title: TASK Channel Deletion Reduces Sensitivity to Local Anesthetic-induced Seizures.
abstract: BACKGROUND
  Local anesthetics (LAs) are typically used for regional anesthesia but can be given systemically to mitigate postoperative pain, supplement general anesthesia, or prevent cardiac arrhythmias. However, systemic application or inadvertent intravenous injection can be associated with substantial toxicity, including seizure induction. The molecular basis for this toxic action remains unclear.
  
  
  METHODS
  We characterized inhibition by different LAs of homomeric and heteromeric K channels containing TASK-1 (K2P3.1, KCNK3) and TASK-3 (K2P9.1, KCNK9) subunits in a mammalian expression system. In addition, we used TASK-1/TASK-3 knockout mice to test the possibility that TASK channels contribute to LA-evoked seizures.
  
  
  RESULTS
  LAs inhibited homomeric and heteromeric TASK channels in a range relevant for seizure induction; channels containing TASK-1 subunits were most sensitive and IC₅₀ values indicated a rank order potency of bupivacaine > ropivacaine >> lidocaine. LAs induced tonic-clonic seizures in mice with the same rank order potency, but higher LA doses were required to evoke seizures in TASK knockout mice. For bupivacaine, which produced the longest seizure times, seizure duration was significantly shorter in TASK knockout mice; bupivacaine-induced seizures were associated with an increase in electroencephalogram power at frequencies less than 5 Hz in both wild-type and TASK knockout mice.
  
  
  CONCLUSIONS
  These data suggest that increased neuronal excitability associated with TASK channel inhibition by LAs contributes to seizure induction. Because all LAs were capable of evoking seizures in TASK channel deleted mice, albeit at higher doses, the results imply that other molecular targets must also be involved in this toxic action.
authors.affiliation: Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
authors.forename: Guizhi
authors.initials: G
authors.lastname: Du
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Chen
authors.forename: Marko S
authors.initials: MS
authors.lastname: Todorovic
authors.forename: Shaofang
authors.initials: S
authors.lastname: Shu
authors.forename: Jaideep
authors.initials: J
authors.lastname: Kapur
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bayliss
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010852:Picrotoxin / Q000494:pharmacology; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced*
chemical_list: D000779:Anesthetics, Local; D009419:Nerve Tissue Proteins; D010852:Picrotoxin; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3