Desensitization of vascular endothelin receptors by G protein-coupled receptor kinase 2

Abstract

At the heart of receptor-mediated signal transduction are two intertwined processes: translation of signals carried by stimulating agents to cells through intracellular messenger molecules and termination/restriction of signalling by cells. The latter is a critical mechanism that protects cells from overreacting to an extended or appropriate stimulus and makes cells ready to react to forthcoming stimulation. G protein-coupled receptors (GPCRs) are a family of receptors composed of seven transmembrane domains that respond to various stimuli. GPCRs usually undergo rapid desensitization after activation, in which GPCR kinases (GRKs), a family consisting of seven members (GRK 1–7), play a critical role.1 Endothelins (ETs) are a family of peptides comprising ET1, ET2, and ET3.2 ETs exert their actions through two types of receptors, ETA and ETB, which belong to the GPCR family.3 Activation of ETA receptors results in vasoconstriction through the generation of 1,4,5-inositol trisphosphate and diacylglycerol as intracellular messengers, which, in turn, trigger intracellular Ca2+ release and protein kinase C activation. Among the ET family members, ET1 is a potent vasoconstrictor that induces contraction at nanomolar concentrations in several vascular beds.3 Significant desensitization of ET1-induced cellular response was soon reported after ET was discovered in 1988,4 but the underlying mechanisms were not fully understood. Morris … *Corresponding author. Tel: +1 905 525 9140 Extn 22477; Fax: +1 905 523 1224. E-mail address : gaoyu{at}mcmaster.ca