Summary
Common G protein-coupled receptor (GPCR) gene variants that encode receptor proteins with a distinct sequence may alter drug efficacy without always resulting in a disease phenotype. GPCR genetic loci harbor numerous variants, such as DNA insertions or deletions and single-nucleotide polymorphisms that alter GPCR expression and function, thereby contributing to interindividual differences in disease susceptibility/progression and drug responses. In this chapter, these pharmacogenetic phenomena are reviewed with respect to a limited sampling of GPCR systems, including the β2-adrenergic receptors, the cysteinyl leukotriene receptors, and the calcium-sensing receptor. In each example, the nature of the disruption to receptor function that results from each variant is discussed with respect to the regulation of gene expression, expression on cell surface (affected by receptor trafficking, dimerization, desensitization/downregulation), or perturbation of receptor function (by altering ligand binding, G protein coupling, and receptor constitutive activity). Despite the breadth of pharmacogenetic knowledge available, assessment for genetic variants is only occasionally applied to drug development projects involving pharmacogenomics or to optimizing the clinical use of GPCR drugs. The continued effort by the basic science of pharmacogenetics may draw the attention of drug discovery projects and clinicians alike to the utility of personalized pharmacogenomics as a means to optimize novel GPCR drug targets.
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Acknowledgments
This work was supported in part by grants from the National Science and Engineering Research Council (NSERC) and the Dairy Farmers of Canada (DFC). A Canadian Institutes of Health Research Award (M.D.T.) also provided support. We thank Dr. Craig Behnke for permission to adapt the images presented in Figs. 8.1 and 8.2. K. Siminovitch is supported by a Canada Research Chair in Immunogenomics and is a McLaughlin Centre of Molecular Medicine Scientist. The work was supported by grant from Ontario Research and Development Challenge Fund.
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Thompson, M.D., Siminovitch, K.A., Cole, D.E.C. (2008). G Protein-Coupled Receptor Pharmacogenetics. In: Yan, Q. (eds) Pharmacogenomics in Drug Discovery and Development. Methods in Molecular Biology™, vol 448. Humana Press. https://doi.org/10.1007/978-1-59745-205-2_8
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