• Dai-Fei Wu, Dave Chandra, Thomas McMahon, Dan Wang, Jahan Dadgar, Viktor N Kharazia, Ying-Jian Liang, Stephen G Waxman, Sulayman D Dib-Hajj, and Robert O Messing.
• Ernest Gallo Clinic and Research Center, Department of Neurology, UCSF, Emeryville, California 94608, USA.
• J. Clin. Invest. 2012 Apr 1;122(4):1306-15.

AbstractMechanical 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.

40 keywords...

hide…