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PMID: 12967988 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 23 ·No. 23 ·2003-09-10 ·Pages 8261-70

Herzog RI, Liu C, Waxman SG, Cummins TR

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 Nav1.1-Nav1.9 indicates that some of the tetrodotoxin-sensitive VGSC isoforms, including NaV1.4 and NaV1.6, 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 NaV1.6 VGSCs. Disrupting the interaction between CaM and the C terminus of NaV1.4 and NaV1.6 channels reduced current amplitude by 99 and 62%, respectively. Overexpression of CaM increased the current generated by Nav1.4 and Nav1.6 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 Nav1.6, but not Nav1.4, 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.

MeSH Terms
Amino Acid Motifs/physiology Animals Biolistics Calcium/metabolism Calmodulin/genetics,metabolism Cells, Cultured Humans Kidney/cytology,metabolism Kinetics Mice Mutagenesis, Site-Directed NAV1.6 Voltage-Gated Sodium Channel Nerve Tissue Proteins Neurons/cytology,metabolism Patch-Clamp Techniques Protein Binding/physiology Protein Isoforms/genetics,metabolism Rats Signal Transduction/physiology Sodium Channels/genetics,metabolism
Chemicals
Calmodulin NAV1.6 Voltage-Gated Sodium Channel Nerve Tissue Proteins Protein Isoforms SCN8A protein, human Scn8a protein, mouse Sodium Channels Calcium
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Herzog Raimund I
Department of Neurology and Paralyzed Veterans of America/Eastern Paralyzed Veterans Association Neuroscience Research Center, Yale School of Medicine, New Haven, Connecticut 06510, USA.
Liu Chuanju
Waxman Stephen G
Cummins Theodore R
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Published
2003-09-10
Pages
8261-70
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6740705
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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