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

• Published in: Nature communications Vol. 10; no. 1; pp. 1514 - 12
• Main Authors: Yoder, Jesse B., Ben-Johny, Manu, Farinelli, Federica, Srinivasan, Lakshmi, Shoemaker, Sophie R., Tomaselli, Gordon F., Gabelli, Sandra B., Amzel, L. Mario
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.04.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 631/1647/1453; 631/45/535/1266; 631/57; 631/57/2272/951; 9/74; Arrhythmia; BASIC BIOLOGICAL SCIENCES; Binding sites; Biophysics; Calcium channels; Calcium ions; Calcium-binding protein; Calmodulin; Crystal structure; Deactivation; Electrophysiology; Humanities and Social Sciences; Inactivation; multidisciplinary; Muscles; Mutation; Science; Science & technology - other topics; Science (multidisciplinary); Skeletal muscle; Sodium; Sodium channels (voltage-gated); Thermodynamics; X-ray crystallography
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09570-7

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. Skeletal muscle voltage-gated Na + channel (Na V 1.4) activity is subject to calmodulin (CaM) mediated Ca 2 + -dependent inactivation while cardiac Na V 1.5 is not. Here authors use structural biology, binding and electrophysiology to parse the Ca 2 + -dependent changes of CaM when bound to the NaV1.4.