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PKC? 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 PKC? in primary afferent nociceptors is a major mechanism that underlies mechanical hyperalgesia, but the PKC? 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 PKC? substrate. PKC?-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 PKC?-null - sensory neurons. PKC? phosphorylated NaV1.8 at S1452, and alanine substitution at this site blocked PKC? modulation of channel properties. Moreover, a specific PKC? activator peptide, ??RACK, 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 PKC? that mediates PKC?-dependent mechanical hyperalgesia.

SUBMITTER: Wu DF

PROVIDER: S-EPMC3315445 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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

Wu Dai-Fei DF Chandra Dave D McMahon Thomas T Wang Dan D Dadgar Jahan J Kharazia Viktor N VN Liang Ying-Jian YJ Waxman Stephen G SG Dib-Hajj Sulayman D SD Messing Robert O RO

The Journal of clinical investigation 20120319 4

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 Na ...[more]

PMID: 22426212

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Project description:BackgroundFunctional alterations in the properties of A? afferent fibers may account for the increased pain sensitivity observed under peripheral chronic inflammation. Among the voltage-gated sodium channels involved in the pathophysiology of pain, Na(v)1.8 has been shown to participate in the peripheral sensitization of nociceptors. However, to date, there is no evidence for a role of Na(v)1.8 in controlling A?-fiber excitability following persistent inflammation.MethodsDistribution and expression of Na(v)1.8 in dorsal root ganglia and sciatic nerves were qualitatively or quantitatively assessed by immunohistochemical staining and by real time-polymerase chain reaction at different time points following complete Freund's adjuvant (CFA) administration. Using a whole-cell patch-clamp configuration, we further determined both total INa and TTX-R Na(v)1.8 currents in large-soma dorsal root ganglia (DRG) neurons isolated from sham or CFA-treated rats. Finally, we analyzed the effects of ambroxol, a Na(v)1.8-preferring blocker on the electrophysiological properties of Nav1.8 currents and on the mechanical sensitivity and inflammation of the hind paw in CFA-treated rats.ResultsOur findings revealed that Na(v)1.8 is up-regulated in NF200-positive large sensory neurons and is subsequently anterogradely transported from the DRG cell bodies along the axons toward the periphery after CFA-induced inflammation. We also demonstrated that both total INa and Na(v)1.8 peak current densities are enhanced in inflamed large myelinated A?-fiber neurons. Persistent inflammation leading to nociception also induced time-dependent changes in A?-fiber neuron excitability by shifting the voltage-dependent activation of Na(v)1.8 in the hyperpolarizing direction, thus decreasing the current threshold for triggering action potentials. Finally, we found that ambroxol significantly reduces the potentiation of Na(v)1.8 currents in A?-fiber neurons observed following intraplantar CFA injection and concomitantly blocks CFA-induced mechanical allodynia, suggesting that Na(v)1.8 regulation in A?-fibers contributes to inflammatory pain.ConclusionsCollectively, these findings support a key role for Na(v)1.8 in controlling the excitability of A?-fibers and its potential contribution to the development of mechanical allodynia under persistent inflammation.

Dataset Information

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

Publications

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

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