Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. |
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| Authors: | R S Ames H M Sarau J K Chambers R N Willette N V Aiyar A M Romanic C S Louden J J Foley C F Sauermelch R W Coatney Z Ao J Disa S D Holmes J M Stadel J D Martin W S Liu G I Glover S Wilson D E McNulty C E Ellis N A Elshourbagy U Shabon J J Trill D W Hay E H Ohlstein D J Bergsma S A Douglas |
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| Institution: | Department of Molecular Biology, Smith Kline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA. bobvames1@sbphrd.com |
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| Abstract: | Urotensin-II (U-II) is a vasoactive 'somatostatin-like' cyclic peptide which was originally isolated from fish spinal cords, and which has recently been cloned from man. Here we describe the identification of an orphan human G-protein-coupled receptor homologous to rat GPR14 and expressed predominantly in cardiovascular tissue, which functions as a U-II receptor. Goby and human U-II bind to recombinant human GPR14 with high affinity, and the binding is functionally coupled to calcium mobilization. Human U-II is found within both vascular and cardiac tissue (including coronary atheroma) and effectively constricts isolated arteries from non-human primates. The potency of vasoconstriction of U-II is an order of magnitude greater than that of endothelin-1, making human U-II the most potent mammalian vasoconstrictor identified so far. In vivo, human U-II markedly increases total peripheral resistance in anaesthetized non-human primates, a response associated with profound cardiac contractile dysfunction. Furthermore, as U-II immunoreactivity is also found within central nervous system and endocrine tissues, it may have additional activities. |
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