Circulation Research. 2002
Published online before print January 17, 2002, doi: 10.1161/hh0402.105177
Published online before print January 17, 2002, doi: 10.1161/hh0402.105177
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Submitted on October 12, 2001
Revised on January 7, 2002
Accepted on January 7, 2002
Localization of Cardiac Sodium Channels in Caveolin-Rich Membrane Domains. Regulation of Sodium Current Amplitude
From the Departments of Physiology and Biophysics (T.L.Y., E.F.S.) and Internal Medicine (T.L., H.-C.L.), University of Iowa College of Medicine, Iowa City, Iowa; and the Department of Veterans' Affairs Medical Center (H.-C.L.), Iowa City, Iowa.
* To whom correspondence should be addressed. E-mail: erwin-shibata{at}uiowa.edu.
This study demonstrates that caveolae, omega-shaped membrane invaginations, are involved in cardiac sodium channel regulation by a mechanism involving the 
subunit of the stimulatory heterotrimeric G-protein, Gs, via stimulation of the cell surface ß-adrenergic receptor. Stimulation of ß-adrenergic receptors with 10 µmol/L isoproterenol in the presence of a protein kinase A inhibitor increased the whole-cell sodium current by a "direct" cAMP-independent G-protein mechanism. The addition of antibodies against caveolin-3 to the cell's cytoplasm via the pipette solution abrogated this direct G protein--induced increase in sodium current, whereas antibodies to caveolin-1 or caveolin-2 did not. Voltage-gated sodium channel proteins were found to associate with caveolin-rich membranes obtained by detergent-free buoyant density separation. The purity of the caveolar membrane fraction was verified by Western blot analyses, which indicated that endoplasmic/sarcoplasmic reticulum, endosomal compartments, Golgi apparatus, clathrin-coated vesicles, and sarcolemmal membranes were excluded from the caveolin-rich membrane fraction. Additionally, the sodium channel was found to colocalize with caveolar membranes by immunoprecipitation, indirect immunofluorescence, and immunogold transmission electron microscopy. These results suggest that stimulation of ß-adrenergic receptors, and thereby Gs, promotes the presentation of cardiac sodium channels associated with caveolar membranes to the sarcolemma.
Key words: caveolae • ion channel • signal transduction • cardiac • adrenergic
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