Activation-Dependent Internalization of The Human Prostacyclin Receptor
Prostacyclin (PGI2), the major cyclooxygenase-derived arachidonic acid metabolite formed in macrovascular endothelial cells’, is a potent vasodilator, an inhibitor of platelet aggregation2 and smooth muscle proliferation3 in vitro and an antithrombotic in mice4. Given the absence of PGI2 antagonists its role in the prevention of vascular disease in vivo has remained speculative.
The actions of PGI2 are transduced via IP, a G protein-coupled receptor (GPCR) which is coupled to activation of adenylyl cyclase (AC) and phospholipase C (PLC)5. GPCR are tightly regulated in response to agonist6. Rapid receptor phosphorylation, by second messenger kinases (PKC(s) and PKA) and/or GPCR kinases (GRKs) results in receptor-G-protein uncoupling and thus desensitization. Binding of an arrestin protein directs receptor internalization via clatharin-coated vesicles (CCVs). Many GPCR follow this pathway although several examples have been reported to diverge from this paradigm.
KeywordsSucrose Lysine Histamine Prostaglandin Half Life
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- 1.J.R. Vane and R.M. Botting, Pharmacodynamic profile of prostacyclin. Am. J. Cardiol. 75: 3A (1995).Google Scholar
- 3.T-P. Zucker, D. Bonisch, A. Hasse, T. Grosser, A-A. Weber and K. Schror. Tolerance development to antimitogenic actions of prostacyclin but not of prostaglandin E1 in coronary artery smooth muscle cells. Eur. J. Pharm. 245: 213 (1998).Google Scholar
- 4.T. Murata, F. Ushikubi, T. Matsuoka, M. Hirata, A. Yamasaki, Y. Sugimoto, A. Ichikawa, Y. Azem, T. Tanaka, N. Yoshida, A. Uano, S. Oh-Ishi and Narumiya, S. Altered pain perception and inflammatory response in mice lacking the prostacyclin receptor. Nature. 388: 678. (1997)PubMedCrossRefGoogle Scholar
- 11.Y. Fukushima, T. Asano, K. Takata, M. Funaki, T. Ogihara, M. Anai, K. Tsukuda, T. Saitoh, H.i Katagiri, M. Aihara, N. Matsuhashi, Y. Oka, Y. Yazaki and K. Sugano. Role of the C terminus in histamine H2 receptor signaling, desensitization, and agonist-induced internalization. J. Biol. Chem. 272: 19464 (1997).PubMedCrossRefGoogle Scholar