Ligand rescue of constitutively active mutant receptors

Abstract

Constitutively active mutants (CAMs) of G protein-coupled receptors are found naturally in disease states and they can be generated by point mutation. As these mutants are able to activate G proteins in the absence of a ligand, they are useful tools in the study of conformational changes leading to receptor activation and in the drug discovery process. Early studies on CAMs noted that they are often expressed at lower levels than their wild-type forms. In this review we discuss the mechanisms responsible for this reduced expression and also provide an explanation for the observation that challenging cells with receptor ligands can increase the CAM expression level. The application of these observations to the development of a high-throughput reporter assay suitable for ligand identification is also discussed.