Localization of cardiac sodium channels in caveolin-rich membrane domains: Regulation of sodium current amplitude

Tracy L. Yarbrough, Tong Lu, Hon Chi Lee, Erwin F. Shibata

Research output: Contribution to journalArticle

184 Scopus citations

Abstract

This study demonstrates that caveolae, omega-shaped membrane invaginations, are involved in cardiac sodium channel regulation by a mechanism involving the α subunit of the stimulatory heterotrimeric G-protein, Gαs, via stimulation of the cell surface β-adrenergic receptor. Stimulation of β-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 β-adrenergic receptors, and thereby Gαs, promotes the presentation of cardiac sodium channels associated with caveolar membranes to the sarcolemma.

Original languageEnglish (US)
Pages (from-to)443-449
Number of pages7
JournalCirculation research
Volume90
Issue number4
DOIs
StatePublished - Mar 8 2002

Keywords

  • Adrenergic
  • Cardiac
  • Caveolae
  • Ion channel
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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