title: Hypoxic depolarization of cerebellar granule neurons by specific inhibition of TASK-1.
abstract: OBJECTIVE
  The mechanisms underlying neuronal excitotoxicity during hypoxic/ischemic episodes are not fully understood. One feature of such insults is a rapid and transient depolarization of central neurons. TASK-1, an open rectifying K+ leak channel, is significant in setting the resting membrane potential of rat cerebellar granule neurons by mediating a standing outward K+ current. In this study we investigate the theory that the transient neuronal depolarization seen during hypoxia is due to the inhibition of TASK-1.
  
  
  METHODS
  Activity of TASK-1 in primary cultures of rat cerebellar granule neurons was investigated by the whole-cell patch-clamp technique. Discriminating pharmacological and electrophysiological maneuvers were used to isolate the specific channel types underlying acute hypoxic depolarizations.
  
  
  RESULTS
  Exposure of cells to acute hypoxia resulted in a reversible and highly reproducible mean membrane depolarization of 14.2+/-2.6 mV (n=5; P<0.01). Two recognized means of inhibiting TASK-1 (decreasing extracellular pH to 6.4 or exposure to the TASK-1-selective inhibitor anandamide) abolished both the hypoxic depolarization and the hypoxic depression of a standing outward current, identifying TASK-1 as the channel mediating this effect.
  
  
  CONCLUSIONS
  Our data provide compelling evidence that hypoxia depolarizes central neurons by specific inhibition of TASK-1. Since this hypoxic depolarization may be an early, contributory factor in the response of central neurons to hypoxic/ischemic episodes, TASK-1 may provide a potential therapeutic target in the treatment of stroke.
authors.affiliation: School of Biomedical Sciences and Institute for Cardiovascular Research, University of Leeds, Leeds, UK.
authors.forename: Leigh D
authors.initials: LD
authors.lastname: Plant
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kemp
authors.forename: Chris
authors.initials: C
authors.lastname: Peers
authors.forename: Zaineb
authors.initials: Z
authors.lastname: Henderson
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Pearson
mesh_terms: D000138:Acidosis / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D063388:Endocannabinoids; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D018408:Patch-Clamp Techniques; D053284:Polyunsaturated Alkamides; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; D051381:Rats
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D009419:Nerve Tissue Proteins; D053284:Polyunsaturated Alkamides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3; D011188:Potassium; C078814:anandamide