Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14.
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.
Ames
R S
RS
Department of Molecular Biology, Smith Kline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA. bobvames1@sbphrd.com
Sarau
H M
HM
Chambers
J K
JK
Willette
R N
RN
Aiyar
N V
NV
Romanic
A M
AM
Louden
C S
CS
Foley
J J
JJ
Sauermelch
C F
CF
Coatney
R W
RW
Ao
Z
Z
Disa
J
J
Holmes
S D
SD
Stadel
J M
JM
Martin
J D
JD
Liu
W S
WS
Glover
G I
GI
Wilson
S
S
McNulty
D E
DE
Ellis
C E
CE
Elshourbagy
N A
NA
Shabon
U
U
Trill
J J
JJ
Hay
D W
DW
Ohlstein
E H
EH
Bergsma
D J
DJ
Douglas
S A
SA
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*
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