title: Calmodulin binds to the C terminus of sodium channels Nav1.4 and Nav1.6 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 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.
authors.affiliation: Department of Neurology and Paralyzed Veterans of America/Eastern Paralyzed Veterans Association Neuroscience Research Center, Yale School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Raimund I
authors.initials: RI
authors.lastname: Herzog
authors.forename: Chuanju
authors.initials: C
authors.lastname: Liu
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Cummins
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D019470:Biolistics; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D016297:Mutagenesis, Site-Directed; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011485:Protein Binding / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D002147:Calmodulin; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C100681:SCN8A protein, human; C491046:Scn8a protein, mouse; D015222:Sodium Channels; D002118:Calcium