Abstract
Heteromers of G protein-coupled receptors offer the potential for a vast array of signaling partners. Research over the last decade has focused on identifying different heteromer complexes and their signaling components in an effort to understand their cellular and physiological functions. Heteromer complexes may serve a modulatory role or form completely novel signaling platforms within the cell. This chapter reviews canonical and biased signaling pathways of GPCR heteromers with a focus on their signaling capabilities and cellular localization.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Oldham WM, Hamm HE. Heterotrimeric G protein activation by G-protein-coupled receptors. Nat Rev Mol Cell Biol. 2008;9:60–71.
Laugwitz KL, et al. The human thyrotropin receptor: a heptahelical receptor capable of stimulating members of all four G protein families. Proc Natl Acad Sci U S A. 1996;93:116–20.
Lefkowitz RJ, Daaka Y, Luttrell LM. Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase a. Nature. 1997;390:88–91.
Okamoto T, et al. Identification of a Gs activator region of the beta 2-adrenergic receptor that is autoregulated via protein kinase A-dependent phosphorylation. Cell. 1991;67:723–30.
Tesmer JJ, Sunahara RK, Gilman AG, Sprang SR. Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS. Science. 1997;278:1907–16.
Slep KC, et al. Structural determinants for regulation of phosphodiesterase by a G protein at 2.0 Å. Nature. 2001;409:1071–7.
Chen Z, Singer WD, Sternweis PC, Sprang SR. Structure of the p115RhoGEF rgRGS domain–Gα13/i1 chimera complex suggests convergent evolution of a GTPase activator. Nat Struct Mol Biol. 2005;12:191–7.
Tesmer VM, Kawano T, Shankaranarayanan A, Kozasa T, Tesmer JJG. Snapshot of activated G proteins at the membrane: the Gαq-GRK2-Gßγ complex. Science (80- ). 2005;310
Smrcka AV. G protein βγ subunits: central mediators of G protein-coupled receptor signaling. Cell Mol life Sci C. 2008;65:2191–214.
Milligan G, Kostenis E. Heterotrimeric G-proteins: a short history. Br J Pharmacol. 2006;147:S46–55.
Dupré DJ, Robitaille M, Rebois RV, Hébert TE. The role of Gbetagamma subunits in the organization, assembly, and function of GPCR signaling complexes. Annu Rev Pharmacol Toxicol. 2009;49:31–56.
Khan SM, et al. The expanding roles of Gβγ subunits in G protein-coupled receptor signaling and drug action. Pharmacol Rev. 2013;65:545–77.
García-Regalado A, et al. G protein-coupled receptor-promoted trafficking of Gbeta1gamma2 leads to AKT activation at endosomes via a mechanism mediated by Gbeta1gamma2-Rab11a interaction. Mol Biol Cell. 2008;19:4188–200.
Navarro G, et al. Quaternary structure of a G-protein-coupled receptor heterotetramer in complex with Gi and Gs. BMC Biol. 2016;14:26.
Pisterzi LF, et al. Oligomeric size of the m2 muscarinic receptor in live cells as determined by quantitative fluorescence resonance energy transfer. J Biol Chem. 2010;285:16723–38.
Patowary S, et al. The muscarinic M 3 acetylcholine receptor exists as two differently sized complexes at the plasma membrane. Biochem J. 2013;452:303–12.
Jonas KC, Fanelli F, Huhtaniemi IT, Hanyaloglu AC. Single molecule analysis of functionally asymmetric G protein-coupled receptor (GPCR) oligomers reveals diverse spatial and structural assemblies. J Biol Chem. 2015;290:3875–92.
Granier S, Kobilka B. A new era of GPCR structural and chemical biology. Nat Chem Biol. 2012;8:670–3.
Manglik A, et al. Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature. 2012;485:321–6.
Nygaard R, et al. The dynamic process of β(2)-adrenergic receptor activation. Cell. 2013;152:532–42.
Kenakin T. Agonist-receptor efficacy II: agonist trafficking of receptor signals. Trends Pharmacol Sci. 1995;16:232–8.
Eason MG, Jacinto MT, Liggett SB. Contribution of ligand structure to activation of alpha 2-adrenergic receptor subtype coupling to Gs. Mol Pharmacol. 1994;45:696–702.
Holloway AC, et al. Side-chain substitutions within angiotensin II reveal different requirements for signaling, internalization, and phosphorylation of type 1A angiotensin receptors. Mol Pharmacol. 2002;61
Wei H, et al. Independent beta-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2. Proc Natl Acad Sci U S A. 2003;100:10782–7.
Rajagopal K, et al. Beta-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes. Proc Natl Acad Sci U S A. 2006;103:16284–9.
Violin JD, Crombie AL, Soergel DG, Lark MW. Biased ligands at G-protein-coupled receptors: promise and progress. Trends Pharmacol Sci. 2014;35:308–16.
Kalso E, Edwards JE, Moore AR, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. 2004;112:372–80.
Bohn LM, et al. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science. 1999;286:2495–8.
Bohn LM, Gainetdinov RR, Lin F-T, Lefkowitz RJ, Caron MG. |[mu]|-opioid receptor desensitization by |[beta]|-arrestin-2 determines morphine tolerance but not dependence. Nature. 2000;408:720–3.
DeWire SM, et al. A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared to morphine. J Pharmacol Exp Ther. 2013;
Soergel DG, et al. Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: a randomized, double-blind, placebo-controlled, crossover study in healthy volunteers. Pain. 2014;155:1829–35.
Violin JD, Crombie AL, Soergel DG, Lark MW. Biased ligands at G-protein-coupled receptors: promise and progress. Trends Pharmacol Sci. 2014;35:308–16.
Canals M, Sexton PM, Christopoulos A. Allostery in GPCRs: ‘MWC’ revisited. Trends Biochem Sci. 2011;36:663–72.
Wootten D, Christopoulos A, Sexton PM. Emerging paradigms in GPCR allostery: implications for drug discovery. Nat Rev Drug Discov. 2013;12:630–44.
Viñals X, et al. Cognitive impairment induced by Delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid cb1 and serotonin 5-HT2A receptors. PLoS Biol. 2015;13:e1002194.
Ferré S, et al. Building a new conceptual framework for receptor heteromers. Nat Chem Biol. 2009;5:131–4.
Ferrada C, et al. Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors. Br J Pharmacol. 2009;157:64–75.
Lefkowitz RJ, Shenoy SK. Transduction of receptor signals by beta-arrestins. Science. 2005;308:512–7.
Shenoy SK, Lefkowitz RJ. β-arrestin-mediated receptor trafficking and signal transduction. Trends Pharmacol Sci. 2011;32:521–33.
Rajagopal S, et al. Beta-arrestin- but not G protein-mediated signaling by the “decoy” receptor CXCR7. Proc Natl Acad Sci U S A. 2010;107:628–32.
Levoye A, Balabanian K, Baleux F, Bachelerie F, Lagane B. CXCR7 heterodimerizes with CXCR4 and regulates CXCL12-mediated G protein signaling. Blood. 2009;113
Décaillot FM, et al. CXCR7/CXCR4 heterodimer constitutively recruits beta-arrestin to enhance cell migration. J Biol Chem. 2011;286:32188–97.
Bellot M, et al. Dual agonist occupancy of AT1-R–α2C-AR heterodimers results in atypical Gs-PKA signaling. Nat Chem Biol. 2015;11:271–9.
Hanyaloglu, A. C. & Zastrow, M. von. Regulation of GPCRs by endocytic membrane trafficking and its potential implications. Annu Rev Pharmacol Toxicol 48, 537–568 (2008).
Sorkin A, von Zastrow M. Endocytosis and signalling: intertwining molecular networks. Nat Rev Mol Cell Biol. 2009;10:609–22.
Roed SN, et al. Functional consequences of glucagon-like peptide-1 receptor cross-talk and trafficking. J Biol Chem. 2015;290:1233–43.
Uto-Konomi A, et al. CXCR7 agonists inhibit the function of CXCL12 by down-regulation of CXCR4. Biochem Biophys Res Commun. 2013;431
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing AG
About this chapter
Cite this chapter
McCormick, P.J., Botta, J. (2017). Heteromers Form Novel Signaling Complexes. In: Herrick-Davis, K., Milligan, G., Di Giovanni, G. (eds) G-Protein-Coupled Receptor Dimers. The Receptors, vol 33. Humana Press, Cham. https://doi.org/10.1007/978-3-319-60174-8_19
Download citation
DOI: https://doi.org/10.1007/978-3-319-60174-8_19
Published:
Publisher Name: Humana Press, Cham
Print ISBN: 978-3-319-60172-4
Online ISBN: 978-3-319-60174-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)