title: PGE2 increases the tetrodotoxin-resistant Nav1.9 sodium current in mouse DRG neurons via G-proteins.
abstract: Inflammation caused by tissue damage results in pain, reflecting an increase in excitability of the primary afferent neurons innervating the area. There is some evidence to suggest that altered function of voltage-gated sodium channels is responsible for the hyperexcitability produced by inflammatory agents, possibly acting through G-proteins, but the role of different channel subtypes has not been fully explored. The tetrodotoxin-resistant (TTX-R) sodium channel Na(v)1.9 is expressed selectively in C- and A-fibre nociceptive-type units and is upregulated by G-protein activation. In this study, we examined the effects of the inflammatory agent prostaglandin-E(2) (PGE(2)) on Na(v)1.9 current in both Na(v)1.8-null and wild-type (WT) mice and explored the role of specific G-proteins in modulation. PGE(2) caused a twofold increase in Na(v)1.9 current (p<0.05) in both systems. Steady-state activation was shifted in a hyperpolarizing direction by 6-8 mV and availability of channels by 12 mV. No differences in the activation and inactivation kinetics could be detected. The increase in current was blocked by pertussis toxin (PTX) but not cholera toxin (CTX), showing involvement of G(i/o) but not G(s) subunits. Our data indicate that Na(v)1.9 current can be increased during inflammation via a G-protein dependent mechanism and suggest that this could contribute to the regulation of electrogenesis in dorsal root ganglia (DRG) neurons.
authors.affiliation: Department of Neurology, Yale University School of Medicine, LCI 707, 333 Cedar St., New Haven, CT 06510, USA.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Rush
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004553:Electric Conductivity; D019204:GTP-Binding Proteins / Q000502:physiology*; D005727:Ganglia, Spinal / Q000166:cytology*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009479:Neuropeptides / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D037342:Pertussis Toxin / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology*
chemical_list: D062558:NAV1.9 Voltage-Gated Sodium Channel; D009479:Neuropeptides; C491885:Scn11a protein, mouse; D015222:Sodium Channels; D012701:Serotonin; D013779:Tetrodotoxin; D002772:Cholera Toxin; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D015232:Dinoprostone