Voltage-gated sodium channel Nav1.6 is modulated by p38 mitogen-activated protein kinase

Na(v)1.6 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(v)1.6 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(v)1.6 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 alpha phosphorylates L1 of Na(v)1.6, specifically at serine 553 (S553), in vitro. None of the other cytoplasmic loops and termini of the channel are phosphorylated by activated p38 alpha in these assays. Activation of p38 in the neuronal ND7/23 cell line transfected with Na(v)1.6 leads to a significant reduction in the peak Na(v)1.6 current amplitude, without a detectable effect on gating properties. The substitution of S553 with alanine within L1 of the Na(v)1.6 channel prevents p38-mediated reduction of Na(v)1.6 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.