QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

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

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI 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 ISI Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Wittmack, E. K. Articles by Dib-Hajj, S. D. Search for Related Content PubMed PubMed Citation Articles by Wittmack, E. K. Articles by Dib-Hajj, S. D.

 Previous Article  |  Next Article 

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

---

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

This article has been cited by other articles:

				A. Hudmon, J.-S. Choi, L. Tyrrell, J. A. Black, A. M. Rush, S. G. Waxman, and S. D. Dib-Hajj Phosphorylation of Sodium Channel Nav1.8 by p38 Mitogen-Activated Protein Kinase Increases Current Density in Dorsal Root Ganglion Neurons J. Neurosci., March 19, 2008; 28(12): 3190 - 3201. [Abstract] [Full Text] [PDF]

				P. T. Redman, K. He, K. A. Hartnett, B. S. Jefferson, L. Hu, P. A. Rosenberg, E. S. Levitan, and E. Aizenman Apoptotic surge of potassium currents is mediated by p38 phosphorylation of Kv2.1 PNAS, February 27, 2007; 104(9): 3568 - 3573. [Abstract] [Full Text] [PDF]

				T. B. Brust, F. S. Cayabyab, N. Zhou, and B. A. MacVicar p38 Mitogen-Activated Protein Kinase Contributes to Adenosine A1 Receptor-Mediated Synaptic Depression in Area CA1 of the Rat Hippocampus J. Neurosci., November 29, 2006; 26(48): 12427 - 12438. [Abstract] [Full Text] [PDF]

				E. Carlier, V. Sourdet, S. Boudkkazi, P. Deglise, N. Ankri, L. Fronzaroli-Molinieres, and D. Debanne Metabotropic glutamate receptor subtype 1 regulates sodium currents in rat neocortical pyramidal neurons J. Physiol., November 15, 2006; 577(1): 141 - 154. [Abstract] [Full Text] [PDF]

				N. P. Poolos, J. B. Bullis, and M. K. Roth Modulation of h-channels in hippocampal pyramidal neurons by p38 mitogen-activated protein kinase. J. Neurosci., July 26, 2006; 26(30): 7995 - 8003. [Abstract] [Full Text] [PDF]

				X. Jin and R. W. Gereau IV Acute p38-Mediated Modulation of Tetrodotoxin-Resistant Sodium Channels in Mouse Sensory Neurons by Tumor Necrosis Factor-{alpha} J. Neurosci., January 4, 2006; 26(1): 246 - 255. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help