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Ca2+-dependent regulation of sodium channels NaV1.4 and NaV1.5 is controlled by the post-IQ motif

Author

Listed:
  • Jesse B. Yoder

    (Johns Hopkins University School of Medicine)

  • Manu Ben-Johny

    (Columbia University)

  • Federica Farinelli

    (Johns Hopkins University School of Medicine)

  • Lakshmi Srinivasan

    (Johns Hopkins University School of Medicine)

  • Sophie R. Shoemaker

    (Johns Hopkins University School of Medicine)

  • Gordon F. Tomaselli

    (Albert Einstein College of Medicine)

  • Sandra B. Gabelli

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

  • L. Mario Amzel

    (Johns Hopkins University School of Medicine)

Abstract

Skeletal muscle voltage-gated Na+ channel (NaV1.4) activity is subject to calmodulin (CaM) mediated Ca2+-dependent inactivation; no such inactivation is observed in the cardiac Na+ channel (NaV1.5). Taken together, the crystal structures of the NaV1.4 C-terminal domain relevant complexes and thermodynamic binding data presented here provide a rationale for this isoform difference. A Ca2+-dependent CaM N-lobe binding site previously identified in NaV1.5 is not present in NaV1.4 allowing the N-lobe to signal other regions of the NaV1.4 channel. Consistent with this mechanism, removing this binding site in NaV1.5 unveils robust Ca2+-dependent inactivation in the previously insensitive isoform. These findings suggest that Ca2+-dependent inactivation is effected by CaM’s N-lobe binding outside the NaV C-terminal while CaM’s C-lobe remains bound to the NaV C-terminal. As the N-lobe binding motif of NaV1.5 is a mutational hotspot for inherited arrhythmias, the contributions of mutation-induced changes in CDI to arrhythmia generation is an intriguing possibility.

Suggested Citation

  • Jesse B. Yoder & Manu Ben-Johny & Federica Farinelli & Lakshmi Srinivasan & Sophie R. Shoemaker & Gordon F. Tomaselli & Sandra B. Gabelli & L. Mario Amzel, 2019. "Ca2+-dependent regulation of sodium channels NaV1.4 and NaV1.5 is controlled by the post-IQ motif," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09570-7
    DOI: 10.1038/s41467-019-09570-7
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