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  • 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 Gq/G11 family members 1184B. The oncogenic potential of Gs 1184C. Gi-mediated cell transformation 1185D. Cellular growth induced by G12/G13 1185

    IX. Concluding Remarks 1185

    Wettschureck, Nina, and Stefan Offermanns. Mammalian G Proteins and Their Cell Type Specific Functions.Physiol Rev 85: 11591204, 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: 11591204, 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 Principlesof 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,400500 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 orphanGPCRs (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 2521,2,3 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, 50

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