title: Role of calcium and calpain in the downregulation of voltage-gated sodium channel expression by the pyrethroid pesticide deltamethrin.
abstract: Voltage-gated sodium channels (Na(v)) are essential for initiation and propagation of action potentials. Previous in vitro studies reported that exposure to the Na(v) toxins veratridine and α scorpion toxin cause persistent downregulation of Na(v) mRNA in vitro. However the mechanism of this downregulation is not well characterized. Here, we report that the type-II pyrethroid deltamethrin, which has a similar mechanism as these toxins, elicited an approximate 25% reduction in Na(v) 1.2 and Na(v) 1.3 mRNA in SK-N-AS cells. Deltamethrin-induced decreases of Na(v) mRNA were blocked with the Na(v) antagonist tetrodotoxin, demonstrating a primary role for interaction with Na(v). Pre-treatment with the intracellular calcium chelator BAPTA-AM and the calpain inhibitor PD-150606 also prevented these decreases, identifying a role for intracellular calcium and calpain activation. Because alterations in Na(v) expression and function can result in neurotoxicity, additional studies are warranted to determine whether or not such effects occur in vivo.
authors.affiliation: Environmental and Occupational Health Sciences Institute and Department of Environmental and Occupational Medicine, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, 08854, USA. Jricha3@eohsi.rutgers.edu.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Magby
authors.forename: Jason R
authors.initials: JR
authors.lastname: Richardson
mesh_terms: D002118:Calcium / Q000502:physiology*; D002154:Calpain / Q000502:physiology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D007306:Insecticides / Q000494:pharmacology*; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D062552:NAV1.3 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology*; D011722:Pyrethrins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D007306:Insecticides; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062552:NAV1.3 Voltage-Gated Sodium Channel; D009570:Nitriles; D011722:Pyrethrins; D012333:RNA, Messenger; C017180:decamethrin; D002154:Calpain; D002118:Calcium
keywords: Calpain; Deltamethrin; Intracellular Calcium; Pyrethroid; Sodium Channel; Tetrodotoxin