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Cardiovascular Research Advance Access first published online on January 30, 2009
This version [Corrected Proof] published online on February 17, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp039
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

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

Vivek Garg, Jundong Jiao and Keli Hu*

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

* Corresponding author. Tel: +1 614 292 5433; fax: +1 614 292 9083. E-mail address: hu.175{at}osu.edu

Aims: ATP-sensitive potassium (KATP) 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 KATP 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 KATP 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 KATP 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 A1 receptors, and caveolin-3. Furthermore, whole-cell voltage clamp studies suggested that adenosine A1 receptor-mediated activation of KATP channels was largely eliminated by disrupting caveolae with methyl-β-cyclodextrin or by small interfering RNA, whereas pinacidil-induced KATP activation was not altered.

Conclusion: We demonstrate that KATP channels are localized to caveolin-enriched microdomains. This microdomain association is essential for adenosine receptor-mediated regulation of KATP channels in cardiac myocytes.

KEYWORDS KATP channel; Caveolin-3; Adenosine receptor

Time for primary review: 29 days


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