@article{0ec062ae1fd84da182b8612c043d4133,
title = " Ca 2+ -dependent regulation of sodium channels Na V 1.4 and Na V 1.5 is controlled by the post-IQ motif ",
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{\textquoteright}s N-lobe binding outside the Na V C-terminal while CaM{\textquoteright}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. ",
author = "Yoder, {Jesse B.} and Manu Ben-Johny and Federica Farinelli and Lakshmi Srinivasan and Shoemaker, {Sophie R.} and Tomaselli, {Gordon F.} and Gabelli, {Sandra B.} and Amzel, {L. Mario}",
note = "Funding Information: This work was funded by NIH NHLBI (HL128743). X-ray data collection was carried out at beamlines FMX and AMX, part of the Life Science Biomedical Technology Research resource (LSBR) primarily supported by the National Institute of Health, National Institute of General Medical Sciences (NIGMS) through a Biomedical Technology Research Resource P41 grant (P41GM111244), and by the DOE Office of Biological and Environmental Research (KP1605010). As a National Synchrotron Light Source II facility resource at Brookhaven National Laboratory, work performed at the LSBR is supported in part by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences Program under contract number and DE-SC0012704 (KC0401040). Special thanks to Richard W. Aldrich (UT Austin) for helpful discussion and insightful comments and suggestions. We thank Rahul Banerjee, Sara Nathan, and Mofeed Nagib for helpful discussions. Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41467-019-09570-7",
language = "English (US)",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}