Linden Anni-Maija, Aller M Isabel, Leppä Elli, Rosenberg Per H, Wisden William, Korpi Esa R
Institute of Biomedicine, Pharmacology, University of Helsinki, POB 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland.
J Pharmacol Exp Ther. 2008 Oct;327(1):277-86. doi: 10.1124/jpet.108.142083. Epub 2008 Jul 25.
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.
双孔结构域渗漏钾离子通道遍布整个大脑。然而，TASK-1和TASK-3基因敲除（KO）小鼠几乎没有神经功能障碍，对吸入性麻醉剂的敏感性仅略有降低，这与这些通道预期的功能和重要性形成对比。TASK-1/-3通道的表达可以补偿GABA(A)α6基因敲除小鼠中GABA(A)受体的缺失。为了研究相反的情况，我们分析了给TASK-1和-3基因敲除小鼠施用对GABA(A)受体亚型具有优先效力的药物后的行为：苯二氮䓬类药物（地西泮和氟西泮，对α1βγ2、α2βγ2、α3βγ2和α5βγ2亚型有活性）、唑吡坦（α1βγ2亚型）、丙泊酚（含β2-3的受体）、加波沙朵（α4βδ和α6βδ亚型）、孕烷醇酮和戊巴比妥（多种亚型）。地西泮和氟西泮给药后，TASK-1基因敲除小鼠在转棒试验和走杆试验中表现出运动障碍增加，但唑吡坦给药后没有。它们还表现出丙泊酚和戊巴比妥诱导的翻正反射丧失时间延长。放射自显影显示GABA(A)受体配体结合水平没有变化。这些对GABA能药物改变的行为反应表明TASK-1基因敲除小鼠中α2β2/3γ2和α3β2/3γ2受体亚型的功能上调。此外，雌性而非雄性TASK-1基因敲除小鼠对加波沙朵更敏感，表明α4βδ或α6βδ亚型的影响增加。TASK-3基因敲除小鼠对苯二氮䓬类药物的敏感性略有增加。我们的结果强调，TASK-1通道在大脑中发挥着如此关键的功能，以至于它们的缺失需要进行补偿。此外，由于吸入性麻醉剂部分通过GABA(A)受体起作用，TASK-1基因敲除小鼠中GABA(A)受体功能的上调可能掩盖了TASK-1通道作为吸入性麻醉剂靶点的重要性。
