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

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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

Fingerprint

Sodium Channels
Cams
Calmodulin
lobes
Cardiac Arrhythmias
Protein Isoforms
deactivation
Binding Sites
calmodulin
arrhythmia
cams
Thermodynamics
Muscle
Skeletal Muscle
Crystal structure
Mutation
Electric potential
skeletal muscle
mutations
thermodynamics

ASJC Scopus subject areas

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

Cite this

Ca 2+ -dependent regulation of sodium channels Na V 1.4 and Na V 1.5 is controlled by the post-IQ motif . / Yoder, Jesse B.; Ben-Johny, Manu; Farinelli, Federica; Srinivasan, Lakshmi; Shoemaker, Sophie R.; Tomaselli, Gordon F.; Gabelli, Sandra B.; Amzel, L. Mario.

In: Nature Communications, Vol. 10, No. 1, 1514, 01.12.2019.

Research output: Contribution to journalArticle

Yoder, JB, Ben-Johny, M, Farinelli, F, Srinivasan, L, Shoemaker, SR, Tomaselli, GF, Gabelli, SB & Amzel, LM 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, vol. 10, no. 1, 1514. https://doi.org/10.1038/s41467-019-09570-7
Yoder, Jesse B. ; Ben-Johny, Manu ; Farinelli, Federica ; Srinivasan, Lakshmi ; Shoemaker, Sophie R. ; Tomaselli, Gordon F. ; Gabelli, Sandra B. ; Amzel, L. Mario. / Ca 2+ -dependent regulation of sodium channels Na V 1.4 and Na V 1.5 is controlled by the post-IQ motif In: Nature Communications. 2019 ; Vol. 10, No. 1.
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