Abstract
TASK two-pore-domain leak K+ channels occur throughout the brain. However, TASK-1 and TASK-3 knockout (KO) mice have few neurological impairments and only mildly reduced sensitivities to inhalational anesthetics, contrasting with the anticipated functions and importance of these channels. TASK-1/-3 channel expression can compensate for the absence of GABAA receptors in GABAA α6 KO mice. To investigate the converse, we analyzed the behavior of TASK-1 and -3 KO mice after administering drugs with preferential efficacies at GABAA receptor subtypes: benzodiazepines (diazepam and flurazepam, active at α1βγ2, α2βγ2, α3βγ2, and α5βγ2 subtypes), zolpidem (α1βγ2 subtype), propofol (β2–3-containing receptors), gaboxadol (α4βδ and α6βδ subtypes), pregnanolone, and pentobarbital (many subtypes). TASK-1 KO mice showed increased motor impairment in rotarod and beam-walking tests after diazepam and flurazepam administration but not after zolpidem. They also showed prolonged loss of righting reflex induced by propofol and pentobarbital. Autoradiography indicated no change in GABAA receptor ligand binding levels. These altered behavioral responses to GABAergic drugs suggest functional up-regulation of α2β2/3γ2 and α3β2/3γ2 receptor subtypes in TASK-1 KO mice. In addition, female, but not male, TASK-1 KO mice were more sensitive to gaboxadol, suggesting an increased influence of α4βδ or α6βδ subtypes. The benzodiazepine sensitivity of TASK-3 KO mice was marginally increased. Our results underline that TASK-1 channels perform such key functions in the brain that compensation is needed for their absence. Furthermore, because inhalation anesthetics act partially through GABAA receptors, the up-regulation of GABAA receptor function in TASK-1 KO mice might mask TASK-1 channel's significance as a target for inhalation anesthetics.
Footnotes
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This work was funded in part by the Academy of Finland (to E.R.K.), the Sigrid Juselius Foundation (to E.R.K.), and the J. Ernest Tait Estate (to W.W). A.-M.L. and M.I.A. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.142083.
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ABBREVIATIONS: K2P, two-pore domain potassium; KO, knockout; LORR, loss of righting reflex; [3H]Ro 15-4513, ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-α]1,4-benzodiazepine-3-carboxylate; [35S]TBPS, t-butyl-bicyclophosphoro[35S]thionate; ANOVA, analysis of variance; PKC, protein kinase C.
- Received June 10, 2008.
- Accepted July 24, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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