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.