title: Long-term inactivation particle for voltage-gated sodium channels.
abstract: Action potential generation is governed by the opening, inactivation, and recovery of voltage-gated sodium channels. A channel's voltage-sensing and pore-forming α subunit bears an intrinsic fast inactivation particle that mediates both onset of inactivation upon membrane depolarization and rapid recovery upon repolarization. We describe here a novel inactivation particle housed within an accessory channel subunit (A-type FHF protein) that mediates rapid-onset, long-term inactivation of several sodium channels. The channel-intrinsic and tethered FHF-derived particles, both situated at the cytoplasmic face of the plasma membrane, compete for induction of inactivation, causing channels to progressively accumulate into the long-term refractory state during multiple cycles of membrane depolarization. Intracellular injection of a short peptide corresponding to the FHF particle can reproduce channel long-term inactivation in a dose-dependent manner and can inhibit repetitive firing of cerebellar granule neurons. We discuss potential structural mechanisms of long-term inactivation and potential roles of A-type FHFs in the modulation of action potential generation and conduction.
authors.affiliation: Department of Physiology,University of Pavia and Brain Connectivity Center, IRCCS C. Mondino, Via Mondino 2, I-27100 Pavia, Italy.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Dover
authors.forename: Sergio
authors.initials: S
authors.lastname: Solinas
authors.forename: Egidio
authors.initials: E
authors.lastname: D'Angelo
authors.forename: Mitchell
authors.initials: M
authors.lastname: Goldfarb
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D002531:Cerebellum / Q000166:cytology / Q000502:physiology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000502:physiology; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena; D005346:Fibroblast Growth Factors / Q000138:chemical synthesis / Q000276:immunology / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D051379:Mice; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000235:genetics; D018408:Patch-Clamp Techniques; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics; D014162:Transfection
chemical_list: D019138:Antibodies, Blocking; D018076:DNA, Complementary; C108110:Fgf12 protein, mouse; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C491046:Scn8a protein, mouse; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D005346:Fibroblast Growth Factors