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G Protein-Coupled Receptors Disrupted in Human Genetic Disease

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Pharmacogenomics in Drug Discovery and Development

Part of the book series: Methods in Molecular Biology™ ((MIMB,volume 448))

Summary

Genetic variation in G protein-coupled receptors (GPCRs) results in the disruption of GPCR function in a wide variety of human genetic diseases. In vitro strategies have been used to elucidate the molecular pathologies that underlie naturally occurring GPCR mutations. Various degrees of inactive, overactive, or constitutively active receptors have been identified. These mutations often alter ligand binding, G protein coupling, receptor desensitization, and receptor recycling. The role of inactivating and activating calcium-sensing receptor (CASR) muta tions is discussed with respect to familial hypocalciuric hypercalemia (FHH) and autosomal dominant hypocalemia (ADH). Among ADH mutations, those associ ated with tonic–clonic seizures are discussed. Other receptors discussed include rhodopsin, thyrotropin, parathyroid hormone, melanocortin, follicle-stimulating hormone, luteinizing hormone, gonadotropin-releasing hormone (GnRHR), adren-ocorticotropic hormone, vasopressin, endothelin-β, purinergic, and the G protein associated with asthma (GPRA). Diseases caused by mutations that disrupt GPCR function are significant because they might be selectively targeted by drugs that rescue altered receptors. Examples of drug development based on targeting GPCRs mutated in disease include the calcimimetics used to compensate for some CASR mutations, obesity therapeutics targeting melanocortin receptors, interventions that alter GnRHR loss from the cell surface in idiopathic hypogonadotropic hypogo nadism and novel drugs that might rescue the P2RY12 receptor in a rare bleeding disorder. The discovery of GPRA suggests that drug screens against variant GPCRs may identify novel drugs. This review of the variety of GPCRs that are disrupted in monogenic disease provides the basis for examining the significance of common pharmacogenetic variants.

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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). The Canadian Institutes of Health Research/Epilepsy Canada provided postdoctoral fellowship support to Dr. Thompson.

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Authors and Affiliations

  1. Department of Laboratory Medicine and Pathobiology, Banting Institute, University of Toronto, Toronto, Ontario, Canada

    Miles D. Thompson & David E. C. Cole

  2. Department of Physiology and Obstetrics and Gynecology, University of Toronto, and Neurogenetics Laboratory, Surrey Place Centre, Toronto, Ontario, Canada

    Maire E. Percy

  3. Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada

    W. McIntyre Burnham

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  1. Miles D. Thompson
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  2. Maire E. Percy
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  3. W. McIntyre Burnham
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  4. David E. C. Cole
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Editors and Affiliations

  1. PharmTao, Santa Clara, CA, USA

    Qing Yan

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Thompson, M.D., Percy, M.E., Burnham, W.M., Cole, D.E. (2008). G Protein-Coupled Receptors Disrupted in Human Genetic Disease. 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_7

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  • DOI: https://doi.org/10.1007/978-1-59745-205-2_7

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-887-4

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