Pathogenic mutations perturb calmodulin regulation of Na_v1.8 channel

The voltage-gated sodium channels play a key role in the generation and propagation of the cardiac action potential. Emerging data indicate that the Na_v1.8 channel, encoded by the SCN10A gene, is a modulator of cardiac conduction and variation in the gene has been associated with arrhythmias such as atrial fibrillation (AF) and Brugada syndrome (BrS). The voltage gated sodium channels contain a calmodulin (CaM)-binding IQ domain involved in channel slow inactivation, we here investigated the role of CaM regulation of Na_v1.8 channel function, and showed that CaM enhanced slow inactivation of the Na_v1.8 channel and hyperpolarized steady-state inactivation curve of sodium currents. The effects of CaM on the channel gating were disrupted in the Na_v1.8 channel truncated IQ domain. We studied Na_v1.8 IQ domain mutations associated with AF and BrS, and found that a BrS-linked mutation (R1863Q) reduced the CaM-induced hyperpolarization shift, AF-linked mutations (R1869C and R1869G) disrupted CaM-induced enhanced inactivation, and effects of CaM on both development and recovery from slow inactivation were attenuated in all pathogenic mutations. Our findings indicate a role of CaM in the regulation of Na_v1.8 channel function in cardiac arrhythmias.