GPCR Folding and Maturation: The Effect of Pharmacological Chaperones

Abstract

Folding and maturation of G protein-coupled receptors (GPCRs) are complex events, which take place before these integral membrane proteins are transported from their site of synthesis in the endoplasmic reticulum (ER) to their site of action at the plasma membrane. Problems in these events (e. g., as a result of minor mutations) often result in the inability of the newly synthesized receptors to function properly because of mislocalization in the cell. Therefore, ways to circumvent difficulties in GPCR folding, maturation, and trafficking could be of primary importance for alleviating diseases related to GPCR mislocalization. This chapter first provides an overview on the biogenesis of GPCRs and then describes the recently discovered concept of pharmacological chaperones. These membrane-permeable compounds have been found to enhance processing and maturation of several wild-type and mutant GPCRs as well as of some other proteins that are normally retained in the ER.