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Regulation of caveolar cardiac sodium current by a single G_s histidine residue

Department of Molecular Physiology and Biophysics, Carver College of Medicine, The University of Iowa, Iowa City, Iowa

Submitted 14 November 2007 ; accepted in final form 12 February 2008

Cardiac sodium channels (voltage-gated Na⁺ channel subunit 1.5) reside in both the plasmalemma and membrane invaginations called caveolae. Opening of the caveolar neck permits resident channels to become functional. In cardiac myocytes, caveolar opening can be stimulated by applying β-receptor agonists, which initiates an interaction between the stimulatory G protein subunit- (G_s) and caveolin-3. This study shows that, in adult rat ventricular myocytes, a functional G_s-caveolin-3 interaction occurs, even in the absence of the caveolin-binding sequence motif of G_s. Consistent with previous data, whole cell experiments conducted in the presence of intracellular PKA inhibitor stimulation with β-receptor agonists increased the sodium current (I_Na) by 35.9 ± 8.6% (P < 0.05), and this increase was mimicked by application of G_s protein. Inclusion of anti-caveolin-3 antibody abolished this effect. These findings suggest that G_s and caveolin-3 are components of a PKA-independent pathway that leads to the enhancement of I_Na. In this study, alanine scanning mutagenesis of G_s (40THR42), in conjunction with voltage-clamp studies, demonstrated that the histidine residue at position 41 of G_s (H41) is a critical residue for the functional increase of I_Na. Protein interaction assays suggest that G_sFL (full length) binds to caveolin-3, but the enhancement of I_Na is observed only in the presence of G_s H41. We conclude that G_s H41 is a critical residue in the regulation of the increase in I_Na in ventricular myocytes.

voltage-gated sodium channel subunit 1.5; caveolae; caveolin; G protein; ventricle