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Regulation of the NaV1.5 cytoplasmic domain by calmodulin

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  • Sandra B. Gabelli

    (Structural Enzymology and Thermodynamics Group, Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    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
    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)

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.

Suggested Citation

  • Sandra B. Gabelli & Agedi Boto & Victoria Halperin Kuhns & Mario A. Bianchet & Federica Farinelli & Srinivas Aripirala & Jesse Yoder & Jean Jakoncic & Gordon F. Tomaselli & L. Mario Amzel, 2014. "Regulation of the NaV1.5 cytoplasmic domain by calmodulin," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6126
    DOI: 10.1038/ncomms6126
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