Introductory Editorial

G Protein-Coupled Receptors:New insights into signaling and regulation

This special issue of Biology of the Cell contains a collec-tion of articles that correspond to work presented at theinternational symposium held in Paris in October 23-24,2003 that was entitled “G Protein-Coupled Receptors : Newinsights into signaling and regulation“ (see Meeting Report,this issue). G Protein-Coupled Receptors (GPCRs) are alsocalled heptahelical or serpentine receptors because of theirconserved structure featuring seven transmembranea-helices. The concept of GPCR emerged following theseminal discovery that GTP is required for activation ofeffectors such as adenylyl cyclase (Rodbell et al., 1971) orretinal phosphodiesterase (Wheeler and Bitensky, 1977), aneffect that revealed the existence of a GTP-binding protein(G protein) linking receptor to effectors. This concept wasextended with the description of an increasing number ofother G protein-coupled systems, the cloning of G proteinsand the growing evidence that this transduction mechanismoccurred in most living organisms (reviewed in Birnbaumer,1990). Ultimately, molecular cloning of mammalianb-adrenergic receptors (Dixon et al., 1986; Yarden et al.,1986) demonstrated their structural homology with rhodop-sin (Lefkowitz et al., 1986) and then with the muscarinicacetylcholine receptor (Kubo et al., 1986; Hall, 1987). Thesize of the family then rapidly increased and, in the humangenome, it is now assumed that at least 600 distinct genesencode GPCRs.

Because these receptors play a central role in transmissionof information across the plasma membrane of cells, theyhave generated considerable interest. In fact, GPCRs areactivated by a remarkable diverse array of signals includingodorant and tasting molecules, light, calcium, peptide andnon-peptide neurotransmitters or hormones. They thus playkey roles in numerous physiological processes like hormonalcommunication, neurotransmission, embryonic develop-ment, sensory transmission, etc..... Furthermore, GPCRs aretargets for many current therapeutic agents and their dys-function often leads to diseases that are often severe.

During recent years, new fascinating advances have im-proved our understanding of the structure, regulation andsignaling properties of GPCRs. It became clear that theGPCR superfamily is considerably larger than even recentlythought, including notably several families differing in theirligand binding domains and their mechanisms of activation.Further, the growing number of genetic models of GPCR-deficient animals as well as the development of techniques

for the detection of protein-protein interactions has revealedthat GPCR signaling was tremendously more complex anddiverse than initially believed.

The first review article in this special issue (Cotecchia etal.) presents a wide and up-to-date review of the a1-adrenergic receptor properties derived notably from dataobtained in the author’s laboratory.

Next several original features of receptor activation aredescribed in the review by Pin et al. who studied the class-IIIreceptors mGluR1 and GABAB. They show that agonists,which bind to a large extracellular domain, induce closure ofthe extracellular Venus Flytrap motif (VFTM) that is suffi-cient for receptor activation and that antagonists prevent theVFTM closure.

In the article by Brede et al., unexpected and novel func-tions of a2-adrenergic receptor subtypes are reviewed. Thesehave been discovered by using a2-receptor-deficient mousemodels. Among the novel identified functions of a2-adrenergic receptor subtypes, one can emphasize the essen-tial role of a2B-receptors in the initiation of the vascularplacental development.

Couty and Gershengorn provide a very complete overviewof the functional properties of a viral GPCR and the biologi-cal consequences of its expression, illustrating how viralGPCR can induce cellular dysfunction and disease. Indeedtheir work using transgenic mice expressing HHV-8-GPCRsuggest that this receptor may be the major mediator ofHHV-8-induced cell transformation in Kaposi’s sarcoma.

During the symposium several lectures addressed the ob-servation that GPCR-mediated responses do not depend on asingle transduction pathway but result from interacting sig-naling pathways that form a network. The article by Eung-damrong and Iyengar describes a computational approachthat is based on the spatial representation of coupled bio-chemical reactions to study the origin and dynamics of spa-tial microdomains in cells.

The current knowledge on an atypical G protein, Ghprotein, is introduced by S. Mhaouty-Kodja. This proteincontains only two subunits: Gha and Gb. S. Mhaouty-Kodjadescribes evidence that Gha, by functioning as a G-protein,can contribute to cell signaling of physiological relevance,namely in signaling leading to myometrial proliferation dur-ing pregnancy.

One of the relatively new actors in the regulation of signaltransduction: are the AGS (Activator of G protein Signaling).

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S. M. Lanier describes here recent data on the three knownAGS (AGS1–3) with a specific attention to the recentlydiscovered AGS3. The characterisation of this protein hasuncovered unexpected mechanisms for signal processing thatmay have implications in various diseases.

The last review in this issue (Gavarini et al.) describes anoriginal proteomic strategy using peptide-affinity chroma-tography to identify proteins interacting with the C-terminusof serotoninergic receptors of the 5-HT2 family. In additionto the characterisation of these complexes the authors de-scribe evidence suggesting that these complexes may regu-late receptor resensitization within cells.

The final article in this special issue (Le Crom et al.)describes original research on evolutionary aspects of D1receptors. This analysis shows that the three D1 receptorsubtypes resulted from two sequential gene duplications. Theevolutionary data is coupled with functional and pharmaco-logical studies and shows that a number of criteria can beused to distinguish the receptor subtypes.

References

Birnbaumer, L., 1990. G proteins in signal transduction. Ann. Rev. Pharma-col. Toxicol. 30, 675–705.

Dixon, R.A.F., Kobilka, B.K., Strader, D.J., Benovic, J.L., Dohlman, H.G.,Frielle, T., Bolanowski, M.A., Bennett, C.D., Rands, E., Diehl, R.E.,Mumford, R.A., Slater, E.E., Sigal, I.S., Caron, M.G., Lefowitz, R.J.,Strader, C.D., 1986. Cloning of the gene and cDNA for mammalianb-adrenergic receptor and homology with rhodopsin. Nature 321, 75–79.

Hall, Z.W., 1987. Three of a kind: the b-adrenergic receptor, the muscarinicacetylcholine receptor, and rhodopsin. Trends Neurosci. 10, 99–101.

Kubo, T., Fukuda, K., Mikami, A., Maeda, A., Takahashi, H., Mishina, M.,Haga, T., Haga, K., Ichiyama, A., Kangawa, K., Kojima, M., Matsuo, H.,Hirose, T., Numa, S., 1986. Cloning, sequencing and expression ofcomplementary DNA encoding the muscarinic acetylcholine receptor.Nature 323, 411–416.

Lefkowitz, R.J., Benovic, J.L., Kobilka, B., Caron, M.G., 1986.b-Adrenergic receptors and rhodopsin; shedding new light on an oldsubject. Trends Pharmacol. Sci. 7, 444–448.

Rodbell, M., Krans, H.M., Pohl, S., Birnbaumer, L., 1971. The glucagon-sensitive adenyl cyclase system in plasma membranes of rat liver. I.Effects of guanylnucleotides on binding of 125I-glucagon. J. Biol. Chem.246, 1872–1876.

Wheeler, G.L., Bitensky, M.W., 1977. A light-activated GTPase in verte-brate photoreceptors: regulation of light-activated cyclic GMP phos-phodiesterase. Proc. Natl. Acad. Sci. U S A 10, 4238–4242.

Yarden,Y., Rodriguez, H., Wong, S.K., Brandt, D.R., May, D.C., Burnier, J.,Harkins, R.N., Chen, E.Y., Ramachandran, J., Ullrich, A., Ross, E.M.,1986. The avian b-adrenergic receptor: primary structure and membranetopology. Proc. Natl. Acad. Sci U S A 18, 6795–6799.

J. Cohen-TannoudjiR. Counis

Physiologie et Physiopathologie, CNRS-UMR 7079,Université P & M Curie, Paris, France

D. HervéTransduction du Signal et

Plasticité dans le Système Nerveux INSERM U 536,Institut du Fer à Moulin, Université P & M Curie,

Paris, France

D.L. ShiBiologie du Développement, CNRS UMR 7622,

Université P & M Curie, Paris, France

D. VergéNeurobiologie des Signaux Intercellulaires,

CNRS UMR 7101, Université P & M Curie,7, quai Saint-Bernard, 75252 Paris cedex 05, France*

E-mail address: Daniel.Verge@snv.jussieu.fr (D. Vergé).

* Corresponding author: Tel. 33(0)1 44 27 26 12 ;Fax. 33(0)1 44 27 25 08

Available online 12 May 2004

326 Introductory Editorial / Biology of the Cell 96 (2004) 325–326