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Pharmacogenomics in Drug Discovery and Development pp 189–242Cite as

Pharmacogenetics of the G Protein-Coupled Receptors

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

Abstract

Pharmacogenetics investigates the influence of genetic variants on physiological phenotypes related to drug response and disease, while pharmacogenomics takes a genome-wide approach to advancing this knowledge. Both play an important role in identifying responders and nonresponders to medication, avoiding adverse drug reactions, and optimizing drug dose for the individual. G protein-coupled receptors (GPCRs) are the primary target of therapeutic drugs and have been the focus of these studies. With the advance of genomic technologies, there has been a substantial increase in the inventory of naturally occurring rare and common GPCR variants. These variants include single-nucleotide polymorphisms and insertion or deletions that have potential to alter GPCR expression of function. In vivo and in vitro studies have determined functional roles for many GPCR variants, but genetic association studies that define the physiological impact of the majority of these common variants are still limited. Despite the breadth of pharmacogenetic data available, GPCR variants have not been included in drug labeling and are only occasionally considered in optimizing clinical use of GPCR-targeted agents. In this chapter, pharmacogenetic and genomic studies on GPCR variants are reviewed with respect to a subset of GPCR systems, including the adrenergic, calcium sensing, cysteinyl leukotriene, cannabinoid CB1 and CB2 receptors, and the de-orphanized receptors such as GPR55. The nature of the disruption to receptor function is discussed with respect to regulation of gene expression, expression on the cell surface (affected by receptor trafficking, dimerization, desensitization/downregulation), or perturbation of receptor function (altered ligand binding, G protein coupling, constitutive activity). The large body of experimental data generated on structure and function relationships and receptor-ligand interactions are being harnessed for the in silico functional prediction of naturally occurring GPCR variants. We provide information on online resources dedicated to GPCRs and present applications of publically available computational tools for pharmacogenetic studies of GPCRs. As the breadth of GPCR pharmacogenomic data becomes clearer, the opportunity for routine assessment of GPCR variants to predict disease risk, drug response, and potential adverse drug effects will become possible.

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Acknowledgments

This work was supported by the Ontario Brain Institute (OBI)—Eplink: The OBI Epilepsy Project; the Scottish Rite Charitable Foundation of Canada; the National Science and Engineering Research Council (NSERC); the Dairy Farmers of Canada (DFC); the Canadian Institutes of Health Research (CIHR); Epilepsy Canada; and an International Scientific Cooperation grant between the Region of Lombardia, Italy and Canada (ID 16755). We thank Dr. Craig Behnke for permission to adapt the image presented in Figs. 1 and 2.

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Authors and Affiliations

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

    Miles D. Thompson & W. McIntyre Burnham

  2. Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King’s College Circle, Toronto, ON, Canada, M5S 1A8

    David E. C. Cole

  3. Laboratory of Molecular Pharmacology, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy

    Valerie Capra & G. Enrico Rovati

  4. Samuel Lunenfeld Research Institute, Mount Sinai Hospital and University of Toronto, 1 King’s College Circle, Toronto, ON, Canada, M5S 1A8

    Katherine A. Siminovitch

  5. Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA

    Brinda K. Rana

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  1. Miles D. Thompson
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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. et al. (2014). Pharmacogenetics of the G Protein-Coupled Receptors. 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_9

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  • DOI: https://doi.org/10.1007/978-1-4939-0956-8_9

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