Regulation of the NaV 1.5 cytoplasmic domain by calmodulin

Abstract

Voltage-gated sodium channels (Nav) underlie the rapid upstroke of action potentials in excitable tissues. Binding of channel-interactive proteins is essential for controlling fast and long-term inactivation. In the structure of the complex of the carboxy-terminal portion of Nav 1.5 (CTNav 1.5) with calmodulin (CaM)-Mg2+ reported here, both CaM lobes interact with the CTNav 1.5. On the basis of the differences between this structure and that of an inactivated complex, we propose that the structure reported here represents a non-inactivated state of the CTNav', that is, the state that is poised for activation. Electrophysiological characterization of mutants further supports the importance of the interactions identified in the structure. Isothermal titration calorimetry experiments show that CaM binds to CTNav 1.5 with high affinity. The results of this study provide unique insights into the physiological activation and the pathophysiology of Nav channels.