Urotensin II Is the Endogenous Ligand of a G-Protein-Coupled Orphan Receptor, SENR (GPR14)

Differential vasoconstrictor activity of human urotensin‐II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey

“…Firstly, mammalian (rat and human) and non-mammalian (goby) U-II isopeptide isoforms are indistinguishable as spasmogens in the rat aorta (Ames et al, 1999; S.A. Douglas, unpublished observation). Similarly, to date, recombinant rat and human U-II receptors have been unable to di erentiate between a range of U-II isopeptides (goby, rat, mouse, pig and human U-II isoforms all exhibit similar sub-nanomolar a nities for human and rat GPR14 as determined by both radioligand binding and [Ca 2+ ] i -mobilization assays using recombinant HEK-293 cells; N.V. Aiyar, unpublished observation).Such ®ndings are in accord with independent studies where ®sh (goby), amphibian (frog) and mammalian (human U-II, porcine U-II A -and U-II B ) U-II isoforms are reported to interact with rat GPR14 with comparable a nities Mori et al, 1999;Nothacker et al, 1999). Further to this, the cyclic octapeptide core sequence of the U-II isopeptide family (D/E[CFWKYC]V/I), one which is absolutely conserved across all species identi®ed, is reported to constitute the minimum sequence required for the retention of full biological activity (Itoh et al, 1987;.…”

“…Since evolutionary pressure has acted to conserve this isopeptide family across a diverse range of species, it has been proposed that this peptide family exerts similar physiological actions in higher species including mammals. This hypothesis is supported by the recent identi®cation of U-II isopeptides in the rat, mouse, pig and man (Ames et al, 1999;Coulouarn et al, 1998;Mori et al, 1999). The present study has evaluated the functional activity of human U-II in a range of native vascular tissue isolated from a variety of mammals.…”

“…The characterization of GPR14, a novel GPCR homologous to a rat`orphan' receptor originally designated SENR or GPR14 (Tal et al, 1995;Marchese et al, 1995), as a selective U-II receptor was originally made by Ames et al (1999) and con®rmed subsequently by several other groups using rat GPR14 Mori et al, 1999;Nothacker et al, 1999). As with U-II, GPR14 expression is evident within the cardiovascular system.…”

“…As such, the identi®cation of novel agonist-GPCR interactions within the cardiovascular system o ers great potential for the development of novel therapeutic modalities. The cloning of the vasoactive cyclic undecapeptide human Urotensin-II (U-II), a selective ligand for the novel serpentine seven transmembrane receptor, GPR14 (Ames et al, 1999), is one such pairing that has met with considerable interest recently (Hare et al, 1999;Davenport & Maguire, 2000;Newby & Jalan, 2000;Gray et al, 2000) since (a) human U-II and GPR14 are both expressed within the vasculature and (b) preliminary pharmacological evaluation indicates that human U-II possesses signi®cant vasoactive properties (Ames et al, 1999;Bottrill et al, 2000;MacLean et al, 2000).GPR14 (Mori et al, 1999;Nothacker et al, 1999). However, in addition to the CNS, U-II is clearly present within the mammalian periphery including the vasculature (cardiac myocytes, coronary atheroma; Ames et al, 1999) and several other peripheral tissues including kidney, adrenal gland, pancreas and liver (Coulouarn et al, 1998;Nothacker et al, 1999).…”

“…Further, in addition to any putative paracrine action, U-II likely functions as an endocrine factor since U-II-like immunoreactivity has been detected within ®sh plasma (*30 pM; Kobayashi et al, 1986;Winter et al, 1999). Irrespectively, however, the fact that the cognate receptor for U-II, GPR14, is expressed within the cardiovasculature (Ames et al, 1999) implies that the heart and peripheral vasculature represent`target organs' for this hormone.The characterization of GPR14, a novel GPCR homologous to a rat`orphan' receptor originally designated SENR or GPR14 (Tal et al, 1995;Marchese et al, 1995), as a selective U-II receptor was originally made by Ames et al (1999) and con®rmed subsequently by several other groups using rat GPR14 Mori et al, 1999;Nothacker et al, 1999). As with U-II, GPR14 expression is evident within the cardiovascular system.…”