Skip to main content
SpringerLink
Log in

Coupling mode of receptors and G proteins

  • Review
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Signaling via G-protein-coupled receptors (GPCRs) is crucial to many physiological and pathophysiological processes in multicellular organisms, and GPCRs themselves are targets for important drugs. Classical cell supplementation experiments suggest a collision coupling model, in which receptors and G proteins diffuse randomly within the cell membrane and interact only if receptors are activated. This model is also backed by kinetic and live cell imaging data. According to the challenging theory, receptors and G proteins are precoupled—meaning they are forming stable complexes in the absence of agonist, which prevail during signaling. This model has been favored on the basis of copurification and coimmunoprecipitation of inactive receptors with G proteins and more recently by some approaches measuring energy transfer between labeled receptors and G proteins. This article reviews key findings regarding the receptor/G protein coupling mode, including most recent findings obtained by optical techniques.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Alousi AA, Jasper JR, Insel PA et al (1991) Stoichiometry of receptor-Gs-adenylate cyclase interactions. FASEB J 5:2300–2303

    PubMed  CAS  Google Scholar 

  • Arad H, Rosenbusch JP, Levitzki A (1984) Stimulatory GTP regulatory unit Ns and the catalytic unit of adenylate cyclase are tightly associated: mechanistic consequences. Proc Natl Acad Sci U S A 81:6579–6583

    Article  PubMed  CAS  Google Scholar 

  • Audet N, Galés C, Archer-Lahlou E et al (2008) Bioluminescence resonance energy transfer assays reveal ligand-specific conformational changes within preformed signaling complexes containing δ-opioid receptors and heterotrimeric G proteins. J Biol Chem 283:15078–15088

    Article  PubMed  CAS  Google Scholar 

  • Bouaboula M, Perrachon S, Milligan L et al (1997) A selective inverse agonist for central cannabinoid receptor inhibits mitogen-activated protein kinase activation stimulated by insulin or insulin-like growth factor 1. Evidence for a new model of receptor/ligand interactions. J Biol Chem 272:22330–22339

    Article  PubMed  CAS  Google Scholar 

  • Braun S, Levitzki A (1979) Adenosine receptor permanently coupled to turkey erythrocyte adenylate cyclase. Biochemistry 18:2134–2138

    Article  PubMed  CAS  Google Scholar 

  • Brown PJ, Schonbrunn A (1993) Affinity purification of a somatostatin receptor-G-protein complex demonstrates specificity in receptor-G-protein coupling. J Biol Chem 268:6668–6676

    PubMed  CAS  Google Scholar 

  • Bünemann M, Brandts B, Pott L (1996) Downregulation of muscarinic M2 receptors linked to K+ current in cultured guinea-pig atrial myocytes. J Physiol 494:351–362

    PubMed  Google Scholar 

  • Bünemann M, Bücheler MM, Philipp M et al (2001) Activation and deactivation kinetics of α2A- and α2C-adrenergic receptor-activated G protein-activated inwardly rectifying K+ channel currents. J Biol Chem 276:47512–47517

    Article  PubMed  Google Scholar 

  • Butcher RW, Sneyd JG, Park CR et al (1966) Effect of insulin on adenosine 3',5'-monophosphate in the rat epididymal fat pad. J Biol Chem 241:1651–1653

    PubMed  CAS  Google Scholar 

  • Chiu TT, Yung LY, Wong YH (1996) Inverse agonistic effect of ICI-174,864 on the cloned δ-opioid receptor: role of G protein and adenylyl cyclase activation. Mol Pharm 50:1651–1657

    CAS  Google Scholar 

  • Citri Y, Schramm M (1980) Resolution, reconstitution and kinetics of the primary action of a hormone receptor. Nature 287:297–300

    Article  PubMed  CAS  Google Scholar 

  • Cuatrecasas P (1975) Hormone receptors—their function in cell membranes and some problems related to methodology. Adv Cycl Nucl Res 5:79–104

    CAS  Google Scholar 

  • De Lean A, Stadel JM, Lefkowitz RJ (1980) A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled β-adrenergic receptor. J Biol Chem 255:7108–7117

    PubMed  Google Scholar 

  • Dowal L, Provitera P, Scarlata S (2006) Stable association between Gαq and phospholipase Cβ1 in living cells. J Biol Chem 281:23999–24014

    Article  PubMed  CAS  Google Scholar 

  • Dupre DJ, Robitaille M, Ethier N et al (2006) Seven transmembrane receptor core signaling complexes are assembled prior to plasma membrane trafficking. J Biol Chem 281:34561–34573

    Article  PubMed  CAS  Google Scholar 

  • Eidne KA, Kroeger KM, Hanyaloglu AC (2002) Applications of novel resonance energy transfer techniques to study dynamic hormone receptor interactions in living cells. Trends Endocrinol Metab 13:415–421

    Article  PubMed  CAS  Google Scholar 

  • Falcón J, Privat K, Ravault JP (1997) Binding of an adenosine A1 receptor agonist and adenosine A1 receptor antagonist to sheep pineal membranes. Eur J Pharmacol 337:325–331

    Article  PubMed  Google Scholar 

  • Fung B, Stryer L (1980) Photolyzed rhodopsin catalyzes the exchange of GTP for bound GDP in retinal rod outer segments. Proc Natl Acad Sci U S A 77:2500–2504

    Article  CAS  Google Scholar 

  • Gales C, Rebois RV, Hogue M et al (2005) Real-time monitoring of receptor and G-protein interactions in living cells. Nat Methods 2:177–184

    Article  PubMed  CAS  Google Scholar 

  • Gales C, Van Durm JJ, Schaak S et al (2006) Probing the activation-promoted structural rearrangements in preassembled receptor–G protein complexes. Nat Struct Biol 13:778–786

    Article  CAS  Google Scholar 

  • Golebiewska U, Scarlata S (2008) Gαq binds two effectors separately in cells: evidence for pre-determined signaling pathways. Biophys J 95:2575–2582

    Google Scholar 

  • Gu YZ, Schonbrunn A (1997) Coupling specificity between somatostatin receptor sst2A and G proteins: isolation of the receptor–G protein complex with a receptor antibody. J Mol Endocrinol 11:527–537 (Baltimore, MD)

    Article  CAS  Google Scholar 

  • Hakak Y, Shrestha D, Goegel MC et al (2003) Global analysis of G-protein-coupled receptor signaling in human tissues. FEBS J 550:11–17

    Article  CAS  Google Scholar 

  • Heck M, Hofmann KP (2001) Maximal rate and nucleotide dependence of rhodopsin-catalyzed transducin activation: initial rate analysis based on a double displacement mechanism. J Biol Chem 276:10000–10009

    Article  PubMed  CAS  Google Scholar 

  • Hein P, Frank M, Hoffmann C et al (2005) Dynamics of receptor/G protein coupling in living cells. EMBO J 24:4106–4114

    Article  PubMed  CAS  Google Scholar 

  • Huang C, Duncan JA, Gilman AG et al (1999) Persistent membrane association of activated and depalmitoylated G protein α subunits. Proc Natl Acad Sci U S A 96:412–417

    Article  PubMed  CAS  Google Scholar 

  • Hynes TR, Mervine SM, Yost EA, Sabo JL, Berlot CF (2004) Live cell imaging of Gs and the β2-adrenergic receptor demonstrates that both αs and β1γ7 internalize upon stimulation and exhibit similar trafficking patterms that differ from that of the β2-adrenergic receptor. J Biol Chem 279:44101–44112

    Article  PubMed  CAS  Google Scholar 

  • Jacobs S, Cuatrecasas P (1976) The mobile receptor hypothesis and “cooperativity” of hormone binding. Application to insulin. Biochim Biophys Acta 433:482–495

    Article  PubMed  CAS  Google Scholar 

  • Jockers R, Linder ME, Hohenegger M et al (1994) Species difference in the G protein selectivity of the human and bovine A1-adenosine receptor. J Biol Chem 269:32077–32084

    PubMed  CAS  Google Scholar 

  • Keirns JJ, Miki N, Bitensky MW et al (1975) A link between rhodopsin and disc membrane cyclic nucleotide phosphodiesterase. Action spectrum and sensitivity to illumination. Biochemistry 14:2760–2766

    Article  PubMed  CAS  Google Scholar 

  • Kenakin TP (1984) The classification of drugs and drug receptors in isolated tissues. Pharmacol Rev 36:165–222

    PubMed  CAS  Google Scholar 

  • Lachance M, Ethier N, Wolbring G et al (1999) Stable association of G proteins with β2AR is independent of the state of receptor activation. Cell Signal 11:523–533

    Article  PubMed  CAS  Google Scholar 

  • Law SF, Reisine T (1992) Agonist binding to rat brain somatostatin receptors alters the interaction of the receptors with guanine nucleotide-binding regulatory proteins. Mol Pharmacol 42:398–402

    PubMed  CAS  Google Scholar 

  • Law SF, Reisine T (1997) Changes in the association of G protein subunits with the cloned mouse δ opioid receptor on agonist stimulation. J Pharmacol Exp Ther 281:1476–1486

    PubMed  CAS  Google Scholar 

  • Law SF, Yasuda K, Bell GI et al (1993) Giα3 and Goα selectively associate with the cloned somatostatin receptor subtype SSTR2. J Biol Chem 268:10721–10727

    PubMed  CAS  Google Scholar 

  • Lee TW, Seifert R, Guan X et al (1999) Restricting the mobility of Gsα: impact on receptor and effector coupling. Biochemistry 38:13801–13809

    Article  PubMed  CAS  Google Scholar 

  • Lefkowitz RJ, De Lean A, Hoffman BB et al (1981) Molecular pharmacology of adenylate cyclase-coupled α- and β-adrenergic receptors. Adv Cycl Nucl Res 14:145–161

    CAS  Google Scholar 

  • Levitzki A (1982) Activation and inhibition of adenylate cyclase by hormones: mechanistic aspects. Trends Pharmacol Sci 3:203–208

    Article  CAS  Google Scholar 

  • Lober RM, Pereira MA, Lambert NA (2006) Rapid activation of inwardly rectifying potassium channels by immobile G-protein-coupled receptors. J Neurosci 26:12602–12608

    Article  PubMed  CAS  Google Scholar 

  • Matesic DF, Manning DR, Wolfe BB et al (1989) Pharmacological and biochemical characterization of complexes of muscarinic acetylcholine receptor and guanine nucleotide-binding protein. J Biol Chem 264:21638–21645

    PubMed  CAS  Google Scholar 

  • McArdle H, Mullaney I, Magee A et al (1988) GTP analogues cause release of the α subunit of the GTP binding protein, Go, from the plasma membrane of NG108-15 cells. Biochem Biophys Res Commun 152:243–251

    Article  PubMed  CAS  Google Scholar 

  • Milligan G, Mullaney I, Unson CG et al (1988) GTP analogues promote release of the α subunit of the guanine nucleotide binding protein, Gi2, from membranes of rat glioma C6 BU1 cells. Biochem J 254:391–396

    PubMed  CAS  Google Scholar 

  • Mueller H, Weingarten R, Ransnas LA et al (1991) Differential amplification of antagonistic receptor pathways in neutrophils. J Biol Chem 266:12939–12943

    PubMed  CAS  Google Scholar 

  • Nanoff C, Mitterauer T, Roka F et al (1995) Species differences in A1 adenosine receptor/G protein coupling: identification of a membrane protein that stabilizes the association of the receptor/G protein complex. Mol Pharmacol 48:806–817

    PubMed  CAS  Google Scholar 

  • Neubig RR (1994) Membrane organization in G-protein mechanisms. FASEB J 8:939–946

    PubMed  CAS  Google Scholar 

  • Nickerson M (1956) Receptor occupancy and tissue response. Nature 178:697–698

    Article  PubMed  CAS  Google Scholar 

  • Nobles M, Benians A, Tinker A (2005) Heterotrimeric G proteins precouple with G protein-coupled receptors in living cells. Proc Natl Acad Sci U S A 102:18706–18711

    Article  PubMed  CAS  Google Scholar 

  • Offermanns S (2003) G-proteins as transducers in transmembrane signalling. Prog Biophys Mol Biol 83:101–130

    Article  PubMed  CAS  Google Scholar 

  • Okuma Y, Reisine T (1992) Immunoprecipitation of α2a-adrenergic receptor-GTP-binding protein complexes using GTP-binding protein selective antisera. Changes in receptor/GTP-binding protein interaction following agonist binding. J Biol Chem 267:14826–14831

    PubMed  CAS  Google Scholar 

  • Orly J, Schramm M (1976) Coupling of catecholamine receptor from one cell with adenylate cyclase from another cell by cell fusion. Proc Natl Acad Sci U S A 73:4410–4414

    Article  PubMed  CAS  Google Scholar 

  • Pfeuffer T, Helmreich EJ (1975) Activation of pigeon erythrocyte membrane adenylate cyclase by guanylnucleotide analogues and separation of a nucleotide binding protein. J Biol Chem 250:867–876

    PubMed  CAS  Google Scholar 

  • Philip F, Sengupta P, Scarlata S (2007) Signaling through a G Protein-coupled receptor and its corresponding G protein follows a stoichiometrically limited model. J Biol Chem 282:19203–19216

    Article  PubMed  CAS  Google Scholar 

  • Qin K, Sethi PR, Lambert NA (2008) Abundance and stability of complexes containing inactive G protein-coupled receptors and G proteins. FASEB J 22:2920–2927

    Article  PubMed  CAS  Google Scholar 

  • Ransnäs LA, Insel PA (1988) Quantitation of the guanine nucleotide binding regulatory protein Gs in S49 cell membranes using antipeptide antibodies to αs. J Biol Chem 263:9482–9485

    PubMed  Google Scholar 

  • Ransnäs LA, Svoboda P, Jasper JR et al (1989) Stimulation of β-adrenergic receptors of S49 lymphoma cells redistributes the alpha subunit of the stimulatory G protein between cytosol and membranes. Proc Natl Acad Sci U S A 86:7900–7903

    Article  PubMed  Google Scholar 

  • Rebois RV, Robitaille M, Gales C et al (2006) Heterotrimeric G proteins form stable complexes with adenylyl cyclase and Kir3.1 channels in living cells. J Cell Sci 119:2807–2818

    Article  PubMed  CAS  Google Scholar 

  • Riven I, Iwanir S, Reuveny E (2006) GIRK channel activation involves a local rearrangement of a preformed G protein channel complex. Neuron 51:561–573

    Article  PubMed  CAS  Google Scholar 

  • Robison GA, Butcher RW, Sutherland EW (1967) Adenyl cyclase as an adrenergic receptor. Ann N Y Acad Sci 139:703–723

    Article  PubMed  CAS  Google Scholar 

  • Rodbell M, Birnbaumer L, Pohl SL (1970) Adenyl cyclase in fat cells. 3. Stimulation by secretin and the effects of trypsin on the receptors for lipolytic hormones. J Biol Chem 245:718–722

    PubMed  CAS  Google Scholar 

  • Ross EM (1981) Physical separation of the catalytic and regulatory proteins of hepatic adenylate cyclase. J Biol Chem 1981:1949–1953

    Google Scholar 

  • Ross EM (1982) Phosphatidylcholine-promoted interaction of the catalytic and regulatory proteins of adenylate cyclase. J Biol Chem 257:10751–10758

    PubMed  CAS  Google Scholar 

  • Ross EM, Gilman AG (1977) Resolution of some components of adenylate cyclase necessary for catalytic activity. J Biol Chem 252:6966–6969

    PubMed  CAS  Google Scholar 

  • Samama P, Cotecchia S, Costa T et al (1993) A mutation-induced activated state of the β2-adrenergic receptor. Extending the ternary complex model. J Biol Chem 268:4625–4636

    PubMed  CAS  Google Scholar 

  • Seifert R, Lee TW, Lam VT, Kobilka BK (1998) Reconstitution of β2 adrenoceptor-GTP-binding-protein interaction in Sf9 cells–high coupling efficiency in a β2-adrenoceptor-Gsα fusion protein. Eur J Biochem 255:369–382

    Article  PubMed  CAS  Google Scholar 

  • Seifert R, Gether U, Wenzel-Seifert K, Kobilka BK (1999) Effects of guanine, inosine, and xanthine nucleotides on β2-adrenergic receptor/Gs interactions: evidence for multiple receptor conformations. Mol Pharm 56:348–358

    CAS  Google Scholar 

  • Senogles SE, Benovic JL, Amlaiky N et al (1987) The D2-dopamine receptor of anterior pituitary is functionally associated with a pertussis toxin-sensitive guanine nucleotide binding protein. J Biol Chem 262:4860–4867

    PubMed  CAS  Google Scholar 

  • Stadel JM, DeLean A, Lefkowitz RJ (1980) A high affinity agonist-β-adrenergic receptor complex is an intermediate for catecholamine stimulation of adenylate cyclase in turkey and frog erythrocyte membranes. J Biol Chem 255:1436–1441

    PubMed  CAS  Google Scholar 

  • Stiles GL (1988) A1 adenosine receptor-G protein coupling in bovine brain membranes: effects of guanine nucleotides, salt, and solubilization. J Neurochem 51:1592–1598

    Article  PubMed  CAS  Google Scholar 

  • Ströher M, Nanoff C, Schütz W (1989) Differences in the GTP-regulation of membrane-bound and solubilized A1-adenosine receptors. Naunyn Schmiedebergs Arch Pharmacol 340:87–92

    Article  PubMed  Google Scholar 

  • Szele FG, Pritchett DB (1993) High affinity agonist binding to cloned 5-hydroxytryptamine2 receptors is not sensitive to GTP analogs. Mol Pharmacol 43:915–920

    PubMed  CAS  Google Scholar 

  • Tian WN, Miller DD, Deth RC (2000) Bidirectional allosteric effects of agonists and GTP at α2A/D adrenoceptors. J Pharmacol Exp Ther 292:664–671

    PubMed  CAS  Google Scholar 

  • Tolkovsky AM, Levitzki A (1978a) Mode of coupling between the β-adrenergic receptor and adenylate cyclase in turkey erythrocytes. Biochemistry 17:3795

    Article  PubMed  CAS  Google Scholar 

  • Tolkovsky AM, Levitzki A (1978b) Coupling of a single adenylate cyclase to two receptors: adenosine and catecholamine. Biochemistry 17:3811–3817

    Article  PubMed  CAS  Google Scholar 

  • Vásquez C, Lewis DL (1999) The CB1 cannabinoid receptor can sequester G-proteins, making them unavailable to couple to other receptors. J Neurosci 19:9271–9280

    PubMed  Google Scholar 

  • Wild KD, Fang L, McNutt RW et al (1993) Binding of BW 373U68, a non-peptidic δ opioid receptor agonist, is not regulated by guanine nucleotides and sodium. Eur J Pharmacol 246:289–292

    Article  PubMed  CAS  Google Scholar 

  • Zhang J, Pratt RE (1996) The AT2 receptor selectively associates with Giα2 and Giα3 in the rat fetus. J Biol Chem 271:15026–15033

    Article  PubMed  CAS  Google Scholar 

  • Zhong H, Wade SM, Woolf PJ et al (2003) A spatial focusing model for G protein signals. Regulator of G protein signaling (RGS) protein-mediated kinetic scaffolding. J Biol Chem 278:7278–7284

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

P. Hein is a Feodor Lynen fellow supported by the Alexander von Humboldt Foundation, Germany. M. Bünemann is supported by the Deutsche Forschungsgemeinschaft (SFB487).

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of California at San Francisco, 600 16th St, UCSF MC 2140, Genentech Hall N216P, San Francisco, CA, 94158-2517, USA

    Peter Hein

  2. Department of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany

    Moritz Bünemann

Authors
  1. Peter Hein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Moritz Bünemann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Hein.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hein, P., Bünemann, M. Coupling mode of receptors and G proteins. Naunyn-Schmied Arch Pharmacol 379, 435–443 (2009). https://doi.org/10.1007/s00210-008-0383-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-008-0383-7

Keywords

Search

Navigation