Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-09570-7
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Funding
- NIH NHLBI [HL128743]
- National Institute of Health, National Institute of General Medical Sciences (NIGMS) through a Biomedical Technology Research Resource P41 grant [P41GM111244]
- DOE Office of Biological and Environmental Research [KP1605010]
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences Program [DE-SC0012704 (KC0401040)]
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Skeletal muscle voltage-gated Na+ channel (Na(V)1.4) activity is subject to calmodulin (CaM) mediated Ca2+-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 Ca2+-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 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(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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