title: Sodium channel slow inactivation interferes with open channel block.
abstract: Mutations in the voltage-gated sodium channel Nav1.7 are linked to inherited pain syndromes such as erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). PEPD mutations impair Nav1.7 fast inactivation and increase persistent currents. PEPD mutations also increase resurgent currents, which involve the voltage-dependent release of an open channel blocker. In contrast, IEM mutations, whenever tested, leave resurgent currents unchanged. Accordingly, the IEM deletion mutation L955 (ΔL955) fails to produce resurgent currents despite enhanced persistent currents, which have hitherto been considered a prerequisite for resurgent currents. Additionally, ΔL955 exhibits a prominent enhancement of slow inactivation (SI). We introduced mutations into Nav1.7 and Nav1.6 that either enhance or impair SI in order to investigate their effects on resurgent currents. Our results show that enhanced SI is accompanied by impaired resurgent currents, which suggests that SI may interfere with open-channel block.
authors.affiliation: Institute of Physiology and Pathophysiology Friedrich-Alexander Universität Erlangen-Nürnberg, Universitaetsstrasse 17, 91054 Erlangen, Germany.|Institute of Physiology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hampl
authors.affiliation: Institute of Physiology and Pathophysiology Friedrich-Alexander Universität Erlangen-Nürnberg, Universitaetsstrasse 17, 91054 Erlangen, Germany.|Department of Anesthesiology, Universitaetsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Krankenhausstrasse 12, 91054 Erlangen.
authors.forename: Esther
authors.initials: E
authors.lastname: Eberhardt
authors.affiliation: Institute of Physiology and Pathophysiology Friedrich-Alexander Universität Erlangen-Nürnberg, Universitaetsstrasse 17, 91054 Erlangen, Germany.|School of Natural Sciences and Psychology, Liverpool John Moores University, Liverpool, UK.
authors.forename: Andrias O
authors.initials: AO
authors.lastname: O'Reilly
authors.affiliation: Institute of Physiology and Pathophysiology Friedrich-Alexander Universität Erlangen-Nürnberg, Universitaetsstrasse 17, 91054 Erlangen, Germany.|Institute of Physiology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Lampert
mesh_terms: D000200:Action Potentials; D002478:Cells, Cultured; D004916:Erythromelalgia / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology; D010146:Pain / Q000235:genetics; D018408:Patch-Clamp Techniques; D012007:Rectum / Q000002:abnormalities
chemical_list: D062557:NAV1.6 Voltage-Gated Sodium Channel; D062556:NAV1.7 Voltage-Gated Sodium Channel; C100681:SCN8A protein, human; C486866:SCN9A protein, human