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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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Research Article Neuroscience Article has an altmetric score of 4

PKCε phosphorylation of the sodium channel NaV1.8 increases channel function and produces mechanical hyperalgesia in mice

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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 6

ψεRACK enhances Nav1.8 current in wild-type but not Prkce–/– DRG neurons.

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ψεRACK enhances Nav1.8 current in wild-type but not Prkce–/– DRG neurons...
(A) Families of current traces recorded in the presence of 300 nM TTX from cells depolarized to a range of voltages (–70 to +50 mV) from a holding potential of –120 mV (left) to elicit NaV1.9 currents or from –70 mV (middle and right) to elicit NaV1.8 currents from Scn10a–/– (middle) or Scn10a+/+ (right) neurons. (B) Voltage-clamp recordings in Prkce+/+ or Prkce–/– neurons incubated with ψεRACK or scrambled ψεRACK using a holding potential of –70 mV. (C) Compared with that in untreated control Prkce+/+ neurons (n = 23), administration of ψεRACK (n = 30) increased the peak sodium current, while scrambled ψεRACK (n = 20) had no effect (*P < 0.05 versus Prkce+/+ control cells or Prkce+/+ cells treated with scrambled ψεRACK by Dunn’s multiple comparison test). Neurons were obtained from 5 to 8 mice of each genotype.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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