title: Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14.
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.
authors.affiliation: Department of Molecular Biology, Smith Kline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA. bobvames1@sbphrd.com
authors.forename: R S
authors.initials: RS
authors.lastname: Ames
authors.forename: H M
authors.initials: HM
authors.lastname: Sarau
authors.forename: J K
authors.initials: JK
authors.lastname: Chambers
authors.forename: R N
authors.initials: RN
authors.lastname: Willette
authors.forename: N V
authors.initials: NV
authors.lastname: Aiyar
authors.forename: A M
authors.initials: AM
authors.lastname: Romanic
authors.forename: C S
authors.initials: CS
authors.lastname: Louden
authors.forename: J J
authors.initials: JJ
authors.lastname: Foley
authors.forename: C F
authors.initials: CF
authors.lastname: Sauermelch
authors.forename: R W
authors.initials: RW
authors.lastname: Coatney
authors.forename: Z
authors.initials: Z
authors.lastname: Ao
authors.forename: J
authors.initials: J
authors.lastname: Disa
authors.forename: S D
authors.initials: SD
authors.lastname: Holmes
authors.forename: J M
authors.initials: JM
authors.lastname: Stadel
authors.forename: J D
authors.initials: JD
authors.lastname: Martin
authors.forename: W S
authors.initials: WS
authors.lastname: Liu
authors.forename: G I
authors.initials: GI
authors.lastname: Glover
authors.forename: S
authors.initials: S
authors.lastname: Wilson
authors.forename: D E
authors.initials: DE
authors.lastname: McNulty
authors.forename: C E
authors.initials: CE
authors.lastname: Ellis
authors.forename: N A
authors.initials: NA
authors.lastname: Elshourbagy
authors.forename: U
authors.initials: U
authors.lastname: Shabon
authors.forename: J J
authors.initials: JJ
authors.lastname: Trill
authors.forename: D W
authors.initials: DW
authors.lastname: Hay
authors.forename: E H
authors.initials: EH
authors.lastname: Ohlstein
authors.forename: D J
authors.initials: DJ
authors.lastname: Bergsma
authors.forename: S A
authors.initials: SA
authors.lastname: Douglas
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary; D019204:GTP-Binding Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008969:Molecular Sequence Data; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution; D014579:Urotensins / Q000378:metabolism / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D018076:DNA, Complementary; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C121697:UTS2R protein, human; D014579:Urotensins; D014662:Vasoconstrictor Agents; C029677:urotensin II; D019204:GTP-Binding Proteins; D002118:Calcium