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G Protein-Coupled Receptor Accessory Proteins and Signaling: Pharmacogenomic Insights

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Pharmacogenomics in Drug Discovery and Development

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1175))

Abstract

The identification and characterization of the genes encoding G protein-coupled receptors (GPCRs) and the proteins necessary for the processes of ligand binding, GPCR activation, inactivation, and receptor trafficking to the membrane are discussed in the context of human genetic disease. In addition to functional GPCR variants, the identification of genetic disruptions affecting proteins necessary to GPCR functions have provided insights into the function of these pathways. Gsα and Gβ subunit polymorphisms have been found to result in complex phenotypes. Disruptions in accessory proteins that normally modify or organize heterotrimeric G-protein coupling may also result in disease states. These include the contribution of variants of the regulator of G protein signaling (RGS) protein to hypertension; the role variants of the activator of G protein signaling (AGS) proteins to phenotypes (such as the type III AGS8 variant to hypoxia); the contribution of G protein-coupled receptor kinase (GRK) proteins, such as GRK4, in disorders such as hypertension. The role of accessory proteins in GPCR structure and function is discussed in the context of genetic disorders associated with disruption of the genes that encode them. An understanding of the pharmacogenomics of GPCR and accessory protein signaling provides the basis for examining both GPCR pharmacogenetics and the genetics of monogenic disorders that result from disruption of given receptor systems.

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Acknowledgements

This work was supported by the Ontario Brain Institute (OBI)—Eplink: The OBI Epilepsy Project (MDT); The National Science and Engineering Research Council (NSERC); and the Dairy Farmers of Canada (DFC). The Canadian Institutes of Health Research (CIHR), The Scottish Rite Charitable Foundation of Canada, and Epilepsy Canada supported the work of Miles Thompson. We thank Dr. Craig Behnke for permission to adapt the image presented in Fig. 1.

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Authors and Affiliations

  1. Department of Pharmacology, University of Toronto, 1 King’s College Circle, Toronto, ON, Canada, M5S 1A8

    Miles D. Thompson

  2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    David E. C. Cole

  3. Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    Pedro A. Jose

  4. Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada

    Peter Chidiac

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  1. Miles D. Thompson
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  4. Peter Chidiac
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Correspondence to Miles D. Thompson .

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  1. PharmTao, Santa Clara, California, USA

    Qing Yan

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Thompson, M.D., Cole, D.E.C., Jose, P.A., Chidiac, P. (2014). G Protein-Coupled Receptor Accessory Proteins and Signaling: Pharmacogenomic Insights. In: Yan, Q. (eds) Pharmacogenomics in Drug Discovery and Development. Methods in Molecular Biology, vol 1175. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-0956-8_7

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