TY - JOUR T1 - Voltage-Gated Sodium Channel Na<sub>v</sub>1.6 Is Modulated by p38 Mitogen-Activated Protein Kinase JF - The Journal of Neuroscience JO - J. Neurosci. SP - 6621 LP - 6630 DO - 10.1523/JNEUROSCI.0541-05.2005 VL - 25 IS - 28 AU - Ellen K. Wittmack AU - Anthony M. Rush AU - Andy Hudmon AU - Stephen G. Waxman AU - Sulayman D. Dib-Hajj Y1 - 2005/07/13 UR - http://www.jneurosci.org/content/25/28/6621.abstract N2 - Nav1.6 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 Nav1.6 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 Nav1.6 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 p38α phosphorylates L1 of Nav1.6, specifically at serine 553 (S553), in vitro. None of the other cytoplasmic loops and termini of the channel are phosphorylated by activated p38α in these assays. Activation of p38 in the neuronal ND7/23 cell line transfected with Nav1.6 leads to a significant reduction in the peak Nav1.6 current amplitude, without a detectable effect on gating properties. The substitution of S553 with alanine within L1 of the Nav1.6 channel prevents p38-mediated reduction of Nav1.6 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. ER -