title: Regulation of the NaV1.5 cytoplasmic domain by calmodulin.
abstract: Voltage-gated sodium channels (Na(v)) 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 Na(v)1.5 (CTNa(v)1.5) with calmodulin (CaM)-Mg(2+) reported here, both CaM lobes interact with the CTNa(v)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 CTNa(v), 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 CTNa(v)1.5 with high affinity. The results of this study provide unique insights into the physiological activation and the pathophysiology of Na(v) channels.
authors.affiliation: 1] Structural Enzymology and Thermodynamics Group, Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 N Wolfe Street, WBSB 608, Baltimore, Maryland 21205, USA [2] Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Building 844, Baltimore, Maryland 21205, USA [3] Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Sandra B
authors.initials: SB
authors.lastname: Gabelli
authors.affiliation: Structural Enzymology and Thermodynamics Group, Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 N Wolfe Street, WBSB 608, Baltimore, Maryland 21205, USA.
authors.forename: Agedi
authors.initials: A
authors.lastname: Boto
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Building 844, Baltimore, Maryland 21205, USA.
authors.forename: Victoria Halperin
authors.initials: VH
authors.lastname: Kuhns
authors.affiliation: 1] Structural Enzymology and Thermodynamics Group, Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 N Wolfe Street, WBSB 608, Baltimore, Maryland 21205, USA [2] Department of Neurology, Johns Hopkins University School of Medicine, 600 N Wolfe Street, Baltimore, Maryland 21287, USA.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Bianchet
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Building 844, Baltimore, Maryland 21205, USA.
authors.forename: Federica
authors.initials: F
authors.lastname: Farinelli
authors.affiliation: Structural Enzymology and Thermodynamics Group, Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 N Wolfe Street, WBSB 608, Baltimore, Maryland 21205, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Aripirala
authors.affiliation: Structural Enzymology and Thermodynamics Group, Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 N Wolfe Street, WBSB 608, Baltimore, Maryland 21205, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Yoder
authors.affiliation: Brookhaven National Laboratory, Photon Science Directorate, National Synchrotron Light Source, Upton, New York 11973, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Jakoncic
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Building 844, Baltimore, Maryland 21205, USA.
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Tomaselli
authors.affiliation: Structural Enzymology and Thermodynamics Group, Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 N Wolfe Street, WBSB 608, Baltimore, Maryland 21205, USA.
authors.forename: L Mario
authors.initials: LM
authors.lastname: Amzel
mesh_terms: D002147:Calmodulin / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D002147:Calmodulin; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human