title: Protein kinase C enhances human sodium channel hNav1.7 resurgent currents via a serine residue in the domain III-IV linker.
abstract: Resurgent sodium currents likely play a role in modulating neuronal excitability. Here we studied whether protein kinase C (PKC) activation can increase resurgent currents produced by the human sodium channel hNav1.7. We found that a PKC agonist significantly enhanced hNav1.7-mediated resurgent currents and this was prevented by PKC antagonists. The enhancing effects were replicated by two phosphorylation-mimicking mutations and were prevented by a phosphorylation-deficient mutation at a conserved PKC phosphorylation site (Serine 1479). Our results suggest that PKC can increase sodium resurgent currents through phosphorylation of a conserved Serine residue located in the domain III-IV linker of sodium channels.
authors.affiliation: Department of Pharmacology and Toxicology and Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: zt2@iupui.edu.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Tan
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: Birgit T
authors.initials: BT
authors.lastname: Priest
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Krajewski
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Knopp
authors.affiliation: Lilly Research Laboratories, Indianapolis, IN 46285, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Nisenbaum
authors.affiliation: Department of Pharmacology and Toxicology and Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Cummins
mesh_terms: D017124:Conserved Sequence; D055724:Electrophysiological Phenomena; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012694:Serine; D012964:Sodium / Q000378:metabolism
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D012694:Serine; D012964:Sodium; D011493:Protein Kinase C
keywords: Mutation; Protein kinase C; Resurgent current; Sodium channel; Voltage clamp; hNav1.7