Ca2+-dependent regulation of sodium channels NaV1.4 and NaV1.5 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

doi:10.1038/s41467-019-09570-7

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

Journal Article · Wed Apr 03 00:00:00 EDT 2019 · Nature Communications

DOI:https://doi.org/10.1038/s41467-019-09570-7· OSTI ID:1624148

Yoder, Jesse B. ^[1]; Ben-Johny, Manu ^[2]; Farinelli, Federica ^[1]; Srinivasan, Lakshmi ^[1]; Shoemaker, Sophie R. ^[1]; Tomaselli, Gordon F. ^[3];

^[1]; Amzel, L. Mario ^[1]

Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine
Columbia Univ., New York, NY (United States)
Albert Einstein College of Medicine, Bronx, NY (United States)

Skeletal muscle voltage-gated Na⁺ channel (Na_V1.4) activity is subject to calmodulin (CaM) mediated Ca²⁺-dependent inactivation; no such inactivation is observed in the cardiac Na⁺ channel (Na_V1.5). Taken together, the crystal structures of the Na_V1.4 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 Na_V1.5 is not present in Na_V1.4 allowing the N-lobe to signal other regions of the Na_V1.4 channel. Consistent with this mechanism, removing this binding site in Na_V1.5 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 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_V1.5 is a mutational hotspot for inherited arrhythmias, the contributions of mutation-induced changes in CDI to arrhythmia generation is an intriguing possibility.

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Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States). National Synchrotron Light Source II (NSLS-II)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); National Heart, Lung and Blood Institute (NHLBI); National Institute of General Medical Sciences (NIGMS); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: SC0012704; P41GM111244

OSTI ID:: 1624148

Journal Information:: Nature Communications, Vol. 10, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 24 works

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

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