K+ channel TASK-1 knockout mice show enhanced sensitivities to ataxic and hypnotic effects of GABA(A) receptor ligands.
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 GABA(A) receptors in GABA(A) alpha6 KO mice. To investigate the converse, we analyzed the behavior of TASK-1 and -3 KO mice after administering drugs with preferential efficacies at GABA(A) receptor subtypes: benzodiazepines (diazepam and flurazepam, active at alpha1betagamma2, alpha2betagamma2, alpha3betagamma2, and alpha5betagamma2 subtypes), zolpidem (alpha1betagamma2 subtype), propofol (beta2-3-containing receptors), gaboxadol (alpha4betadelta and alpha6betadelta 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 GABA(A) receptor ligand binding levels. These altered behavioral responses to GABAergic drugs suggest functional up-regulation of alpha2beta2/3gamma2 and alpha3beta2/3gamma2 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 alpha4betadelta or alpha6betadelta 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 GABA(A) receptors, the up-regulation of GABA(A) receptor function in TASK-1 KO mice might mask TASK-1 channel's significance as a target for inhalation anesthetics.
Linden
Anni-Maija
AM
Institute of Biomedicine, Pharmacology, University of Helsinki, POB 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland. anni-maija.linden@helsinki.fi
Aller
M Isabel
MI
Leppä
Elli
E
Rosenberg
Per H
PH
Wisden
William
W
Korpi
Esa R
ER
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001259:Ataxia / Q000139:chemically induced*; D001569:Benzodiazepines / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology; D005260:Female; D005479:Flurazepam / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010424:Pentobarbital / Q000494:pharmacology; D024683:Potassium Channels, Tandem Pore Domain / Q000502:physiology*; D015742:Propofol / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D012737:Sex Factors; D013116:Spinal Cord / Q000378:metabolism
D014151:Anti-Anxiety Agents; D006993:Hypnotics and Sedatives; D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C420132:potassium channel subfamily K member 3; D011493:Protein Kinase C; D010424:Pentobarbital; D005479:Flurazepam; D003975:Diazepam; D015742:Propofol