Structural analyses of Ca(2+)/CaM interaction with Na(V) channel C-termini reveal mechanisms of calcium-dependent regulation

Ca(2+) regulates voltage-gated Na(+) (Na(V)) channels and perturbed Ca(2+) regulation of Na(V) function is associated with epilepsy syndromes, autism, and cardiac arrhythmias. Understanding the disease mechanisms, however, has been hindered by a lack of structural information and competing models for how Ca(2+) affects Na(V) channel function. Here, we report the crystal structures of two ternary complexes of a human Na(V) cytosolic C-terminal domain (CTD), a fibroblast growth factor homologous factor, and Ca(2+)/calmodulin (Ca(2+)/CaM). These structures rule out direct binding of Ca(2+) to the Na(V) CTD, and uncover new contacts between CaM and the Na(V) CTD. Probing these new contacts with biochemical and functional experiments allows us to propose a mechanism by which Ca(2+) could regulate Na(V) channels. Further, our model provides hints towards understanding the molecular basis of the neurologic disorders and cardiac arrhythmias caused by Na(V) channel mutations.