Calmodulin and calcium differentially regulate the neuronal Nav1.1 voltage-dependent sodium channel

► Both Ca++-Calmodulin (CaM) and Ca++-free CaM bind to the C-terminal region of Nav1.1. ► Ca++ and CaM have both opposite and convergent effects on INav1.1. ► Ca++-CaM modulates INav1.1 amplitude. ► CaM hyperpolarizes the voltage-dependence of activation, and increases the inactivation rate. ► Ca++ alone antagonizes CaM for both effects, and depolarizes the voltage-dependence of inactivation.