PKCε phosphorylation of the sodium channel NaV1.8 increases channel function and produces mechanical hyperalgesia in mice
Dai-Fei Wu, … , Sulayman D. Dib-Hajj, Robert O. Messing
Dai-Fei Wu, … , Sulayman D. Dib-Hajj, Robert O. Messing
Published March 19, 2012
Citation Information: J Clin Invest. 2012;122(4):1306-1315. https://doi.org/10.1172/JCI61934.
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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

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Figure 8

PKCε-dependent mechanical hyperalgesia is substantially reduced in Scn10a–/– mice, which lack Nav1.8 channels.

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PKCε-dependent mechanical hyperalgesia is substantially reduced in Scn10...
(A) Pretreatment with ψεRACK reduced the latency to withdraw the paw upon thermal stimulation in Prkce+/+ mice (n = 8) but not in Prkce–/– mice (n = 10) (*P < 0.05 compared with wild-type baseline or Prkce–/– mice treated with ψεRACK). (B) ψεRACK increased the response to von Frey filament stimulation in wild-type mice (n = 6) but not in Prkce–/– mice (n = 6) (*P < 0.05 compared with other conditions). (C) Nocifensive behavior lasted longer after administration of ψεRACK than after administration of saline in wild-type mice (n = 5) but not in Prkce–/– mice (*P < 0.05 compared with wild-type mice treated with saline or Prkce–/– mice treated with ψεRACK). (D) ψεRACK reduced the latency to withdraw the paw upon thermal stimulation in both wild-type mice (n = 12) and Scn10a–/– mice (n = 12). (E) ψεRACK increased the response to von Frey filament stimulation in wild-type mice (n = 14) but not in Scn10a–/– mice (n = 12) (*P < 0.01 compared with other conditions). (F) ψεRACK elicited nocifensive behavior that lasted for a similar amount of time in wild-type mice (n = 6) and in Scn10a–/– (n = 3) mice; the scrambled ψεRACK peptide did not elicit spontaneous pain in either genotype.