Pkc Epsilon Phosphorylation Of The Sodium Channel Na(V)1.8 Increases Channel Function And Produces Mechanical Hyperalgesia In Mice

Mechanical hyperalgesia is a common and potentially disabling complication of many inflammatory and neuropathic conditions. Activation of the enzyme PKC epsilon in primary afferent nociceptors is a major mechanism that underlies mechanical hyperalgesia, but the PKC epsilon substrates involved downstream are not known. Here, we report that in a proteomic screen we identified the Na(V)1.8 sodium channel, which is selectively expressed in nociceptors, as a PKC epsilon substrate. PKC epsilon-mediated phosphorylation increased Na(V)1.8 currents, lowered the threshold voltage for activation, and produced a depolarizing shift in inactivation in wild-type - but not in PKC epsilon-null - sensory neurons. PKC epsilon phosphorylated Na(V)1.8 at S1452, and alanine substitution at this site blocked PKC epsilon modulation of channel properties. Moreover, a specific PKC epsilon activator peptide, psi epsilon RACK, produced mechanical hyperalgesia in wild-type mice but not in Scn10a(-/-) mice, which lack Na(V)1.8 channels. These studies demonstrate that Na(V)1.8 is an important, direct substrate of PKC epsilon that mediates PKC epsilon-dependent mechanical hyperalgesia.