Ca ²⁺ -dependent regulation of sodium channels Na _V 1.4 and Na _V 1.5 is controlled by the post-IQ motif

Skeletal muscle voltage-gated Na ⁺ channel (Na _V 1.4) activity is subject to calmodulin (CaM) mediated Ca ²⁺ -dependent inactivation; no such inactivation is observed in the cardiac Na ⁺ channel (Na _V 1.5). Taken together, the crystal structures of the Na _V 1.4 C-terminal domain relevant complexes and thermodynamic binding data presented here provide a rationale for this isoform difference. A Ca ²⁺ -dependent CaM N-lobe binding site previously identified in Na _V 1.5 is not present in Na _V 1.4 allowing the N-lobe to signal other regions of the Na _V 1.4 channel. Consistent with this mechanism, removing this binding site in Na _V 1.5 unveils robust Ca ²⁺ -dependent inactivation in the previously insensitive isoform. These findings suggest that Ca ²⁺ -dependent inactivation is effected by CaM’s N-lobe binding outside the Na _V C-terminal while CaM’s C-lobe remains bound to the Na _V C-terminal. As the N-lobe binding motif of Na _V 1.5 is a mutational hotspot for inherited arrhythmias, the contributions of mutation-induced changes in CDI to arrhythmia generation is an intriguing possibility.