Abstract 358: Intracellular Ca2+ Can Directly Regulate NaV1.5 Through An Efl Motif In The Absence Of Calmodulin Binding.
Intracellular Ca2+ regulates gating of voltage-dependent cardiac sodium channels (NaV1.5). The roles of the calmodulin (CaM) binding IQ motif and the upstream EF-hand like (EFL) motif in C-terminus (CT) in Ca2+ regulation of NaV1.5 are uncertain. Increasing intracellular Ca2+ shifts the steady-state availability of NaV1.5 in the depolarizing direction compared to the Ca2+-free condition (Table 1⇓). A similar depolarizing shift in the V1/2 of inactivation is still evident after the truncation of CT proximal to the IQ motif, NaV1.51885 which retains the EFL (Table 1⇓). However mutations in the four EFL residues E1788A, D1790A, D1792A, E1799A (NaV1.54X) with an intact IQ motif abolishes Ca2+ mediated channel regulation (Table 1⇓) but unmasked a CaM-mediated shift in the voltage-dependence of inactivation of NaV1.5 similar to that observed with for 2+ binding to EFL motif has a critical role in controlling NaV1.4 (1 Table⇓). We conclude that the Ca2+ independent of the CaM/IQ NaV1.5 availability in the heart through direct binding of Ca interaction. Disease-associated mutations in the EFL region of NaV1.5 may be associated with an arrhythmogenic exaggerated CaM-induced shift in gating.