title: [Orn5]URP acts as a pure antagonist of urotensinergic receptors in rat cortical astrocytes.
abstract: Cultured rat astrocytes, which express functional urotensin II (UII)/UII-related peptide (URP) receptors (UT), represent a very suitable model to investigate the pharmacological profile of UII and URP analogs towards native UT. We have recently designed three URP analogs [D-Trp4]URP, [Orn5]URP and [D-Tyr6]URP, that act as UT antagonists in the rat aortic ring bioassay. However, it has been previously reported that UII/URP analogs capable of inhibiting the contractile activity of UII possess agonistic activity on UT-transfected cells. In the present study, we have compared the ability of URP analogs to compete for [125 I]URP binding and to modulate cytosolic calcium concentration ([Ca2+]c) in cultured rat astrocytes. All three analogs displaced radioligand binding: [D-Trp4]URP and [D-Tyr6]URP interacted with high- and low-affinity sites whereas [Orn5]URP only bound high-affinity sites. [D-Trp4]URP and [D-Tyr6]URP both induced a robust increase in [Ca2+]c in astrocytes while [Orn5]URP was totally devoid of activity. [Orn5]URP provoked a concentration-dependent inhibition of URP- and UII-evoked [Ca2+]c increase and a rightward shift of the URP and UII dose-response curves. The present data indicate that [D-Trp4]URP and [D-Tyr6]URP, which act as UII antagonists in the rat aortic ring assay, behave as agonists in the [Ca2+]c mobilization assay in cultured astrocytes, whereas [Orn5]URP is a pure selective antagonist in both rat aortic ring contraction and astrocyte [Ca2+]c mobilization assays.
authors: INSERM U413, Laboratory of Cellular and Molecular Neuroendocrinology, Mont-Saint-Aignan, France.
authors: Mickaël
authors: M
authors: Diallo
authors: Marie
authors: M
authors: Jarry
authors: Laurence
authors: L
authors: Desrues
authors: Hélène
authors: H
authors: Castel
authors: David
authors: D
authors: Chatenet
authors: Jérôme
authors: J
authors: Leprince
authors: Hubert
authors: H
authors: Vaudry
authors: Marie-Christine
authors: MC
authors: Tonon
authors: Pierrick
authors: P
authors: Gandolfo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D036361:Peptide Hormones / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014579:Urotensins / Q000235:genetics / Q000378:metabolism*
chemical_list: D036361:Peptide Hormones; D043562:Receptors, G-Protein-Coupled; D014579:Urotensins; C473142:Uts2r protein, rat; C479081:urotensin II-related peptide, rat; C029677:urotensin II; D002118:Calcium