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The Journal of Neuroscience, September 10, 2003, 23(23):8261-8270

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Calmodulin Binds to the C Terminus of Sodium Channels Na_v1.4 and Na_v1.6 and Differentially Modulates Their Functional Properties

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

Department of Neurology and Paralyzed Veterans of America/Eastern Paralyzed Veterans Association Neuroscience Research Center, Yale School of Medicine, New Haven, Connecticut 06510, and Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare, West Haven, Connecticut 06516

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 Na_v1.1-Na_v1.9 indicates that some of the tetrodotoxin-sensitive VGSC isoforms, including Na_V1.4 and Na_V1.6, are able to bind CaM in a calcium-independent manner. Here we demonstrate that association with CaM is important for functional expression of Na_V1.4 and Na_V1.6 VGSCs. Disrupting the interaction between CaM and the C terminus of Na_V1.4 and Na_V1.6 channels reduced current amplitude by 99 and 62%, respectively. Overexpression of CaM increased the current generated by Na_v1.4 and Na_v1.6 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 Na_v1.6, but not Na_v1.4, 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.

Key words: sodium channel; sodium current; current amplitude; calmodulin; calcium/calmodulin; fast inactivation

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Received April 30, 2003; revised July 22, 2003; accepted July 29, 2003.

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