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 Cummins

Research output: Contribution to journalArticle

114 Citations (Scopus)

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

Fingerprint

Sodium Channels
Calmodulin
Calcium
Voltage-Gated Sodium Channels
Neuronal Plasticity
Tetrodotoxin
Protein C
Protein Isoforms

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Calmodulin binds to the C terminus of sodium channels Nav1.4 and Navl.6 and differentially modulates their functional properties. / Herzog, Raimund I.; Liu, Chuanju; Waxman, Stephen G.; Cummins, Theodore.

In: Journal of Neuroscience, Vol. 23, No. 23, 10.09.2003, p. 8261-8270.

Research output: Contribution to journalArticle

@article{7c5038d347154f1d97e568fbfbec9caf,
title = "Calmodulin binds to the C terminus of sodium channels Nav1.4 and Navl.6 and differentially modulates their functional properties",
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.",
keywords = "Calcium/calmodulin, Calmodulin, Current amplitude, Fast inactivation, Sodium channel, Sodium current",
author = "Herzog, {Raimund I.} and Chuanju Liu and Waxman, {Stephen G.} and Theodore Cummins",
year = "2003",
month = "9",
day = "10",
language = "English",
volume = "23",
pages = "8261--8270",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "23",

}

TY - JOUR

T1 - Calmodulin binds to the C terminus of sodium channels Nav1.4 and Navl.6 and differentially modulates their functional properties

AU - Herzog, Raimund I.

AU - Liu, Chuanju

AU - Waxman, Stephen G.

AU - Cummins, Theodore

PY - 2003/9/10

Y1 - 2003/9/10

N2 - 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.

AB - 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.

KW - Calcium/calmodulin

KW - Calmodulin

KW - Current amplitude

KW - Fast inactivation

KW - Sodium channel

KW - Sodium current

UR - http://www.scopus.com/inward/record.url?scp=0141856484&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0141856484&partnerID=8YFLogxK

M3 - Article

C2 - 12967988

AN - SCOPUS:0141856484

VL - 23

SP - 8261

EP - 8270

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 23

ER -