title: Consequences of acute Nav1.1 exposure to deltamethrin.
abstract: BACKGROUND
  Pyrethroid insecticides are the most popular class of insecticides in the world, despite their near-ubiquity, their effects of delaying the onset of inactivation of voltage-gated sodium (Nav) channels have not been well-evaluated in all the mammalian Navisoforms.
  
  
  OBJECTIVE
  Here we compare the well-studied Nav1.6 isoforms to the less-understood Nav1.1 in their responses to acute deltamethrin exposure.
  
  
  METHODS
  We used patch-clamp electrophysiology to record sodium currents encoded by either Nav1.1 or Nav1.6 channels stably expressed in HEK293 cells. Protocols evaluating both resting and use-dependent modification were employed.
  
  
  RESULTS
  We found that exposure of both isoforms to 10μM deltamethrin significantly potentiated persistent and tail current densities without affecting peak transient current densities, and only Nav1.1 maintained these significant effects at 1μM deltamethrin. Window currents increased for both as well, and while only Nav1.6 displayed changes in activation slope and V1/2of steady-state inactivation for peak currents, V1/2of persistent current activation was hyperpolarized of ∼10mV by deltamethrin in Nav1.1 cells. Evaluating use-dependence, we found that deltamethrin again potentiated persistent and tail current densities in both isoforms, but only Nav1.6 demonstrated use-dependent enhancement, indicating the primary deltamethrin-induced effects on Nav1.1 channels are not use-dependent.
  
  
  CONCLUSIONS
  Collectively, these data provide evidence that Nav1.1 is indeed vulnerable to deltamethrin modification at lower concentrations than Nav1.6, and this effect is primarily mediated during the resting state.
  
  
  CONCLUSIONS
  These findings identify Nav1.1 as a novel target of pyrethroid exposure, which has major implications for the etiology of neuropsychiatric disorders associated with loss of Nav1.1-expressing inhibitory neurons.
authors.affiliation: Department of Pharmacology & Toxicology, University of Texas Medical Branch, USA; Neuroscience Graduate Program, University of Texas Medical Branch, USA.
authors.forename: T F
authors.initials: TF
authors.lastname: James
authors.affiliation: Department of Pharmacology & Toxicology, University of Texas Medical Branch, USA.
authors.forename: Miroslav N
authors.initials: MN
authors.lastname: Nenov
authors.affiliation: Department of Pharmacology & Toxicology, University of Texas Medical Branch, USA.
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Tapia
authors.affiliation: Department of Biotechnology and Bioscience, University of Milano-Bicocca, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Lecchi
authors.affiliation: Department of Pharmacology & Toxicology, University of Texas Medical Branch, USA; Center for Addiction Research, University of Texas Medical Branch, USA.
authors.forename: Shyny
authors.initials: S
authors.lastname: Koshy
authors.affiliation: Department of Pharmacology & Toxicology, University of Texas Medical Branch, USA; Center for Addiction Research, University of Texas Medical Branch, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Green
authors.affiliation: Department of Pharmacology & Toxicology, University of Texas Medical Branch, USA; Mitchell Center for Neurodegenerative Diseases, USA; Center for Environmental Toxicology, University of Texas Medical Branch, USA; Center for Addiction Research, University of Texas Medical Branch, USA. Electronic address: felaezza@utmb.edu.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Laezza
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D007306:Insecticides / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000502:physiology*; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology*; D020033:Protein Isoforms / Q000502:physiology; D011722:Pyrethrins / Q000494:pharmacology*
chemical_list: D007306:Insecticides; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009570:Nitriles; D020033:Protein Isoforms; D011722:Pyrethrins; C568242:SCN1A protein, human; C100681:SCN8A protein, human; C017180:decamethrin