Endothelin Receptor Signaling: New Insight Into Its Regulatory Mechanisms

抄録

The endothelin (ET) system consists of two G protein coupled–receptors (GPCRs), ET type A receptor (ET_AR) and ET type B receptor (ET_BR), and three endogenous ligands, ET-1, ET-2, and ET-3. Stimulation of ETRs with ET-1 induces an increase in intracellular Ca²⁺ concentration that is involved in a diverse array of physiological and pathophysiological processes, including vasoconstriction, and cell proliferation. Store-operated Ca²⁺ entry and receptor-operated Ca²⁺ entry triggered by activation of ETRs are regulated or modulated by endoplasmic reticulum Ca²⁺ sensor (stromal interaction molecule 1) and voltage-independent cation channels (transient receptor potential canonical channels and Orai1). The ET-1–induced Ca²⁺ mobilization results from activation of heterotrimeric G proteins by ETRs. In contrast, GPCR biology including modulation of receptor function and trafficking is regulated by a variety of GPCR interacting proteins (GIPs) that generally interact with the C-terminal domain of GPCRs. The ETR signaling is also regulated by GIPs such as Jun activation domain-binding protein 1. This review focuses on the regulatory mechanisms of the ETR signaling with special attention to the components involved in Ca²⁺ signaling and to GIPs in the signal transduction, modification, and degradation of ETRs.