Constitutive activation of G protein-coupled receptors and diseases: insights into mechanisms of activation and therapeutics

Abstract

The existence of constitutive activity for G protein-coupled receptors (GPCRs) was first described in 1980s. In 1991, the first naturally occurring constitutively active mutations in GPCRs that cause diseases were reported in rhodopsin. Since then, numerous constitutively active mutations that cause human diseases were reported in several additional receptors. More recently, loss of constitutive activity was postulated to also cause diseases. Animal models expressing some of these mutants confirmed the roles of these mutations in the pathogenesis of the diseases. Detailed functional studies of these naturally occurring mutations, combined with homology modeling using rhodopsin crystal structure as the template, lead to important insights into the mechanism of activation in the absence of crystal structure of GPCRs in active state. Search for inverse agonists on these receptors will be critical for correcting the diseases cause by activating mutations in GPCRs. Theoretically, these inverse agonists are better therapeutics than neutral antagonists in treating genetic diseases caused by constitutively activating mutations in GPCRs.

Fig. 1

Structure of bovine rhodopsin, with coordinates from PDB entry 1L9H. Shown in A is the overall structure of rhodopsin. Shown in B–D are close-up views of the active site highlighting the locations of the three night blindness mutations: (B) A292, (C) G90, and (D) T94. Reprinted with permission from A. K. Gross et al. 2003. Biochemistry 42:2009–2015. Copyright (2003). American Chemical Society.

Fig. 2

A. Basal activities of L(3.43)R mutants in several GPCRs. Data were obtained from references listed in the article with the exception of MC4R that is my own unpublished data. B. Packing interactions of CAMs, including L124 (3.43), with uncoupling mutations in the β₂-AR. Panel B is reprinted with permission from D. M. Rosenbaum et al. 2007. Science 318:1266–1273. Copyright (2007). AAAS.

Fig. 3

Different susceptibility in rFSHR and hFSHR to D(6.44)G-mutation induced constitutive activation. Panel A showed that two mutations, one in TM6 and one in TM7, can reverse the susceptibility to D(6.44)G-mutation induced constitutive activation. Panel B is a model of the two receptors suggesting that different hydrophobic interactions in TM6 and TM7 might be responsible for the different susceptibility to D(6.44)G-mutation induced constitutive activation. These data and models were modified and reprinted with permission from Tao et. al. 2002. Mol. Endocrinol. 16:1881–1892. Copyright (2002). The Endocrine Society.