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(Circulation Research. 2005;97:707.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Arrestin-Independent Internalization and Recycling of the Urotensin Receptor Contribute to Long-Lasting Urotensin II–Mediated Vasoconstriction

Günter Giebing^*, Markus Tölle^*, Jana Jürgensen, Jenny Eichhorst, Jens Furkert, Michael Beyermann, Frank Neuschäfer-Rube, Walter Rosenthal, Walter Zidek, Markus van der Giet, Alexander Oksche

From the Med. Klinik IV-Nephrologie, Charité, Campus Benjamin Franklin, Berlin (G.G., M.T., W.Z., M.v.d.G.); Institut für Pharmakologie, Charité, Campus Benjamin Franklin, Berlin (J.J., A.O.); Forschungsinstitut für Molekulare Pharmakologie, Berlin (J.E., J.F., M.B., W.R.); and Universität Potsdam, Institut für Ernährungswissenschaft, Nuthetal (F.N.-R.), Germany.

Correspondence to Prof Dr med Markus van der Giet, Charite-Campus Benjamin Franklin, Med. Klinik IV-Nephrologie, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail markus.vandergiet{at}charite.de

Urotensin II (UII), which acts on the G protein-coupled urotensin (UT) receptor, elicits long-lasting vasoconstriction. The role of UT receptor internalization and intracellular trafficking in vasoconstriction has yet not been analyzed. Therefore, UII-mediated contractile responses of aortic ring preparations in wire myography and rat UT (rUT) receptor internalization and intracellular trafficking in binding and imaging analyses were compared. UII elicited a concentration-dependent vasoconstriction of rat aorta (–log EC50, mol/L:9.0±0.1). A second application of UII after 30 minutes elicited a reduced contraction (36±4% of the initial response), but when applied after 60 minutes elicited a full contraction. In internalization experiments with radioactive labeled VII (¹²⁵I-UII), 70% of rUT receptors expressed on the cell surface of human embryonic kidney 293 cells were sequestered within 30 minutes (half life [t_h]: 5.6±0.2 minutes), but recycled quantitatively within 60 minutes (t_h 31.9±2.6 minutes). UII-bound rUT receptors were sorted to early and recycling endosomes, as evidenced by colocalization of rUT receptors with the early endosomal antigen and the transferrin receptor. Real-time imaging with a newly developed fluorescent UII (Cy3-UII) revealed that rUT receptors recruited arrestin3 green fluorescent protein to the plasma membrane. Arrestin3 was not required for the endocytosis of the rUT receptor, however, as internalization of Cy3-UII was not altered in mouse embryonic fibroblasts lacking endogenous arrestin2/arrestin3 expression. The data demonstrate that the rUT receptor internalizes arrestin independently and recycles quantitatively. The continuous externalization of rUT receptors provides the basis for repetitive and lasting UII-mediated vasoconstriction.

Key Words: urotensin II • vascular tone • urotensin receptor • recycling • internalization

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