- Review Article
- Published:
Oligomerization of G-protein-coupled transmitter receptors
Nature Reviews Neurosciencevolume 2, pages274–286 (2001)Cite this article
3767Accesses
7Altmetric
Key Points
Since their biochemical purification in the 1970s and molecular cloning in the late 1980s, G-protein-coupled receptors (GPCRs) have generally been shown as monomeric transmembrane proteins that allosterically interact with heterotrimeric G proteins upon ligand binding. However, the complexity of radio-ligand binding properties of some receptors, combined with indirect biochemical data, provide evidence that GPCRs exist as oligomeric complexes.
The observation that receptor mutants can have dominant-negative effect on wild-type receptors, and that receptor function can be rescued by coexpressing receptors inactivated by mutations in distinct domains, implied that GPCRs can function as dimers. Co-immunoprecipitation of differentially tagged receptors provided the first direct biochemical evidence for this; however, GPCRs are very hydrophobic and could form artefactual aggregates resembling dimers. Biophysical approaches such as bioluminescence or fluorescence energy transfer (BRET or FRET) have confirmed that GPCRs exist as dimers in living cells.
The metabotropic GABAB receptor illustrates a convincing role for GPCR dimerization. The expression of a functional GABAB receptor at the cell surface depends entirely on heterodimerization between the GABABR1 and GABABR2 isoforms. When these are co-expressed, the heterodimer formed is trafficked at the cell surface as a functional receptor, indicating that dimerization could play a role in both chaperoning and signalling. Additional evidence for a role of dimerization in signal transduction includes the observation that preventing dimer formation abrogates β2-adrenergic receptor signal transduction.
Heterodimers can form between other receptor subtypes; for example, between δ- and μ- or κ-opioid receptors, or between receptors for different transmitters; for example, between the dopamine and somatostatin, the angiotensin and bradykinin, and the opioid and adrenergic receptors. Heterodimerization often gives different pharmacological and/or functional properties to the individual receptors, implying a diversity that was not anticipated. Heterodimerization might also be one of the mechanisms underlying cross-talk signalling between receptor systems.
Heterodimerization between GPCRs and non-GPCR proteins is also important. For the calcitonin-receptor-like-receptor, stable association with receptor-activity-modifying-proteins (RAMPs) is necessary for cell-surface targeting and determines its pharmacological properties. A direct interaction between a dopamine receptor and the ionotropic GABAA receptor leads to a reciprocal regulation of the two receptors. Heterotypic oligomeric assemblies might be the rule rather than the exception in GPCR-mediated signalling.
Relatively little is known about the dynamics and regulation of GPCR dimer formation. One of the most debated issues is whether ligands promote assembly or disassembly of dimers, or whether they bind to preformed dimers and change their conformation.
GPCRs might use different dimerization interfaces to associate. For example, hydrophobic packing of transmembrane domains has been suggested for monoamine receptors such as the β2-adrenergic and dopamine receptors. A coiled-coil interaction between the carboxyl-terminal domains causes heterodimerization of GABABR1 and R2, whereas dimers between calcium-sensing and metabotropic glutamate receptors are stabilized by disulphide bonds within their amino-terminal portions. It remains to be determined whether this diversity reflects the existence of multiple sites of interaction for all GPCR dimers, or indicates distinct strategies used by different classes of receptor.
Abstract
Examples of G-protein-coupled receptors that can be biochemically detected in homo- or heteromeric complexes are emerging at an accelerated rate. Biophysical approaches have confirmed the existence of several such complexes in living cells and there is strong evidence to support the idea that dimerization is important in different aspects of receptor biogenesis and function. While the existence of G-protein-coupled-receptor homodimers raises fundamental questions about the molecular mechanisms involved in transmitter recognition and signal transduction, the formation of heterodimers raises fascinating combinatorial possibilities that could underlie an unexpected level of pharmacological diversity, and contribute to cross-talk regulation between transmission systems. Because G-protein-coupled receptors are major pharmacological targets, the existence of dimers could have important implications for the development and screening of new drugs. Here, we review the evidence supporting the existence of G-protein-coupled-receptor dimerization and discuss its functional importance.
This is a preview of subscription content,access via your institution
Access options
Subscription info for Japanese customers
We have a dedicated website for our Japanese customers. Please go tonatureasia.com to subscribe to this journal.
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Suryanarayana, S., Von Zastrow, M. & Kobilka, B. K. Identification of intramolecular interactions in adrenergic receptors.J. Biol. Chem.267, 21991–21994 (1992).
Bockaert, J. & Pin, J. P. Molecular tinkering of G protein-coupled receptors: an evolutionary success.EMBO J.18, 1723–1729 (1999).
Crespo, P., Cachero, T. G., Xu, N. & Gutkind, J. S. Dual effect of β-adrenergic receptors on mitogen-activated protein kinase. J. Biol. Chem.270, 25259–25265 (1995).
Bogoyevitch, M. A. et al. Adrenergic receptor stimulation of the mitogen-activated protein kinase cascade and cardiac hypertrophy.Biochem. J. 314, 115–121 (1996).
Yamamoto, J., Nagao, M., Kaziro, Y. & Itoh, H. Activation of p38 mitogen-activated protein kinase by signaling through G protein-coupled receptors. Involvement of Gi and Gq/11 subunits.J. Biol. Chem. 272, 27771–27777 (1997).
Williams, N. G., Zhong, H. & Minneman, K. P. Differential coupling of α1-, α2-, and β-adrenergic receptors to mitogen-activated protein kinase pathways and differentiation in transfected PC12 cells.J. Biol. Chem.273, 24624–24632 (1998).
Gerhardt, C. C., Gros, J., Strosberg, A. D. & Issad, T. Stimulation of the extracellular signal-regulated kinase 1/2 pathway by human β-3 adrenergic receptor: new pharmacological profile and mechanism of activation .Mol. Pharmacol.55, 255– 262 (1999).
Soeder, K. J. et al. The β-3 adrenergic receptor activates mitogen-activated protein kinase in adipocytes through a Gi-dependent mechanism. J. Biol. Chem.274, 12017–12022 (1999).
van Biesen, T. et al. Receptor-tyrosine-kinase- and Gβγ-mediated MAP kinase activation by a common signalling pathway.Nature 376, 781–784 (1995).
Zou, Y. et al. Both Gs and Gi proteins are critically involved in isoproterenol-induced cardiomyocyte hypertrophy.J. Biol. Chem.274, 9760–9770 ( 1999).
Luttrell, L. M., Della, R. G., van Biesen, T., Luttrell, D. K. & Lefkowitz, R. J. Gβγ subunits mediate Src-dependent phosphorylation of the epidermal growth factor receptor. A scaffold for G protein-coupled receptor-mediated Ras activation.J. Biol. Chem.272, 4637–4644 ( 1997).
Luttrell, L. et al. Beta-arrestin-dependent formation of β-2-adrenergic receptor-Src protein kinase complexes.Science283, 655 –661 (1999).
Hall, R. A. et al. The β-2 adrenergic receptor interacts with the Na/H-exchanger regulatory factor to control NA/H exchange.Nature 329, 626–630 (1998).
Mellado, M. et al. The chemokine monocyte chemotactic protein 1 triggers Janus kinase 2 activation and tyrosine phosphorylation of the CCR2B receptor. J. Immunol.161, 805–813 (1998).
Ali, M. S. et al. Dependence on the motif YIPP for the physical association of Jak2 kinase with the intracellular carboxyl tail of the angiotensin II AT1 receptor.J. Biol. Chem.272, 23382– 23388 (1997).
Wreggett, K. A. & Wells, J. W. Cooperativity manifest in the binding properties of purified cardiac muscarinic receptors .J. Biol. Chem.270, 22488– 22499 (1995).
Heldin, C. H. Dimerization of cell surface receptors in signal transduction. Cell80, 213–223 ( 1995).
Limbird, L. E., Meyts, P. D. & Lefkowitz, R. J. Beta-adrenergic receptors: evidence for negative cooperativity.Biochem. Biophys. Res. Commun.64, 1160–1168 (1975).
Potter, L. T. et al. Evidence for paired M2 muscarinic receptors.Mol. Pharmacol.39, 211–221 ( 1991).
Limbird, L. E. & Lefkowitz, R. J. Negative cooperativity among β-adrenergic receptors in frog erythrocyte membranes .J. Biol. Chem.251, 5007– 5014 (1976).
Mattera, R., Pitts, B. J., Entman, M. L. & Birnbaumer, L. Guanine nucleotide regulation of a mammalian myocardial muscarinic receptor system. Evidence for homo- and heterotropic cooperativity in ligand binding analysed by computer-assisted curve fitting.J. Biol. Chem. 260, 7410–7421 (1985).
Hirschberg, B. T. & Schimerlik, M. I. A kinetic model for oxotremorine M binding to recombinant porcine m2 muscarinic receptors expressed in Chinese hamster ovary cells.J. Biol. Chem. 269, 26127–26135 (1994).
Seeman, P. et al. The cloned dopamine D2 receptor reveals different densities for dopamine receptor antagonist ligands. Implications for human brain positron emission tomography.Eur. J. Pharmacol.227, 139–146 (1992).
Avissar, S., Amitai, G. & Sokolovsky, M. Oligomeric structure of muscarinic receptors is shown by photoaffinity labeling: subunit assembly may explain high- and low-affinity agonist states.Proc. Natl Acad. Sci. USA80, 156–159 (1983).
Fraser, C. M. & Venter, J. C. The size of the mammalian lung β-2-adrenergic receptor as determined by target size analysis and immunoaffinity chromatography .Biochem. Biophys. Res. Commun.109, 21 –29 (1982).
Venter, J. C., Schaber, J. S., U' Prichard, D. C. & Fraser, C. M. Molecular size of the human platelet α2-adrenergic receptor as determined by radiation inactivation.Biochem. Biophys. Res. Commun. 116, 1070–1075 (1983).
Venter, J. C., Horne, P., Eddy, B., Greguski, R. & Fraser, C. M. Alpha 1-adrenergic receptor structure. Mol. Pharmacol.26, 196–205 (1984).
Crine, P., Aubry, M. & Potier, M. Incorporation of radiolabeled amino acids into protein subunits of the rat leydig cell gonadotropin receptor: application to the study of receptor structure and turnover.Ann. NY Acad. Sci. 438, 224–236 (1984).
Conn, P. M. & Venter, J. C. Radiation inactivation (target size analysis) of the gonadotropin-releasing hormone receptor: evidence for a high molecular weight complex.Endocrinology116, 1324–1326 (1985).
Bouvier, C. et al. Solubilization and characterization of D2-dopamine receptors in an estrone-induced, prolactin-secreting rat pituitary adenoma. J. Neurochem.47, 1653–1660 (1986).
Frame, L. T., Yeung, S. M., Venter, J. C. & Cooper, D. M. Target size of the adenosine R1 receptor.Biochem. J. 235, 621–624 (1986).
Herberg, J. T., Codina, J., Rich, K. A., Rojas, F. J. & Iyengar, R. The hepatic glucagon receptor. Solubilization, characterization, and development of an affinity adsorption assay for the soluble receptor. J. Biol. Chem.259, 9285–9294 (1984).
Peterson, G. L., Rosenbaum, L. C., Broderick, D. J. & Schimerlick, M. I. Physical properties of the purified cardiac muscarinic acetylcholine receptor .Biochemistry25, 3189– 3202 (1986).
Maggio, R., Vogel, Z. & Wess, J. Co-expression studies with mutant muscarinic/adrenergic receptors provide evidence for intermolecular 'cross-talk' between G-protein-linked receptors .Proc. Natl Acad. Sci. USA90, 3103– 3107 (1993).Using α2-adrenergic/M3 muscarinic chimeric proteins, this study documented the occurrence of intermolecular functional complementation indicating that G-protein-coupled receptors can function as dimeric entities.
Monnot, C. et al. Polar residues in the transmembrane domain of the type 1 angiotensin II receptor are required for binding and coupling. Reconstitution of the binding site by co-expression of two deficient mutants.J. Biol. Chem.271, 1507–1513 ( 1996).
Bai, M., Trivedi, S., Kifor, O., Quinn, S. J. & Brown, E. M. Intermolecular interactions between dimeric calcium-sensing receptor monomers are important for its normal function.Proc. Natl Acad. Sci. USA96, 2834–2839 (1999).
Bai, M. et al. Expression and characterization of inactivating and activating mutations in the human Ca2+-sensing receptor.J. Biol. Chem.271, 19537–19545 (1996).
Zhu, X. & Wess, J. Truncated V2 vasopressin receptors as negative regulators of wild-type V2 receptor function.Biochemistry37, 15773–15784 ( 1998).
Benkirane, M., Jin, D. Y., Chun, R. F., Koup, R. A. & Jeang, K. T. Mechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by ccr5delta32.J. Biol. Chem.272, 30603–30606 (1997).
Rodriguez-Frade, J. M. et al. The chemokine monocyte chemoattractant protein-1 induces functional responses through dimerization of its receptor CCR2.Proc. Natl Acad. Sci. USA96, 3628–3633 (1999).
Overton, M. C. & Blumer, K. J. G Protein coupled receptors function as oligomersin vivo.Curr. Biol. 10, 341–344 (2000). Using non-disruptive bioluminescence and fluorescence resonance energy transfer approaches, this paper and references54 and57 all demonstrated simultaneously and independently that G-protein-coupled receptors form dimers in living cells.
Hebert, T. E. et al. A peptide derived from a β2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation.J. Biol. Chem.271, 16384–16392 ( 1996).Using differential epitope tagging and co-immunoprecipitation, this study provided direct biochemical evidence that wild-type G-protein-coupled receptors exist and might function as dimers.
White, J. H. et al. Heterodimerization is required for the formation of a functional GABA(B) receptor.Nature396, 679– 682 (1998).
Jones, K. A. et al. GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2.Nature396, 674–679 (1998).
Kaupmann, K. et al. GABA(B)-receptor subtypes assemble into functional heteromeric complexes.Nature396, 683– 687 (1998).References43–45 showed simultaneously and independently that not only could heterodimerization between GABABR1 and GABABR2 receptors occur, but that it is essential to the formation of a functional receptor expressed at the cell surface.
Romano, C., Yang, W. L. & O'Malley, K. L. Metabotropic glutamate receptor 5 is a disulfide-linked dimer.J. Biol. Chem.271, 28612– 28616 (1996).Biochemical demonstration that dimerization of the metabotropic glutamate receptor involves the formation of disulphide bridges between their large extracellular amino-terminal domains.
Jordan, B. A. & Devi, L. A. G-protein-coupled receptor heterodimerization modulates receptor function.Nature399, 697–700 (1999).A combination of co-immunoprecipitation and pharmacological analysis of coexpressed δ- and κ-opioid receptors suggested for the first time that dimerization between distinct receptor subtypes could lead to the formation of a receptor with unique pharmacological properties.
Bai, M., Trivedi, S. & Brown, E. M. Dimerization of the extracellular calcium-sensing receptor (CaR) on the cell surface of CaR-transfected HEK293 cells. J. Biol. Chem.273, 23605–23610 (1998).
Zeng, F. Y. & Wess, J. Identification and molecular characterization of m3 muscarinic receptor dimers.J. Biol. Chem.274, 19487–19497 (1999).
Furthmayr, H. & Marchesi, V. T. Subunit structure of human erythrocyte glycophorin A.Biochemistry15, 1137– 1144 (1976).
Cvejic, S. & Devi, L. A. Dimerization of the δ-opioid receptor: implication for a role in receptor internalization. J. Biol. Chem.272, 26959–26964 (1997).
Ciruela, F. et al. Immunological identification of A1 adenosine receptors in brain cortex.J. Neurosci. Res.42, 818– 828 (1995).
Ng, G. Y.et al. Dopamine D2 receptor dimers and receptor-blocking peptides. Biochem. Biophys. Res. Commun.227, 200– 204 (1996).
Angers, S. et al. Detection of β2-adrenergic receptor dimerization in living cells using bioluminescence resonance energy transfer (BRET). Proc. Natl Acad. Sci. USA97, 3684– 3689 (2000).
McVey, M.et al. Monitoring receptor oligomerization using time-resolved fluorescence resonance energy transfer and bioluminescence resonance energy transfer: The human δ-opioid receptor displays constitutive oligomerization at the cell surface which is not regulated by receptor occupancy.J. Biol. Chem. (in the press).
Kroeger, K. M., Hanyaloglu, A. C., Seeber, R. M., Miles, L. E. C. & Eidne, K. A. Constitutive and agonist-dependent homo-oligomerizationof the thyrotropin-releasing hormone receptor; detection in living cells using bioluminescence resonance energy transfer.J. Biol. Chem. (in the press).
Rocheville, M. et al. Subtypes of the somatostatin receptor assemble as functional homo-and heterodimers.J. Biol. Chem.275, 7862–7869 (2000).
Roess, D. A., Horvat, R. D., Munnelly, H. & Barisas, B. G. Luteinizing hormone receptors are self-associated in the plasma membrane. Endocrinology141, 4518–4523 (2000).
Bond, R. A. & Bouvier, M.Receptor-based Drug Design (ed. Leff, P.) 363–377 (Marcel Dekker, New York, 1998).
Ng, G. Y.et al. Identification of a GABAB receptor subunit, gb2, required for functional GABAB receptor activity.J. Biol. Chem.274, 7607–7610 ( 1999).
Kuner, R.et al. Role of heteromer formation in GABAB receptor function .Science283, 74–77 (1999).
Couve, A.et al. Intracellular retention of recombinant GABAB receptors .J. Biol. Chem.273, 26361– 26367 (1998).
Margeta-Mitrovic, M., Jan, Y. N. & Jan, L. Y. A trafficking checkpoint controls GABA(B) receptor heterodimerization .Neuron27, 97–106 (2000).Identification of an endoplasmic retention signal within the carboxyl tail of the GABABR1 that is masked by heterodimerization with GABABR2. In addition to highlighting the importance of dimerization for the transport of G-protein-coupled receptors, this paper also shows that GABAB receptor heterodimerization is required for function once it has reached the cell surface.
Morello, J. P. et al. Pharmacological chaperones rescue cell-surface expression and function of misfolded V2 vasopressin receptor mutants.J. Clin. Invest.105, 887–895 ( 2000).
Deng, H.et al. Identification of a major co-receptor for primary isolates of HIV-1.Nature381, 661– 666 (1996).
Samson, M. et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene.Nature 382, 722–725 (1996).
Liu, R. et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection.Cell 86, 367–377 (1996).
Karpa, K. D., Lin, R., Kabbani, N. & Levenson, R. The dopamine D3 receptor interacts with itself and the truncated D3 splice variant d3nf: D3-D3nf interaction causes mislocalization of D3 receptors.Mol. Pharmacol.58, 677–683 ( 2000).
Nimchinsky, E. A., Hof, P. R., Janssen, W. G. M., Morrison, J. H. & Schmauss, C. Expression of dopamine D3 receptor dimers and tetramers in brain and in transfected cells.J. Biol. Chem.272, 29229–29237 ( 1997).
George, S. R. et al. A transmembrane domain-derived peptide inhibits D1 dopamine receptor function without affecting receptor oligomerization. J. Biol. Chem.273, 30244–30248 (1998).
Mijares, A., Lebesgue, D., Wallukat, G. & Hoebeke, J. From agonist to antagonist: Fab fragments of an agonist-like monoclonal anti-β2-adrenoceptor antibody behave as antagonists.Mol. Pharmacol.58, 373–379 (2000).
Conn, P. M., Rogers, D. C., Stewart, J. M., Niedel, J. & Sheffield, T. Conversion of a gonadotropin-releasing hormone antagonist to an agonist.Nature296, 653–655 (1982).
Hazum, E. & Keinan, D. Gonadotropin releasing hormone activation is mediated by dimerization of occupied receptors.Biochem. Biophys. Res. Commun.133, 449–456 (1985).
Gregory, H., Taylor, C. L. & Hopkins, C. R. Luteinizing hormone release from dissociated pituitary cells by dimerization of occupied LHRH receptors.Nature 300, 269–271 (1982).
Carrithers, M. D. & Lerner, M. R. Synthesis and characterization of bivalent peptide ligands targeted to G-protein-coupled receptors.Chem. Biol.3, 537– 542 (1996).
Vila-Coro, A. J. et al. HIV-1 infection through the CCR5 receptor is blocked by receptor dimerization.Proc. Natl Acad. Sci. USA97, 3388–3393 (2000).
Zukin, R. S., Eghbali, M., Olive, D., Unterwald, E. M. & Tempel, A. Characterization and visualization of rat and guinea pig brain κ-opioid receptors: evidence for κ1 and κ2 opioid receptors.Proc. Natl Acad. Sci. USA85, 4061–4065 (1988).
AbdAlla, S., Lother, H. & Quitterer, U. AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration.Nature407, 94–98 (2000).
Gines, S.et al. Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes.Proc. Natl Acad. Sci. USA97, 8606–8611 (2000).
George, S. R. et al. Oligomerization of μ- and δ-opioid receptors. Generation of novel functional properties.J. Biol. Chem.275, 26128–26135 (2000).
Rocheville, M. et al. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity.Science288, 154–157 (2000).
Jordan, B. A., Trapaidze, N., Gomes, I., Nivarthi, R. & Devi, L. A. Oligomerization of opioid receptors with β2-adrenergic receptors: a role in trafficking and mitogen-activated protein kinase activation .Proc. Natl Acad. Sci. USA98, 343– 348 (2001).
Jordan, B. A. & Devi, L. A. G-protein-coupled receptor heterodimerization modulates receptor function.Nature399, 697–700 (1999).
Zeng, F. Y. & Wess, J. Identification and molecular characterization of m3 muscarinic receptor dimers.J. Biol. Chem.274, 19487–19497 (1999).
Cornea, A., Janovick, J. A., Maya-Nunez, G. & Conn, P. M. Gonadotropin releasing hormone microaggregation: rate monitored by fluorescence resonance energy transfer.J. Biol. Chem. (in the press).
Kunishima, N. et al. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor.Nature407, 971– 977 (2000).The resolution of the three-dimensional structure of the ligand-binding domain of the metabotropic glutamate receptor revealed that it is a dimer both in the presence and absence of glutamate, indicating that G-protein-coupled receptors might be constitutive dimers.
Tsuji, Y.et al. Cryptic dimer interface and domain organization of the extracellular region of metabotropic glutamate receptor subtype 1.J. Biol. Chem.275, 28144–28151 ( 2000).
Ray, K. & Hauschild, B. C. Cys-140 is critical for metabotropic glutamate receptor-1 dimerization.J. Biol. Chem.275, 34245–34251 (2000).
Romano, C. et al. Covalent and noncovalent interactions mediate metabotropic glutamate receptor mGlu(5) dimerization.Mol. Pharmacol. 59, 46–53 (2001).
Zhang, Z., Sun, S., Quinn, S. J., Brown, E. M. & Bai, M. The extracellular calcium-sensing receptor dimerizes through multiple types of intermolecular interactions.J. Biol. Chem. (2000).
Lemmon, M. A. et al. Glycophorin A dimerization is driven by specific interactions between transmembrane alpha-helices.J. Biol. Chem. 267, 7683–7689 (1992).
Lemmon, M. A. & Engelman, D. M. Specificity and promiscuity in membrane helix interactions.FEBS Lett.346, 17–20 (1994).
Gouldson, P. R. et al. Dimerization and domain swapping in G-protein-coupled receptors. A computational study.Neuropsychopharmacology23, S60–S77 (2000).
Ng, G. Y.et al. Gamma-aminobutyric acid type B receptors with specific heterodimer composition and postsynaptic actions in hippocampal neurons are targets of anticonvulsant gabapentin action.Mol. Pharmacol.59, 144–152 (2001). This paper describes the formation of heterodimers between GABABR2 and different splice variants of the GABABR1, leading to receptors with different pharmacological selectivity to the action of anticonvulsant drugs.
Xu, Y., Piston, D. W. & Johnson, C. H. A bioluminescence resonance energy transfer (BRET) system: application to interacting circadian clock proteins.Proc. Natl Acad. Sci. USA96, 151–156 (1999).
Hovius, R., Vallotton, P., Wohland, T. & Vogel, H. Fluorescence techniques: shedding light on ligand-receptor interactions. Trends Pharmacol. Sci.21, 266–273 (2000).
Njuki, F.et al. A new calcitonin-receptor-like sequence in rat pulmonary blood vessels.Clin. Sci.85, 385– 388 (1993).
Fluhmann, B., Muff, R., Hunziker, W., Fischer, J. A. & Born, W. A human orphan calcitonin receptor-like structure. Biochem. Biophys. Res. Commun.206, 341– 347 (1995).
McLatchie, L. M. et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor.Nature393, 333–339 (1998).The first demonstration that heterodimerization between a G-protein-coupled receptor (the calcitonin receptor-like receptor) and accessory proteins known as the receptor-activity-modifying proteins (RAMPs) is involved both in the cell-surface transport and the pharmacological properties of the resulting calcitonin-gene-related peptide and adrenomedullin receptors.
Christopoulos, G. et al. Multiple amylin receptors arise from receptor activity-modifying protein interaction with the calcitonin receptor gene product. Mol. Pharmacol.56, 235–242 (1999).
Dwyer, N. D., Troemel, E. R., Sengupta, P. & Bargmann, C. I. Odorant receptor localization to olfactory cilia is mediated by ODR-4, a novel membrane-associated protein.Cell93, 455 –466 (1998).
Liu, F.et al. Direct protein–protein coupling enables cross-talk between dopamine D5 and γ-aminobutyric acid A receptors.Nature 403, 274–280 (2000). This paper reports a physical association between a seven-transmembrane-domain dopamine receptor and a channel GABAA receptor, which leads to reciprocal regulation of the two classes of receptors on co-activation.
Bergson, C. et al. Regional, cellular, and subcellular variations in the distribution of D1 and D5 dopamine receptors in primate brain.J. Neurosci.15, 7821–7836 ( 1995).
Acknowledgements
The author is grateful to Stephane Angers, Ali Salahpour, Jean-François Mercier, Sandrine Hilairet, Lynda Adam and Momique Lagacé for the numerous discussions and their critical reading of the manuscript.
Author information
Authors and Affiliations
Department of Biochemistry and Groupe de Recherche sur le système Nerveux Autonome, Faculté de Médecine Université de Montréal, P.O. Box 6128, Down-Town Station, Montréal, H3C 3J7 , Quebec, Canada
Michel Bouvier
- Michel Bouvier
You can also search for this author inPubMed Google Scholar
Related links
Related links
DATABASE LINKS
gonadotropin-releasing hormone receptor
FURTHER INFORMATION
Domain swapping in G-protein-coupled-receptor dimers
ENCYCLOPEDIA OF LIFE SCIENCES
Glossary
- BIOGENIC AMINES
A series of molecules that can act as neurotransmitters and include noradrenaline and adrenaline.
- ALLOSTERIC
A term to describe proteins that have two or more receptor sites, one of which (the active site) binds the principal substrate, whereas the other(s) bind(s) effector molecules that can influence its biological activity.
- DOMINANT-NEGATIVE
A mutant protein that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.
- SDS–PAGE
(Sodium dodecyl sulphate–polyacrylamide gel electrophoresis). A method for resolving a protein into its subunits and determining their separate molecular weights.
- MOLECULAR CHAPERONE
A protein that assists in the non-covalent assembly of a protein complex but does not participate in its function.
- COILED-COIL INTERACTION
A type of protein–protein interaction that involves interlacing of two helical domains.
- VASOPRESSIN
Antidiuretic hormone.
- FAB FRAGMENT
The antigen-binding portion of an antibody.
- CALCITONIN
A polypeptide hormone, consisting of 32 amino-acid residues, that regulates calcium and phosphate levels in the blood.
- HOMOTROPIC
Interaction between proteins of the same class.
- ADRENOMEDULLIN
A hypotensive peptide hormone secreted by the medulla of the adrenal gland.
- AMYLIN
A peptide consisting of 37 amino-acid residues that is secreted with insulin and might act to modulate its stimulatory effects on glucose metabolism in muscle. Also known as islet amyloid peptide.
- VINBLASTIN
An alkaloid that arrests mitosis in metaphase by binding to spindle microtubules.
- CYTOCHALASIN
Any of a group of fungal metabolites that interfere with the assembly and diassembly of actin filaments. One of the consequences of treating cells with these agents is that cleavage of the cytoplasm after nuclear division is prevented.
- DYNAMIN
A protein involved in the formation of microtubule bundles and in membrane transport.
- PROTOMERS
Identical subunits in an oligomeric protein complex.
- GLYCOPHORIN A
A carbohydrate-rich sialoglycoprotein that is abundant in erythrocyte membranes.
- ANXIOLYTIC AGENT
A drug used to reduce anxiety, such as benzodiazepines.
Rights and permissions
About this article
Cite this article
Bouvier, M. Oligomerization of G-protein-coupled transmitter receptors.Nat Rev Neurosci2, 274–286 (2001). https://doi.org/10.1038/35067575
Issue Date:
Share this article
Anyone you share the following link with will be able to read this content:
Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative
