Association of muscarinic M₃ receptors and Kir6.1 with caveolae in human detrusor muscle

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• 作者：Mari Ekman^a ; ¹ ; Catarina Rippe^a ; ¹ ; Mardjaneh Karbalaei Sadegh^a ; Saeed Dabestani^b ; Matthias Mö ; rgelin^c ; Bengt Uvelius^b ; Karl Swä ; rd^a ; ^{karl.sward@med.lu.se}
• 关键词：Carbachol ; Detrusor ; Glibenclamide ; Cyclodextrin ; Smooth muscle
• 刊名：European Journal of Pharmacology
• 出版年：2012
• 期刊代码：24_00142999
• 类别：neu
• 出版时间：15 May, 2012
• 卷：683
• 期：1-3
• 页码：238-245
• 文件大小：1946 K

摘要

Caveolae are 50-100 nm large membrane invaginations that play a role in cellular signaling. The aim of the present study was to assess whether muscarinic M₃ receptors and the K_ATP channel subunit Kir6.1 are associated with human detrusor caveolae, and to pharmacologically assess the relevance of this organization for contractility. Detrusor strips were dissected and used in ultrastructural, biochemical and mechanical studies. Caveolae were manipulated by cholesterol desorption using m尾cd (methyl-尾-cyclodextrin). M尾cd disrupted caveolae and caused a cholesterol-dependent ~ 3-fold rightward shift of the concentration-response curve for the muscarinic receptor agonist carbachol. The effect of m尾cd was inhibited by the K_ATP blockers glibenclamide, repaglinide and PNU-37883, and it was mimicked by the K_ATP activator levcromakalim. Immunoelectron microscopy showed muscarinic M₃ receptors and Kir6.1 to be enriched in caveolae. In conclusion, pharmacological K_ATP channel inhibition antagonizes the effect of caveolae disruption on muscarinic contractility in the human detrusor, and the K_ATP channel subunit Kir6.1 co-localizes with M₃ receptors in caveolae.