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

Caveolae are 50–100nm 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 KATP channel subunit Kir6.1 are associated with human detrusor caveolae, and to pharmacologically assess the relevance of this...

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Veröffentlicht in:	European journal of pharmacology 2012-05, Vol.683 (1-3), p.238-245
Hauptverfasser:	Ekman, Mari, Rippe, Catarina, Sadegh, Mardjaneh Karbalaei, Dabestani, Saeed, Mörgelin, Matthias, Uvelius, Bengt, Swärd, Karl
Format:	Artikel
Sprache:	eng
Schlagworte:	Aged agonists ATP-Binding Cassette Transporters - genetics ATP-Binding Cassette Transporters - metabolism beta-Cyclodextrins - antagonists & inhibitors beta-Cyclodextrins - pharmacology Carbachol Caveolae - drug effects Caveolae - metabolism Caveolae - ultrastructure cholesterol Cyclodextrin desorption Detrusor Female Gene Expression Glibenclamide Humans In Vitro Techniques KATP Channels - agonists KATP Channels - antagonists & inhibitors KATP Channels - genetics KATP Channels - metabolism Male Membrane Transport Modulators - pharmacology microscopy Muscarinic Agonists - pharmacology Muscle Contraction - drug effects Muscle, Smooth - drug effects Muscle, Smooth - metabolism Muscle, Smooth - ultrastructure muscles Potassium Channels, Inwardly Rectifying - genetics Potassium Channels, Inwardly Rectifying - metabolism Protein Isoforms - genetics Protein Isoforms - metabolism Protein Subunits - agonists Protein Subunits - antagonists & inhibitors Protein Subunits - genetics Protein Subunits - metabolism Protein Transport - drug effects Receptor, Muscarinic M3 - agonists Receptor, Muscarinic M3 - metabolism receptors Receptors, Drug - genetics Receptors, Drug - metabolism RNA, Messenger - metabolism Smooth muscle Sulfonylurea Receptors Urinary Bladder - drug effects Urinary Bladder - metabolism Urinary Bladder - ultrastructure
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Zusammenfassung:	Caveolae are 50–100nm 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 KATP 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 mβcd (methyl-β-cyclodextrin). Mβcd 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 mβcd was inhibited by the KATP blockers glibenclamide, repaglinide and PNU-37883, and it was mimicked by the KATP activator levcromakalim. Immunoelectron microscopy showed muscarinic M3 receptors and Kir6.1 to be enriched in caveolae. In conclusion, pharmacological KATP channel inhibition antagonizes the effect of caveolae disruption on muscarinic contractility in the human detrusor, and the KATP channel subunit Kir6.1 co-localizes with M3 receptors in caveolae.
ISSN:	0014-2999 1879-0712
DOI:	10.1016/j.ejphar.2012.02.039