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The Journal of Neuroscience, July 13, 2005, 25(28):6621-6630; doi:10.1523/JNEUROSCI.0541-05.2005

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Cellular/Molecular
Voltage-Gated Sodium Channel Na_v1.6 Is Modulated by p38 Mitogen-Activated Protein Kinase

Ellen K. Wittmack,^1,3,4 Anthony M. Rush,^2,3,4 Andy Hudmon,^2,3,4 Stephen G. Waxman,^1,2,3,4 and Sulayman D. Dib-Hajj^2,3,4

Departments of ¹Pharmacology and ²Neurology and ³The Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, and ⁴Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516

Na_v1.6 is the major sodium channel isoform at nodes of Ranvier in myelinated axons and, additionally, is distributed along unmyelinated C-fibers of sensory neurons. Thus, modulation of the sodium current produced by Na_v1.6 might significantly impact axonal conduction. Mitogen-activated protein kinases (MAPKs) are expressed in neurons and are activated after injury, for example, after sciatic nerve transection and hypoxia. Although the role of MAPK in signal transduction and in injury-induced regulation of gene expression is well established, the ability of these kinases to phosphorylate and modulate voltage-gated sodium channels has not been reported. Sequence analysis shows that Na_v1.6 contains a putative MAP kinase-recognition module in the cytoplasmic loop (L1), which joins domains 1 and 2. We show in this study that sodium channels and p38 MAP kinase colocalize in rat brain tissue and that activated p38 phosphorylates L1 of Na_v1.6, specifically at serine 553 (S553), in vitro. None of the other cytoplasmic loops and termini of the channel are phosphorylated by activated p38 in these assays. Activation of p38 in the neuronal ND7/23 cell line transfected with Na_v1.6 leads to a significant reduction in the peak Na_v1.6 current amplitude, without a detectable effect on gating properties. The substitution of S553 with alanine within L1 of the Na_v1.6 channel prevents p38-mediated reduction of Na_v1.6 current density. This is the first demonstration of MAPK phosphorylation and modulation of a voltage-gated sodium channel, and this modulation may represent an additional role for MAPK in regulating the neuronal response to injury.

Key words: protein kinase; kinase inhibitor; ion channel; patch clamp; anisomycin; stress

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Received Feb 9, 2005; revised June 2, 2005; accepted June 3, 2005.

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