title: 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.affiliation: Ernest Gallo Clinic and Research Center, Department of Neurology, UCSF, Emeryville, California 94608, USA.
authors.forename: Dai-Fei
authors.initials: DF
authors.lastname: Wu
authors.forename: Dave
authors.initials: D
authors.lastname: Chandra
authors.forename: Thomas
authors.initials: T
authors.lastname: McMahon
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.forename: Jahan
authors.initials: J
authors.lastname: Dadgar
authors.forename: Viktor N
authors.initials: VN
authors.lastname: Kharazia
authors.forename: Ying-Jian
authors.initials: YJ
authors.lastname: Liang
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.forename: Robert O
authors.initials: RO
authors.lastname: Messing
mesh_terms: D000200:Action Potentials; D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects; D005727:Ganglia, Spinal / Q000166:cytology; D006930:Hyperalgesia / Q000201:enzymology / Q000209:etiology*; D015640:Ion Channel Gating; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020125:Mutation, Missense; D062559:NAV1.8 Voltage-Gated Sodium Channel; D017354:Point Mutation; D051744:Protein Kinase C-epsilon / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D051381:Rats; D011984:Sensory Receptor Cells / Q000201:enzymology / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000032:analysis / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013314:Stress, Mechanical; D013379:Substrate Specificity
chemical_list: D062559:NAV1.8 Voltage-Gated Sodium Channel; C568318:Scn10a protein, mouse; C568319:Scn10a protein, rat; D015222:Sodium Channels; D012964:Sodium; C497256:Prkce protein, mouse; C497257:Prkce protein, rat; D051744:Protein Kinase C-epsilon