[Orn5]URP acts as a pure antagonist of urotensinergic receptors in rat cortical astrocytes

Mickael Diallo (1, 2) , Marie Jarry (1, 2) , Laurence Desrues (1, 2) , Hélène Castel (1, 2) , David Chatenet (1, 2) , Jérôme Leprince (1, 2) , Hubert Vaudry (1, 2) , Marie-Christine Tonon (1, 2) , Pierrick Gandolfo (1, 2)

1 Neuroendocrinologie cellulaire et moléculaire
2 IFRMP 23 - Institut Fédératif de Recherches Multidisciplinaires sur les Peptides

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.

Domaines: Chimie thérapeutique; Interactions cellulaires [q-bio.CB]; Neurobiologie; Pharmacologie

Mickael Diallo, Marie Jarry, Laurence Desrues, Hélène Castel, David Chatenet, et al.. [Orn5]URP acts as a pure antagonist of urotensinergic receptors in rat cortical astrocytes. Peptides, 2008, 29 (5), pp.813-819. ⟨10.1016/j.peptides.2007.10.023⟩. ⟨hal-01962707⟩