Regulation of the NaV1.5 cytoplasmic domain by calmodulin

Sandra B. Gabelli (), Agedi Boto, Victoria Halperin Kuhns, Mario A. Bianchet, Federica Farinelli, Srinivas Aripirala, Jesse Yoder, Jean Jakoncic, Gordon F. Tomaselli () and L. Mario Amzel ()
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Sandra B. Gabelli: Structural Enzymology and Thermodynamics Group, Johns Hopkins University School of Medicine
Agedi Boto: Structural Enzymology and Thermodynamics Group, Johns Hopkins University School of Medicine
Victoria Halperin Kuhns: Johns Hopkins University School of Medicine
Mario A. Bianchet: Structural Enzymology and Thermodynamics Group, Johns Hopkins University School of Medicine
Federica Farinelli: Johns Hopkins University School of Medicine
Srinivas Aripirala: Structural Enzymology and Thermodynamics Group, Johns Hopkins University School of Medicine
Jesse Yoder: Structural Enzymology and Thermodynamics Group, Johns Hopkins University School of Medicine
Jean Jakoncic: Brookhaven National Laboratory, Photon Science Directorate, National Synchrotron Light Source
Gordon F. Tomaselli: Johns Hopkins University School of Medicine
L. Mario Amzel: Structural Enzymology and Thermodynamics Group, Johns Hopkins University School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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 Nav1.5 (CTNav1.5) with calmodulin (CaM)–Mg2+ reported here, both CaM lobes interact with the CTNav1.5. 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 CTNav1.5 with high affinity. The results of this study provide unique insights into the physiological activation and the pathophysiology of Nav channels.

Date: 2014
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DOI: 10.1038/ncomms6126

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