PKCε phosphorylation of the sodium channel NaV1.8 increases channel function and produces mechanical hyperalgesia in mice.

Abstract

Mechanical hyperalgesia is a common and potentially disabling complication of many inflammatory and neuropathic conditions. Activation of the enzyme PKCε in primary afferent nociceptors is a major mechanism that underlies mechanical hyperalgesia, but the PKCε substrates involved downstream are not known. Here, we report that in a proteomic screen we identified the NaV1.8 sodium channel, which is selectively expressed in nociceptors, as a PKCε substrate. PKCε-mediated phosphorylation increased NaV1.8 currents, lowered the threshold voltage for activation, and produced a depolarizing shift in inactivation in wild-type - but not in PKCε-null - sensory neurons. PKCε phosphorylated NaV1.8 at S1452, and alanine substitution at this site blocked PKCε modulation of channel properties. Moreover, a specific PKCε activator peptide, ψεRACK, produced mechanical hyperalgesia in wild-type mice but not in Scn10a-/- mice, which lack NaV1.8 channels. These studies demonstrate that NaV1.8 is an important, direct substrate of PKCε that mediates PKCε-dependent mechanical hyperalgesia.

• Authors: Dai-Fei Wu, Dave Chandra, Thomas McMahon, Dan Wang, Jahan Dadgar, Viktor N Kharazia, Ying-Jian Liang, Stephen G Waxman, Sulayman D Dib-Hajj, Robert O Messing
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 122 Issue 4 Pg. 1306-15 (Apr 2012) ISSN: 1558-8238 [Electronic] United States
• PMID: 22426212 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• NAV1.8 Voltage-Gated Sodium Channel
• Scn10a protein, mouse
• Scn10a protein, rat
• Sodium Channels
• Sodium
• Prkce protein, mouse
• Prkce protein, rat
• Protein Kinase C-epsilon

Topics

• Action Potentials
• Amino Acid Substitution
• Animals
• Cells, Cultured (drug effects)
• Ganglia, Spinal (cytology)
• Hyperalgesia (enzymology, etiology)
• Ion Channel Gating
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mutation, Missense
• NAV1.8 Voltage-Gated Sodium Channel
• Point Mutation
• Protein Kinase C-epsilon (analysis, genetics, physiology)
• Protein Processing, Post-Translational
• Rats
• Sensory Receptor Cells (enzymology, physiology)
• Sodium (metabolism)
• Sodium Channels (analysis, chemistry, deficiency, genetics, physiology)
• Stress, Mechanical
• Substrate Specificity