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 language | English (US) |
|---|---|
| Article number | 1514 |
| Journal | Nature Communications |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2019 |
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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 journal › Article
}
TY - JOUR
T1 - Ca 2+ -dependent regulation of sodium channels Na V 1.4 and Na V 1.5 is controlled by the post-IQ motif
AU - Yoder, Jesse B.
AU - Ben-Johny, Manu
AU - Farinelli, Federica
AU - Srinivasan, Lakshmi
AU - Shoemaker, Sophie R.
AU - Tomaselli, Gordon F.
AU - Gabelli, Sandra B.
AU - Amzel, L. Mario
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85063964641&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-09570-7
DO - 10.1038/s41467-019-09570-7
M3 - Article
C2 - 30944319
AN - SCOPUS:85063964641
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1514
ER -