Pharmacogenomics of G Protein-Coupled Receptor

Abstract

The identification and characterization of the processes of G protein-coupled receptor (GPCR) activation and inactivation have refined not only the study of the GPCRs but also the genomics of many accessory proteins necessary for these processes. This has accelerated progress in understanding the fundamental mechanisms involved in GPCR structure and function, including receptor transport to the membrane, ligand binding, activation and inactivation by GRK-mediated (and other) phosphorylation. The catalog of G(s)alpha and Gbeta subunit polymorphisms that result in complex phenotypes has complemented the effort to catalog the GPCRs and their variants. The study of the genomics of GPCR accessory proteins has also provided insight into pathways of disease, such as the contributions of regulator of G protein signaling (RGS) protein to hypertension and activator of G protein signaling (AGS) proteins to the response to hypoxia. In the case of the G protein-coupled receptor kinases (GRKs), identified originally in the retinal tissues that converge on rhodopsin, proteins such as GRK4 have been identified that have been subsequently associated with hypertension. Here, we review the structure and function of GPCR and associated proteins in the context of the gene families that encode them and the genetic disorders associated with their altered function. An understanding of the pharmacogenomics of GPCR signaling provides the basis for examining the GPCRs disrupted in monogenic disease and the pharmacogenetics of a given receptor system.