Structural basis for the modulation of the neuronal Voltage-gated sodium channel Na v 1.6 by calmodulin

Vishnu Priyanka Reddy Chichili, Yucheng Xiao, J. Seetharaman, Theodore Cummins, J. Sivaraman

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The neuronal-voltage gated sodium channel (VGSC), Na V 1.6, plays an important role in propagating action potentials along myelinated axons. Calmodulin (CaM) is known to modulate the inactivation kinetics of Na V 1.6 by interacting with its IQ motif. Here we report the crystal structure of apo-CaM:Na V 1.6IQ motif, along with functional studies. The IQ motif of Na V 1.6 adopts an α-helical conformation in its interaction with the C-lobe of CaM. CaM uses different residues to interact with Na V 1.6IQ motif depending on the presence or absence of Ca2+. Three residues from Na V 1.6, Arg1902, Tyr1904 and Arg1905 were identified as the key common interacting residues in both the presence and absence of Ca2+. Substitution of Arg1902 and Tyr1904 with alanine showed a reduced rate of Na V 1.6 inactivation in electrophysiological experiments in vivo. Compared with other CaM:Na V complexes, our results reveal a different mode of interaction for CaM:Na V 1.6 and provides structural insight into the isoform-specific modulation of VGSCs.

Original languageEnglish
Article number2435
JournalScientific Reports
Volume3
DOIs
StatePublished - 2013

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Voltage-Gated Sodium Channels
Calmodulin
Alanine
Action Potentials
Axons
Protein Isoforms

Keywords

  • Ion Channels In The Nervous System
  • Proteins
  • Sodium Channels
  • Subject Areas
  • X-Ray Crystallography

ASJC Scopus subject areas

  • General

Cite this

Structural basis for the modulation of the neuronal Voltage-gated sodium channel Na v 1.6 by calmodulin. / Chichili, Vishnu Priyanka Reddy; Xiao, Yucheng; Seetharaman, J.; Cummins, Theodore; Sivaraman, J.

In: Scientific Reports, Vol. 3, 2435, 2013.

Research output: Contribution to journalArticle

Chichili, Vishnu Priyanka Reddy ; Xiao, Yucheng ; Seetharaman, J. ; Cummins, Theodore ; Sivaraman, J. / Structural basis for the modulation of the neuronal Voltage-gated sodium channel Na v 1.6 by calmodulin. In: Scientific Reports. 2013 ; Vol. 3.
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AU - Cummins, Theodore

AU - Sivaraman, J.

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