Endothelin receptor signaling: new insight into its regulatory mechanisms.
The endothelin (ET) system consists of two G protein coupled-receptors (GPCRs), ET type A receptor (ETAR) and ET type B receptor (ETBR), and three endogenous ligands, ET-1, ET-2, and ET-3. Stimulation of ETRs with ET-1 induces an increase in intracellular Ca(2+) concentration that is involved in a diverse array of physiological and pathophysiological processes, including vasoconstriction, and cell proliferation. Store-operated Ca(2+) entry and receptor-operated Ca(2+) entry triggered by activation of ETRs are regulated or modulated by endoplasmic reticulum Ca(2+) sensor (stromal interaction molecule 1) and voltage-independent cation channels (transient receptor potential canonical channels and Orai1). The ET-1-induced Ca(2+) 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 Ca(2+) signaling and to GIPs in the signal transduction, modification, and degradation of ETRs.
Department of Cellular Pharmacology, Hokkaido University Graduate School of Medicine, Japan.
Takahiro
T
Horinouchi
Koji
K
Terada
Tsunehito
T
Higashi
Soichi
S
Miwa
D000818:Animals; D000075686:COP9 Signalosome Complex; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology; D049109:Cell Proliferation; D004721:Endoplasmic Reticulum; D019332:Endothelin-1 / Q000502:physiology*; D019333:Endothelin-2 / Q000502:physiology*; D019334:Endothelin-3 / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008024:Ligands; D008565:Membrane Proteins / Q000502:physiology; D009363:Neoplasm Proteins / Q000502:physiology; D000071740:ORAI1 Protein; D010447:Peptide Hydrolases / Q000502:physiology; D044022:Receptor, Endothelin A / Q000378:metabolism / Q000502:physiology*; D044023:Receptor, Endothelin B / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology*; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels / Q000502:physiology; D014661:Vasoconstriction
D015220:Calcium Channels; D019332:Endothelin-1; D019333:Endothelin-2; D019334:Endothelin-3; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D050052:TRPC Cation Channels; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D019204:GTP-Binding Proteins; D002118:Calcium