PKCε phosphorylation of the sodium channel Na _V1.8 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 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 Na _V1.8 sodium channel, which is selectively expressed in nociceptors, as a PKCε substrate. PKCε-mediated phosphorylation increased Na _V1.8 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 Na _V1.8 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 Na _V1.8 channels. These studies demonstrate that Na _V1.8 is an important, direct substrate of PKCε that mediates PKCε-dependent mechanical hyperalgesia.