Phosphorylation of sodium channel Na(v)1.8 by p38 mitogen-activated protein kinase increases current density in dorsal root ganglion neurons.
The sensory neuron-specific sodium channel Na(v)1.8 and p38 mitogen-activated protein kinase are potential therapeutic targets within nociceptive dorsal root ganglion (DRG) neurons in inflammatory, and possibly neuropathic, pain. Na(v)1.8 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(v)1.8 and p38 are colocalized in DRG neurons, that Na(v)1.8 within DRG neurons is a substrate for p38, and that direct phosphorylation of the Na(v)1.8 channel by p38 regulates its function in these neurons. We show that direct phosphorylation of Na(v)1.8 at two p38 phospho-acceptor serine residues on the L1 loop (S551 and S556) causes an increase in Na(v)1.8 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(v)1.8 current density.
Hudmon
Andy
A
Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Choi
Jin-Sung
JS
Tyrrell
Lynda
L
Black
Joel A
JA
Rush
Anthony M
AM
Waxman
Stephen G
SG
Dib-Hajj
Sulayman D
SD
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D002478:Cells, Cultured; D004558:Electric Stimulation / Q000379:methods; D018274:Electroporation / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D005727:Ganglia, Spinal / Q000166:cytology*; D007093:Imidazoles / Q000600:supply & distribution; D047468:Immunoprecipitation; D008297:Male; D008954:Models, Biological; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000502:physiology; D011500:Protein Synthesis Inhibitors; D011725:Pyridines / Q000600:supply & distribution; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D007093:Imidazoles; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D011500:Protein Synthesis Inhibitors; D011725:Pyridines; C568319:Scn10a protein, rat; D015222:Sodium Channels; D012694:Serine; D000841:Anisomycin; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580