Structural basis for the modulation of the neuronal Voltage-gated sodium channel Na v 1.6 by calmodulin

Abstract

The neuronal-voltage gated sodium channel (VGSC), Na V 1.6, plays an important role in propagating action potentials along myelinated axons. Calmodulin (CaM) is known to modulate the inactivation kinetics of Na V 1.6 by interacting with its IQ motif. Here we report the crystal structure of apo-CaM:Na V 1.6IQ motif, along with functional studies. The IQ motif of Na V 1.6 adopts an α-helical conformation in its interaction with the C-lobe of CaM. CaM uses different residues to interact with Na V 1.6IQ motif depending on the presence or absence of Ca2+. Three residues from Na V 1.6, Arg1902, Tyr1904 and Arg1905 were identified as the key common interacting residues in both the presence and absence of Ca2+. Substitution of Arg1902 and Tyr1904 with alanine showed a reduced rate of Na V 1.6 inactivation in electrophysiological experiments in vivo. Compared with other CaM:Na V complexes, our results reveal a different mode of interaction for CaM:Na V 1.6 and provides structural insight into the isoform-specific modulation of VGSCs.