Isoform-specific modulation of voltage-gated Na+ channels by calmodulin

Calmodulin (CaM) is a calcium-sensing protein that binds to Na+ channels, with unknown functional consequences. Wild-type CaM produced a hyperpolarizing shift in the steady-state availability of expressed skeletal muscle (mu1) but not cardiac (hHI) Na+ channels. Mutant CaM1234 did not alter the voltage dependence or the kinetics of gating of either mu1 or hH1. Mutation of the highly conserved IQ motif in the carboxyl terminus of both isoforms (IQ/AA) slowed the kinetics of current decay and abolished the effect of wild-type CaM on mu1, but did not alter hH1 currents. The IQ/AA mutation eliminated CaM binding to the carboxyl terminus of both mu1 and hHI channels. Inhibition of Ca2+/CaM kinase (CaM-K) slowed the current decay, the rate of entry into inactivation, and shifted the voltage dependence of hHI in the depolarizing direction independent of CaM overexpression with no effect on A 1 Na+ channels. CaM signaling modulates Na+ currents in an isoform-specific manner, via direct interaction with skeletal muscle Na+ channels and through CaM-K in the case of the cardiac isoform. The fall text of this article is available at http://www.circresaha.org.