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Cardiovasc Res. 2009 Apr 1;82(1):51-8. doi: 10.1093/cvr/cvp039. Epub 2009 Jan 30.

Regulation of ATP-sensitive K+ channels by caveolin-enriched microdomains in cardiac myocytes.

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  • 1Division of Pharmacology, College of Pharmacy, The Ohio State University, 530 Parks Hall, 500 West 12th Avenue, Columbus, OH 43210, USA.

Abstract

AIMS:

ATP-sensitive potassium (K(ATP)) channels in the heart are critical regulators of cellular excitability and action potentials during ischaemia. However, little is known about subcellular localization of these channels and their regulation. The present study was designed to explore the potential role of caveolae in the regulation of K(ATP) channels in cardiac ventricular myocytes.

METHODS AND RESULTS:

Both adult and neonatal rat cardiomyocytes were used. Subcellular fractionation by density gradient centrifugation, western blotting, co-immunoprecipitation, and immunofluorescence confocal microscopy were employed in combination with whole-cell voltage clamp recordings and siRNA gene silencing. We detected that the majority of K(ATP) channels on the plasma membrane of cardiac myocytes were localized in caveolin-3-enriched microdomains by cell fractionation and ultracentrifugation followed by western blotting. Immunofluorescence confocal microscopy revealed extensive colocalization of K(ATP) channel pore-forming subunit Kir6.2 and caveolin-3 along the plasma membrane. Co-immunoprecipitation of cardiac myocytes showed significant association of Kir6.2, adenosine A(1) receptors, and caveolin-3. Furthermore, whole-cell voltage clamp studies suggested that adenosine A(1) receptor-mediated activation of K(ATP) channels was largely eliminated by disrupting caveolae with methyl-beta-cyclodextrin or by small interfering RNA, whereas pinacidil-induced K(ATP) activation was not altered.

CONCLUSION:

We demonstrate that K(ATP) channels are localized to caveolin-enriched microdomains. This microdomain association is essential for adenosine receptor-mediated regulation of K(ATP) channels in cardiac myocytes.

PMID:
19181933
[PubMed - indexed for MEDLINE]
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