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

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• 作者：Mickaë ; l Diallo ; Marie Jarry ; Laurence Desrues ; Hé ; lè ; ne Castel ; David Chatenet ; Jé ; rô ; me Leprince ; Hubert Vaudry ; Marie-Christine Tonon ; Pierrick G ; olfo
• 关键词：Urotensin II ; Urotensin II-related peptide (URP) ; UT antagonists ; Cytosolic calcium ; Binding ; Astrocytes
• 刊名：Peptides
• 出版年：2008
• 期刊代码：59_01969781
• 类别：neu
• 出版时间：May 2008
• 卷：29
• 期：5
• 页码：813-819
• 文件大小：509 K

摘要

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 [¹²⁵I]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.