Calmodulin binds to the C terminus of sodium channels Nav1.4 and Navl.6 and differentially modulates their functional properties

Raimund I. Herzog, Chuanju Liu, Stephen G. Waxman, Theodore R. Cummins

Research output: Contribution to journalArticle

118 Scopus citations

Abstract

Modulation of voltage-gated sodium channels (VGSC) can have a major impact on cell excitability. Analysis of calmodulin (CaM) binding to GST-fusion proteins containing the C-terminal domains of Navl.l-Na vl.9 indicates that some of the tetrodotoxin-sensitive VGSC isoforms, including Navl.4 and Navl.6, are able to bind CaM in a calcium-independent manner. Here we demonstrate that association with CaM is important for functional expression of Nav1.4 and Navl.6 VGSCs. Disrupting the interaction between CaM and the C terminus of Na vl.4 and Navl.6 channels reduced current amplitude by 99 and 62%, respectively. Overexpression of CaM increased the current generated by Navl.4 and Navl.6 C-terminal mutant constructs that exhibited intermediate current densities and intermediate binding affinities for CaM, demonstrating that this effect on current density was directly dependent on the ability of the C terminus to bind CaM. In addition to the effects on current density, calmodulin also was able to modulate the inactivation kinetics of Navl.6, but not Navl.4 currents in a calcium-dependent manner. Our data demonstrate that CaM can regulate the properties of VGSCs via calcium-dependent and calcium-independent mechanisms and suggest that modulation of neuronal sodium channels may play a role in calcium-dependent neuronal plasticity.

Original languageEnglish (US)
Pages (from-to)8261-8270
Number of pages10
JournalJournal of Neuroscience
Volume23
Issue number23
DOIs
StatePublished - Sep 10 2003

Keywords

  • Calcium/calmodulin
  • Calmodulin
  • Current amplitude
  • Fast inactivation
  • Sodium channel
  • Sodium current

ASJC Scopus subject areas

  • Neuroscience(all)

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