Ca 2+ -dependent regulation of sodium channels Na V 1.4 and Na V 1.5 is controlled by the post-IQ motif

Jesse B. Yoder, Manu Ben-Johny, Federica Farinelli, Lakshmi Srinivasan, Sophie R. Shoemaker, Gordon F. Tomaselli, Sandra B. Gabelli, L. Mario Amzel

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Skeletal muscle voltage-gated Na + channel (Na V 1.4) activity is subject to calmodulin (CaM) mediated Ca 2+ -dependent inactivation; no such inactivation is observed in the cardiac Na + channel (Na V 1.5). Taken together, the crystal structures of the Na V 1.4 C-terminal domain relevant complexes and thermodynamic binding data presented here provide a rationale for this isoform difference. A Ca 2+ -dependent CaM N-lobe binding site previously identified in Na V 1.5 is not present in Na V 1.4 allowing the N-lobe to signal other regions of the Na V 1.4 channel. Consistent with this mechanism, removing this binding site in Na V 1.5 unveils robust Ca 2+ -dependent inactivation in the previously insensitive isoform. These findings suggest that Ca 2+ -dependent inactivation is effected by CaM’s N-lobe binding outside the Na V C-terminal while CaM’s C-lobe remains bound to the Na V C-terminal. As the N-lobe binding motif of Na V 1.5 is a mutational hotspot for inherited arrhythmias, the contributions of mutation-induced changes in CDI to arrhythmia generation is an intriguing possibility.

Original languageEnglish (US)
Article number1514
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint Dive into the research topics of 'Ca <sup>2+</sup> -dependent regulation of sodium channels Na <sub>V</sub> 1.4 and Na <sub>V</sub> 1.5 is controlled by the post-IQ motif'. Together they form a unique fingerprint.

  • Cite this

    Yoder, J. B., Ben-Johny, M., Farinelli, F., Srinivasan, L., Shoemaker, S. R., Tomaselli, G. F., Gabelli, S. B., & Amzel, L. M. (2019). Ca 2+ -dependent regulation of sodium channels Na V 1.4 and Na V 1.5 is controlled by the post-IQ motif Nature communications, 10(1), [1514]. https://doi.org/10.1038/s41467-019-09570-7