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�Corresponding aPharmacology, UniveMoro 5, 00185 Romefax: +39 06 4450307.

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Metabotropic glutamate receptors: Beyond theregulation of synaptic transmission

Ferdinando Nicolettia,b,�, Giuseppe Battagliab, Marianna Stortob,Richard T. Ngombab, Luisa Iacovellia, Antonietta Arcellab, Roberto Gradinib,c,Patrizio Salec, Liborio Rampellod, Teresa De Vitaa, Roberto Di Marcob,e,Daniela Melchiorria,f, Valeria Brunoa,b

aDepartment of Human Physiology and Pharmacology, University of Rome ‘‘La Sapienza’’, ItalybIstituto Neurologico Mediterraneo Neuromed, Pozzilli, ItalycDepartment of Experimental Medicine, University of Rome ‘‘La Sapienza’’, ItalydDepartment of Neurology, University of Catania, ItalyeDepartment of Health Sciences, University of Molise, ItalyfI.R.C.C.S. San Raffaele Pisana, Rome, Italy

Received 3 April 2007; accepted 24 April 2007

KEYWORDSMetabotropic gluta-mate receptors;Brain tumors;Stem cells;Immunologicalsynapse;Antigen presentingcells;Allosteric modulators

nt matter & 2007uen.2007.04.015

uthor. Departmenrsity of Rome ‘‘, Italy. Tel.: +39 0

erdinandonicolett

ticle as: Nicolettrinology (2007), do

SummaryMetabotropic glutamate (mGlu) receptors are G-protein coupled receptors activated byglutamate, the major excitatory neurotransmitter of the CNS. A growing body of evidencesuggests that the function of mGlu receptors is not restricted to the regulation of synaptictransmission. mGlu receptors are expressed in a variety of peripheral cells, including interalia hepatocytes, pancreatic cells, osteoblasts and immune cells. Within the immunolo-gical synapses, mGlu receptors expressed by T cells might contribute to the vast array ofsignals generated by the antigen-presenting cells. mGlu receptors are also found inembryonic and neural stem cells. This suggests their involvement in the pathophysiology ofbrain tumors, which likely originates from cancer stem cells similar to neural stem cells.Ligands of mGlu3 and mGlu4 receptors are potential candidates for the experimentaltreatment of malignant gliomas and medulloblastomas, respectively.& 2007 Published by Elsevier Ltd.

Published by Elsevier Ltd.

t of Human Physiology andLa Sapienza’’, Piazzale Aldo6 49912969;

i@hotmail.com (F. Nicoletti).

i, F., et al., Metabotropic glutami:10.1016/j.psyneuen.2007.04.01

1. Introduction

Metabotropic glutamate (mGlu) receptors are members ofclass-C G-protein coupled receptors (GCPRs), which alsoincludes the GABAB receptor, the Ca2+-sensing receptor,taste receptors, and pheromone receptors. Structurally,

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mGlu receptors are characterized by (i) a long N-terminusdomain, which contains a glutamate binding region termedVenus fly trap; (ii) an heptahelical domain, which is commonto all GCPRs; and (iii) an intracellular C-terminus domain ofvarious length depending on the specific mGlu receptorsubtype. mGlu receptors function as dimers, with twomolecules of glutamate being required for a full receptoractivation. Positive and negative allosteric modulators bindto the heptahelical domain (Kunishima et al., 2000; Pinet al., 2004). There are eight mGlu receptor subtypesdivided into three groups on the basis of their amino acidsequence, pharmacological profile, and transduction me-chanisms. Group I includes mGlu1 and mGlu5 receptors(splice variants: mGlu1a-e; mGlu5a,b), which are coupled toGq. Their activation stimulates the hydrolysis of phospha-tidylinositol-4,5-bisphosphate (PtdIns-4,5-P2) generating thesecond messengers inositol-1,4,5-trisphosphate (Ins-1,4,5-P3) and diacylglycerol (DAG). Ins-1,4,5-P3 releases Ca2+

from intracellular stores, whereas DAG facilitates theactivation of protein kinase C (PKC). Both mGlu1 and mGlu5receptors are activated by 3,5-dihydroxyphenylglycine(DHPG). Compounds Ro-016128 and CPCCOEt are examplesof positive and negative allosteric modulators of mGlu1receptors, respectively. Compounds CDPPB, CPPHA, andADX47273 behave as positive allosteric modulators of mGlu5receptors, whereas MPEP, SIB1893, and the anxyolitic drug,fenobam, negatively modulate mGlu5 receptors. Group IIincludes mGlu2 and mGlu3 receptors, which are bothcoupled to Gi. Their activation produces pleiotropic effectsincluding inhibition of adenylyl cyclase, inhibition ofvoltage-sensitive Ca2+ channels, and activation of K+

channels. Both receptor subtypes are potently activatedby a series of conformationally constrained glutamateanalogues, which include LY354740 and LY379268. Com-pound LY341495 acts as an orthosteric mGlu2/3 receptorantagonist at nanomolar concentrations. A growing numberof positive allosteric modulators including compounds3-MPPTS and yPPTS selectively amplify responses mediatedby mGlu2 receptors. Group III includes mGlu4, mGlu6,mGlu7, and mGlu8 receptors. All these receptors arecoupled to Gi/Go proteins and produce effects similar tothose produced by mGlu2/3 receptors. All these receptorsubtypes are activated by L-2-amino-4-phosphonobutanoate(L-AP4) and by the endogenous compound, L-serine-O-phosphate. PHCCC behaves as a selective positive allostericmodulator of mGlu4 receptors (reviewed by Nakanishi,1992; Pin and Duvoisin, 1995; Schoepp et al., 1999; De Blasiet al., 2001). Since the time of their discovery (Sladeczeket al., 1985; Nicoletti et al., 1986), mGlu receptors havebeen considered as classical synaptic receptors. mGlu1 andmGlu5 receptors are preferentially localized on postsynapticdensities, where their activation contributes to the induc-tion of long-term changes in synaptic efficacy. mGlu2,mGlu3, mGlu4, mGlu7, and mGlu8 receptors are mainly(but not exclusively) found in presynaptic terminals, wheretheir activation negatively modulates neurotransmitterrelease. Different mGlu receptor subtypes are consideredas potential targets for the treatment of neurologicaland psychiatric disorders. These include generalized anxietyand panic attacks (agonists/positive modulators of mGlu2 andmGlu3 receptors; negative modulators of mGlu5 receptors)(Swanson et al., 2005); chronic pain (antagonists/negative

Please cite this article as: Nicoletti, F., et al., Metabotropic glutamPsychoneuroendocrinology (2007), doi:10.1016/j.psyneuen.2007.04.01

modulators of mGlu1 and mGlu5 receptors; agonists/positive modulators of mGlu2 and mGlu3 receptors) (Varneyand Gereau 4th, 2002); drug addiction (negative modulatorsof mGlu5 receptors; agonists/positive modulators of mGlu2and mGlu3 receptors) (Kenny and Markou, 2004); schizo-phrenia (positive modulators of mGlu5 receptors) (Shipe etal., 2005); and fragile X syndrome (negative modulators ofmGlu5 receptors) (Bear et al., 2004).

In spite of all this, the study of mGlu receptors should notbe confined to the regulation of synaptic transmission and tothe treatment of neurological and psychiatric disorders.Here, we will review a growing body of evidence thatextends the function of mGlu receptors to non-neuronalcells and suggests that these receptors are key regulators ofbasic processes of cell biology, such as cell proliferation,differentiation, and survival. This moves from three curiousfindings related to mGlu receptors. First, the ability ofglutamate to stimulate PtdIns-4,5,-P2 hydrolysis in brainslices is prominent in the first 10 days of postnatal life (up to20–30 fold increase in inositolphosphate formation) butdisappears in slices from adult animals, where mGlu1 andmGlu5 receptors are presumed to regulate synaptic trans-mission (Nicoletti et al., 1986). Second, mGlu1a and mGlu5receptors show constitutive activity, i.e., they are alsoactive in the absence of synaptic glutamate (reviewed by Pinand Duvoisin, 1995). Third, functional mGlu1 and mGlu5receptors have been found in the cell nuclear membrane,and their activation generates Ca2+ transients inside thenucleus (O’Malley et al., 2003; Jong et al., 2005). Whatactivates nuclear mGlu receptors and whether thesereceptors are involved in the regulation of the cell cycleor other nuclear processes is unclear, as yet.

2. Expression and function of mGlu receptorsin non-neuronal cells that reside outside theCNS

The strongest suggestion that mGlu receptors are notexclusively synaptic receptors derives from numerousstudies that demonstrate the presence of functional mGlureceptors in a number of peripheral non-neuronal cells,many of which do not even originate from the neural crest.Gu and Publicover (2000) found the presence of mGlu1b inrat femoral osteoblasts, where mGlu1 receptor agonistsbehave similarly to parathyroid hormone in inhibitingresponses mediated by NMDA receptors. As a follow-up ofthese findings, Yoneda’s group found that functional mGlu4and mGlu8 receptors are present in cultured osteoblasts(Hinoi et al., 2001), and that activation of these receptorswith L-AP4 inhibits chondral mineralization in the rodentcartilage (Wang et al., 2005). Liver cells instead expressmGlu5 receptors, the activation of which stimulates PtdIns-4,5-P2 hydrolysis, and is protective against cell damageproduced by hypoxia or acetaminophen (Sureda et al., 1997;Storto et al., 2000, 2003, 2004). mGlu receptors have beenimplicated in the regulation of pancreatic hormone secre-tion, although their exact role is unclear (Tong et al., 2002;Uehara et al., 2004; Storto et al., 2006). An intriguingfinding is the presence of mGlu5 receptors in insulin-containing vesicles purified from clonal pancreatic beta-cells, which also express vesicular glutamate transporters

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(Storto et al., 2006). Perhaps the metabolic glutamate thatis synthesized in response to beta-cell activation and istransported inside the insulin-containing granules transmitssignals across the granule membrane by activating mGlu5receptors (Storto et al., 2006). Expression of mGlu1 andmGlu5 receptors is also found in rat and human testis, withmGlu5 receptors being present and functionally active inmature human sperm (Storto et al., 2001). Finally, anexciting set of data move mGlu receptors from the classicalneurosynapsis to the ‘‘immunological synapsis’’ between theantigen-presenting cell (APC) and the T lymphocyte. Stortoet al. (2000) first showed the expression of group I and groupII mGlu receptors in isolated thymocytes and thymic stromalcell lines. Interestingly, mGlu1 receptors were found inimmature CD4�/CD8� thymocytes, whereas expression ofmGlu5 receptors was restricted to the more mature CD4+/CD8+ and CD4+/CD8� thymocytes (Storto et al., 2000). Theexistence of mGlu receptors in the thymus has beenconfirmed by Rezzani et al. (2003), who have found that(i) mGlu2/3, mGlu4, and mGlu5 receptors are widelyexpressed in thymic cells; (ii) mGlu5 receptors are prefer-entially expressed in thymic medullary cells; and (iii) a2-day treatment with the immunosuppressant, cyclosporin-A, inhibits the expression of all mGlu receptor subtypes inthe thymus. A role for mGlu receptors in the activation andfunction of lymphocytes is emerging from a series of studiesthat focus on group I and group III mGlu receptors. BothmGlu1 and mGlu5 receptors are expressed by human JurkatT-cell lines, whereas only the mGlu5 receptor is expressedby the human B-cell line, SKW6.4. In blood lymphocytes, themGlu5 receptor is expressed constitutively and is positivelycoupled to adenylyl cyclase, whereas the mGlu1 receptor isexpressed in response to T-cell receptor activation, and iscoupled to the activation of the MAPK pathway (Pachecoet al., 2004). Group III mGlu receptors are also expressed byrodent lymphocytes, and their pharmacological activationgenerates intracellular radical oxygen species and causescell death (Boldyrev et al., 2004, 2005). In contrast,activation of group I mGlu receptors protects human Tlymphocytes against activation-induced cell death (Miglioet al., 2005; Chiocchetti et al., 2006). Of great interest isthat glutamate is now considered as a putative non-peptidicmediator of the immunological synapsis. APC in contact withT cells release substantial amount of glutamate through themembrane cystine/glutamate co-transporter. ‘‘Immunosy-naptic’’ glutamate appears to activate group I mGlureceptors, thus contributing to regulate the initiation of T-cell-mediated immune responses (Pacheco et al., 2006).

3. mGlu receptors in stem/progenitor cells

That the action of glutamate extends beyond the classicalniche of synaptic regulation is further suggested by thepresence of mGlu receptors in stem cells of different origin.Interestingly, the mGlu5 receptor is the only mGlu receptorsubtype expressed by undifferentiated embryonic stemcells, which are pluripotent cells isolated from the innermass of the blastocyst. In these cells, activation of mGlu5receptor cooperates with the cytokine, leukemia inhibitoryfactor in supporting self-renewal (Cappuccio et al., 2005).Pharmacological blockade of mGlu5 receptors with MPEP or

Please cite this article as: Nicoletti, F., et al., Metabotropic glutamPsychoneuroendocrinology (2007), doi:10.1016/j.psyneuen.2007.04.01

receptor knockdown inhibits self-renewal and promotesdifferentiation of cultured embryonic stem cells by enhan-cing ubiquitination and degradation of c-Myc (Spinsantiet al., 2006). Differentiation of embryonic stem cells into‘‘embryoid bodies’’ (floating aggregates of cells differen-tiating into cells of the three main germ layers) is associatedwith the induction of mGlu4 receptors, the activation ofwhich drives cell differentiation toward the endoderm andmesoderm lineages (Cappuccio et al., 2006). At least mGlu3and mGlu5 receptors are also expressed by neural stemcells, i.e., by stem/progenitor cells resident in the CNS,which give rise to neurons, astrocytes, and oligodendrocytes(Luyt et al., 2003, 2004). Neural stem cells can be isolatedeither from the embryonic brain or from two regions ofpersistent neurogenesis of the adult brain: the subventri-cular zone (SVZ) lining the lateral ventricles, and thesubgranular zone (SGZ) of the hippocampal dentate gyrus.In neural stem cells isolated from the developing brain,activation of mGlu3 and mGlu5 receptors supports cellproliferation and survival, and knockout mice lacking mGlu5receptors show a lower number of proliferating neuropro-genitors in the SVZ and SGZ (Di Giorgi-Gerevini et al., 2005).In cultured neural stem cells isolated from the mouse SVZ,pharmacological activation of mGlu3 receptors inhibits celldifferentiation into GFAP+ astrocyte-like cells, an effect thatmay follow the inhibition of cAMP formation (Ciceroni et al.,2006). Functional mGlu3 and mGlu5 receptors are also foundin progenitor cells of the astrocytic/oligodendrocytic line-age (Luyt et al., 2003, 2004). How mGlu receptors functionin these cells is unknown, although activation of mGlu5receptors has been found to protect cultured oligodendro-cyte progenitors against excitotoxic death (Kelland andToms, 2001).

4. mGlu receptors and cancer cells

The increasing awareness that cancer stem cells are theputative tumor-initiating cells in leukemias and a variety ofsolid tumors provides a link for the study of mGlu receptorsin oncology. Putative stem cells of malignant gliomas (themost frequent malignant brain tumor of the adult age) bearsimilarities with type-B cells of the SVZ, including thegeneration of neurospheres in culture, the expression ofimmature markers, the response to the same mitogens anddifferentiating agents (Doetsch et al., 1999; Gritti et al.,1999; Reya et al., 2001; Sanai et al., 2005; Piccirillo et al.,2006; Schulemburg, 2006; Vescovi et al., 2006). If activationof mGlu3 receptors stimulates proliferation and inhibitsdifferentiation of neural stem cells, then one expects thatreceptor activation produces similar effects in glioma stemcells. Although this has not been examined, as yet, a numberof studies indicate that mGlu3 receptor blockade inhibitsproliferation of glioma cells. This has been shown usingcultured cells prepared from human grade IV astrocytomas(glioblastoma multiforme) and glioma cell lines (D’Onofrioet al., 2003), and has been replicated in in vivo studies.Systemic administration of the mGlu2/3 receptor antago-nist, LY341495, inhibits the growth of glioma cells implantedeither under the skin or in the brain parenchima of nudemice (Arcella et al., 2005). This is particularly promisingbecause malignant gliomas are highly resistant to chemo-

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and radiotherapy, and almost invariably recur followingsurgery. Activation of mGlu4 receptors can instead reducethe growth of medulloblastomas. These tumors, which aremost frequent in children, originate from the transformedneuroprecursors of cerebellar granule cells. Initial studieshave shown that granule cell neuroprecursors grown inculture respond to the mGlu4 receptor enhancer, PHCCC,with a reduced proliferation and an increased differentia-tion into mature neurons (Canudas et al., 2004). The samedrug is also able to reduce proliferation of medulloblastomacells in culture, and to limit the growth of medulloblastomasin mice lacking one allele of the Sonic Hedgehog receptor,Patch-1 (Iacovelli et al., 2006). What is even moreinteresting is that mGlu4 receptors are detected in biopticsamples of human medulloblastomas, and their expression isinversely related to the severity of medulloblastomas(Iacovelli et al., 2006). Finally, mGlu receptors may have arole in tumor growth even outside the CNS. Suzy Chen andcollaborators have found by serendipity that the insertionalmutant mouse TG3 develops spontaneous melanomas.Interestingly, the transgene is inserted into the mGlu1receptor gene, and causes an ectopic expression of mGlu1receptors in melanocytes (Pollock et al., 2003). Transgenicmice expressing mGlu1 receptors in melanocytes also formmalignant melanomas (Pollock et al., 2003). It is intuitivethat mGlu1 receptor antagonists/negative modulators mayhave a future in the experimental treatment of malignantmelanomas.

5. Final comment

The emerging function of mGlu receptors in non-neuronalcells rises the question of how these receptors can beactivated in the absence of synaptic glutamate. One shouldtake into account that glutamate has a large metabolic pooland can be synthesized from a-oxo-glutarate, a by-productof the Krebs cycle. Metabolic glutamate that is not clearedintracellularly can be transported outside the cell where itactivates paracrine mechanisms of cell-to-cell communica-tion or autocrine mechanisms of self-regulation. Bothmembrane mGlu receptors and intracellular mGlu receptors(e.g., nuclear receptors) might sense the state of metabolicactivation of the cell. Finally, as discussed above, somemGlu receptors are constitutively active, and, therefore,their function critically depends on the expression levels.The new findings we have highlighted pave the way to amore integrated approach to the study of mGlu receptors,which may increase our knowledge of the real function ofmGlu receptors and may gain new insights into basicmechanisms regulating cell biology and cell-to-cell commu-nication.

Role of the funding source

University of Lille 1, USTL (France), contributed witheditorial assistance, reviewed drafts of the manuscript andcontributed to the decision to submit the manuscript forpublication. The authors retained full editorial controland responsibilities throughout the preparation of themanuscripts.

Please cite this article as: Nicoletti, F., et al., Metabotropic glutamPsychoneuroendocrinology (2007), doi:10.1016/j.psyneuen.2007.04.01

Conflict of interest

None declared.

Acknowledgments

This supplement is based on the proceedings from LilleSummer School in Neurosciences-Brain Plasticity in Life Spanheld in France in 2006. The supplement is supportedfinancially by University of Lille 1, USTL (France), Servier(France) and Nestle (Switzerland).

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