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The Journal of Neuroscience, March 19, 2008, 28(12):3190-3201; doi:10.1523/JNEUROSCI.4403-07.2008

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Cellular/Molecular
Phosphorylation of Sodium Channel Na_v1.8 by p38 Mitogen-Activated Protein Kinase Increases Current Density in Dorsal Root Ganglion Neurons

Andy Hudmon,^1,2,3 Jin-Sung Choi,^1,2,3 Lynda Tyrrell,^1,2,3 Joel A. Black,^1,2,3 Anthony M. Rush,^1,2,3 Stephen G. Waxman,^1,2,3 and Sulayman D. Dib-Hajj^1,2,3

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

Correspondence should be addressed to Dr. Sulayman D. Dib-Hajj, The Center for Neuroscience and Regeneration Research, 127A, Building 34, Veterans Affairs Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516. Email: sulayman.dib-hajj{at}yale.edu

The sensory neuron-specific sodium channel Na_v1.8 and p38 mitogen-activated protein kinase are potential therapeutic targets within nociceptive dorsal root ganglion (DRG) neurons in inflammatory, and possibly neuropathic, pain. Na_v1.8 channels within nociceptive DRG neurons contribute most of the inward current underlying the depolarizing phase of action potentials. Nerve injury and inflammation of peripheral tissues cause p38 activation in DRG neurons, a process that may contribute to nociceptive neuron hyperexcitability, which is associated with pain. However, how substrates of activated p38 contribute to DRG neuron hyperexcitability is currently not well understood. We report here, for the first time, that Na_v1.8 and p38 are colocalized in DRG neurons, that Na_v1.8 within DRG neurons is a substrate for p38, and that direct phosphorylation of the Na_v1.8 channel by p38 regulates its function in these neurons. We show that direct phosphorylation of Na_v1.8 at two p38 phospho-acceptor serine residues on the L1 loop (S551 and S556) causes an increase in Na_v1.8 current density that is not accompanied by changes in gating properties of the channel. Our study suggests a mechanism by which activated p38 contributes to inflammatory, and possibly neuropathic, pain through a p38-mediated increase of Na_v1.8 current density.

Key words: channel modulation; SB203580; kinase inhibitor; inflammation; nociception; anisomycin; stress

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Received Oct. 26, 2006; revised Feb. 7, 2008; accepted Feb. 7, 2008.

Correspondence should be addressed to Dr. Sulayman D. Dib-Hajj, The Center for Neuroscience and Regeneration Research, 127A, Building 34, Veterans Affairs Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516. Email: sulayman.dib-hajj{at}yale.edu

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