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This Article Full Text Full Text (PDF) All Versions of this Article: 96/1/97    most recent 00854.2005v2 00854.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by Choi, J.-S. Articles by Dib-Hajj, S. D. Search for Related Content PubMed PubMed Citation Articles by Choi, J.-S. Articles by Dib-Hajj, S. D.

Calmodulin Regulates Current Density and Frequency-Dependent Inhibition of Sodium Channel Na_v1.8 in DRG Neurons

¹Department of Neurology and ²The Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven; and ³Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut

Submitted 15 August 2005; accepted in final form 3 April 2006

Sodium channel Na_v1.8 produces a slowly inactivating, tetrodotoxin-resistant current, characterized by recovery from inactivation with fast and slow components, and contributes a substantial fraction of the current underlying the depolarizing phase of the action potential of dorsal root ganglion (DRG) neurons. Na_v1.8 C-terminus carries a conserved calmodulin-binding isoleucine–glutamine (IQ) motif. We show here that calmodulin coimmunoprecipitates with endogenous Na_v1.8 channels from native DRG, suggesting that the two proteins can interact in vivo. Treatment of native DRG neurons with a calmodulin-binding peptide (CBP) reduced the current density of Na_v1.8 by nearly 65%, without changing voltage dependency of activation or steady-state inactivation. To investigate the functional role of CaM binding to the IQ motif in the Na_v1.8 C-terminus, the IQ dipeptide was substituted by DE; we show that this impairs the binding of CaM to the IQ motif. Mutant Na_v1.8IQ/DE channels produce currents with roughly 50% amplitude, but with unchanged voltage dependency of activation and inactivation when expressed in DRG neurons from Na_v1.8-null mice. We also show that blocking the interaction of CaM and Na_v1.8 using CBP or the IQ/DE substitution causes a buildup of inactivated channels and, in the case of the IQ/DE mutation, stimulation even at a low frequency of 0.1 Hz significantly enhances the frequency-dependent inhibition of the Na_v1.8 current. This study presents, for the first time, evidence that calmodulin associates with a sodium channel, Na_v1.8, in native neurons, and demonstrates a regulation of Na_v1.8 currents that can significantly affect electrogenesis of DRG neurons in which Na_v1.8 is normally expressed.

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