq/G11-coupled receptors can enhance mitogenesisand tumorigenicity (14), and the virally encoded KSHV-Gprotein-coupled receptor, which is a constitutively activeGq/G11-coupled receptor, has been shown to behave as aviral oncogene and angiogenesis activator and appears tobe involved in Kaposi sarcoma progression (26, 29, 458).

B. The Oncogenic Potential of G�s

Gs-mediated increases in cAMP can induce growthinhibition in some tissues while in others it can have atransforming potential. The gsp oncogene encodes aGTPase-deficient mutant of G�s and has been found in upto 30% of thyroid toxic adenomas and in a few thyroidcarcinomas. A constitutively active mutant of G�s hasalso been found in GH-secreting pituitary adenomas aswell as in the McCune-Albright syndrome (172, 599). In-terestingly, responses to constitutively active G�s are celltype specific. In some cells, an increase in cAMP andconsecutive activation of PKA can inhibit Raf kinase andprevent transformation of cells (102). In contrast, in var-ious neuronal and neuroendocrine cells, G�s-mediatedcAMP formation activates cell growth (164, 551). Thetransforming potential of Gs obviously depends on thecellular context that links Gs-mediated cAMP formationto inhibition or stimulation of ERK (604). While variouskinases upstream of ERK have been involved in cAMP/PKA-induced ERK regulation, the determinants of the netproliferative effect of cAMP remain elusive (604). A pro-posed role of the cAMP-activated Epac/Rap1 pathway incAMP-mediated ERK activation has been questioned(163).

The potential of Gs-mediated signaling to induce tu-mor formation in endocrine cells is also underlined by thefact that constitutively active mutants of various Gs-cou-pled receptors have been detected in human tumors. Upto 80% of hyperfunctioning human thyroid adenomas anda minority of differentiated thyroid carcinomas have beenshown to contain constitutively active TSH receptors(507, 508). Similarly, mutations resulting in constitutiveactivation of the luteinizing hormone receptor have beenshown to cause hyperplastic growth of Leydig cells in aform of familial male precautious puberty (578) as well asin Leydig cell tumors (393).



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C. Gi-Mediated Cell Transformation

The gip2 oncogene that encodes an active mutant ofG�i2 has been found in adrenal cortical tumors as well asin human ovarian sex cord stromal tumors (406). It is amatter of debate how frequent these G�i2 mutations occurin these tumors. Expression of constitutively active G�i2

in fibroblast cell lines leads to cell transformation, aneffect which has not been completely understood yet, butmay result from the derepression of the Ras/ERK pathwayin response to a decrease in cellular cAMP levels (446,640). Depending on the cellular system, Gi-mediated re-lease of free ��-subunits may also be involved in thegrowth-promoting effect of G�i2 (122).

D. Cellular Growth Induced by G�12/G�13

The G protein �-subunit G�12 was identified as anoncogene present in soft tissue sarcoma (93). This onco-gene, termed gep, encoded the wild-type form of G�12. Atthe same time, the potent transforming ability of consti-tutively active mutants of G�12 and G�13 could be shownin various systems (307, 645, 655, 703, 704). While noactivating mutation of G�12 or G�13 has been found inhuman tumors, increased expression levels of both pro-teins have been detected in various human cancers (230).Both G�12 and G�13 can induce activation of the smallGTPase RhoA via regulation of a subgroup of RhoGEFproteins (195, 236). Interestingly, RhoA has been found tobe overexpressed in various tumor types (2, 192, 320), andRho GTPases have been involved in carcinogenesis andcancer progression (385, 564). Recently, an interestinglink between G12/G13- and cadherin-mediated signalingwas described (327, 434, 435). Active G�12 and G�13 caninteract with the cytoplasmic domain of some type I andtype II class cadherins, like E-cadherin, N-cadherin, orcadherin-14, causing the release of �-catenin from cad-herins and its relocalization to the cytoplasm and nucleus,where it is involved in transcriptional activation. In addi-tion, activated G�12 can block cadherin-mediated cell ad-hesion in various cells including breast cancer cells (434).This downregulation of cadherin-mediated cell adhesionand the release of �-catenin from cadherins may be amechanism by which G�12/G�13 induces cellular transfor-mation and metastatic tumor progression.

IX. CONCLUDING REMARKS

The field of heterotrimeric G proteins was launchedmore than 30 years ago when the involvement of guaninenucleotides in the hormonal stimulation of adenylyl cy-clase was discovered. Since then, the field has enor-mously expanded, and G protein-mediated signal trans-duction has turned out to be the most widely used trans-

membrane signaling system in higher organisms. Itconsists of hundreds of receptors that signal to dozens ofG proteins and effectors. The modular nature of thissignal transduction system with multiple components en-ables cells to assemble vast, combinatorially complexsignaling units that allow different cells in different con-texts to respond adequately to extracellular signals. Thereis probably not a single cell in a mammalian organism thatdoes not employ several G protein-mediated signalingpathways. Often these pathways integrate the informationconveyed by several receptors recognizing different li-gands. Only in recent years did we gain a more systematicinsight into the role of individual G proteins on a cellularand supracellular level. However, many aspects of G pro-tein-mediated signaling, especially under in vivo condi-tions, still remain to be elucidated. While many compo-nents of the system have been identified, new approachesare required to determine the exact composition of indi-vidual signaling units and to define their exact cellularlocalization. This will probably lead to the identificationof even more proteins and nonprotein factors that mod-ulate G protein-mediated signaling. An increasing use ofin vivo models is necessary to test the significance ofsignaling mechanisms described in vitro under normalconditions as well as in disease states. The parallel appli-cation of genetic, genomic, and of new proteomic ap-proaches will be required to continue to define how the Gprotein-mediated signaling system works on a molecular,cellular, and systemic level. Such an integrated view willprovide the basis for a full understanding of the physio-logical and pathophysiological role of G protein-mediatedsignaling and will allow the full exploitation of this mul-tifaceted signaling system as a target for pharmacologicalinterventions.

ACKNOWLEDGMENTS

Address for reprint requests and other correspondence: S.Offermanns, Institute of Pharmacology, Univ. of Heidelberg, ImNeuenheimer Feld 366, D-69120 Heidelberg, Germany (E-mail:[email protected]).

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