| First Author | Wu DF | Year | 2012 |
| Journal | J Clin Invest | Volume | 122 |
| Issue | 4 | Pages | 1306-15 |
| PubMed ID | 22426212 | Mgi Jnum | J:184549 |
| Mgi Id | MGI:5424305 | Doi | 10.1172/JCI61934 |
| Citation | Wu DF, et al. (2012) PKCepsilon phosphorylation of the sodium channel NaV1.8 increases channel function and produces mechanical hyperalgesia in mice. J Clin Invest 122(4):1306-15 |
| abstractText | Mechanical hyperalgesia is a common and potentially disabling complication of many inflammatory and neuropathic conditions. Activation of the enzyme PKCepsilon in primary afferent nociceptors is a major mechanism that underlies mechanical hyperalgesia, but the PKCepsilon 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 PKCepsilon substrate. PKCepsilon-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 PKCepsilon-null - sensory neurons. PKCepsilon phosphorylated NaV1.8 at S1452, and alanine substitution at this site blocked PKCepsilon modulation of channel properties. Moreover, a specific PKCepsilon activator peptide, psiepsilonRACK, 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 PKCepsilon that mediates PKCepsilon-dependent mechanical hyperalgesia. |
