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Publication Abstract from PubMed

The neuronal-voltage gated sodium channel (VGSC), NaV1.6, plays an important role in propagating action potentials along myelinated axons. Calmodulin (CaM) is known to modulate the inactivation kinetics of NaV1.6 by interacting with its IQ motif. Here we report the crystal structure of apo-CaM:NaV1.6IQ motif, along with functional studies. The IQ motif of NaV1.6 adopts an alpha-helical conformation in its interaction with the C-lobe of CaM. CaM uses different residues to interact with NaV1.6IQ motif depending on the presence or absence of Ca(2+). Three residues from NaV1.6, Arg1902, Tyr1904 and Arg1905 were identified as the key common interacting residues in both the presence and absence of Ca(2+). Substitution of Arg1902 and Tyr1904 with alanine showed a reduced rate of NaV1.6 inactivation in electrophysiological experiments in vivo. Compared with other CaM:NaV complexes, our results reveal a different mode of interaction for CaM:NaV1.6 and provides structural insight into the isoform-specific modulation of VGSCs.

Structural Basis for the Modulation of the Neuronal Voltage-Gated Sodium Channel NaV1.6 by Calmodulin.,Chichili VP, Xiao Y, Seetharaman J, Cummins TR, Sivaraman J Sci Rep. 2013 Aug 14;3:2435. doi: 10.1038/srep02435. PMID:23942337^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.