Abstract
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.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
J.R. Vane and R.M. Botting, Pharmacodynamic profile of prostacyclin. Am. J. Cardiol. 75: 3A (1995).
S.Moncada, and J.R. Vane, Prostacyclin: homeostatic regulation or biological curiosity? Clinical Science 61: 369 (1981).
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).
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)
Y. Boie, T.H. Rushmore, A. Darmon-Goodwin, R. Grygorczyk, D.M. Slipetz, K.M. Metters and M. Abramovitz. Cloning and expression of a cDNA for the human prostanoid IP receptor. J. Biol. Chem. 269: 12173 (1994).
S.S.G. Ferguson and M.G. Caron. G protein-coupled receptor adaptation mechanims. Sem. Cell Dev. Biol. 9: 119 (1998).
E.M. Smyth, P.V. Nestor and G.A FitzGerald. Agonist-induced phosphorylation of an epitope-tagged prostacyclin receptor. J. Biol. Chem. 271: 33698 (1996).
E.M. Smyth, W. Hong Li and G.A. FitzGerald. Phosphorylation of the prostacyclin receptor during homologous desensitization: a critical role for PKC. J. Biol. Chem. 273: 23258 (1998).
S. Giovanazzi, M.R. Accomazzo, O. Letari, D. Oliva and S. Nicosia. Internalization and down-regulation of the prostacyclin receptor in human platelets. Biochem. J. 325: 71 (1997).
J.L. Parent, P. Labrecque, M.J. Orsini and J.L. Benovic. Internalization of the TXA2 receptor alpha and beta isoforms. Role of the differentially spliced COOH terminus in agonist-promoted receptor internalization. J. Biol. Chem. 27: 8941 (1999).
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).
R. Pals-Rylaarsdam, Y. Xu, P. Witt-Enderby, J.L. Benovic and M.M. Hosey. Desensitization and internalization of the m2 muscarinic acetylcholine receptor are directed by independent mechanisms. J. Biol. Chem. 270: 29004 (1995).
K. Nakamura, J.G. Krupnick, J.L. Benovic and M. Ascoli. Signaling and phosphorylation-impaired mutants of the rat follitropin receptor reveal an activation-and phosphorylation-independent but arrestindependent pathway for Internalization. J. Biol. Chem. 273: 24346 (1998).
S.R. Murray, C.J. Evans and M. von Zastrow. Phosphorylation is not required for dynamin-dependent endocytosis of a truncated mutant opioid receptor. J. Biol. Chem. 273: 24987 (1998).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Springer Science+Business Media New York
About this chapter
Cite this chapter
Smyth, E.M., Austin, S.C., FitzGerald, G.A. (2002). Activation-Dependent Internalization of The Human Prostacyclin Receptor . In: Honn, K.V., Marnett, L.J., Nigam, S., Dennis, E., Serhan, C. (eds) Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury, 5. Advances in Experimental Medicine and Biology, vol 507. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0193-0_45
Download citation
DOI: https://doi.org/10.1007/978-1-4615-0193-0_45
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-4960-0
Online ISBN: 978-1-4615-0193-0
eBook Packages: Springer Book Archive