TASK Channel Deletion Reduces Sensitivity to Local Anesthetic-induced Seizures.
TASK Channel Deletion Reduces Sensitivity to Local Anesthetic-induced Seizures.
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DOI：
10.1097/aln.0b013e3182343660
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发表时间：
2011-11
期刊：
影响因子：
8.8
通讯作者：
Bayliss DA
中科院分区：
文献类型：
--
作者：
Du G;Chen X;Todorovic MS;Shu S;Kapur J;Bayliss DA
局部麻醉剂（LA）通常用于局部麻醉，但也可全身给药，以减轻术后疼痛，补充全身麻醉或预防心律失常。然而，全身应用或意外静脉注射可能与大量毒性相关，包括癫痫发作诱导。这种毒性作用的分子基础尚不清楚。我们表征了不同LA对哺乳动物表达系统中含有ASK-1（K2P3.1，KCNK 3）和ASK-3（K2P9.1，KCNK 9）亚基的同源和异源K+通道的影响。此外，我们使用了ASK-1/ASK-3基因敲除小鼠来测试ASK通道有助于LA诱发癫痫发作的可能性。LA在与癫痫诱导相关的范围内抑制同聚体和异聚体的ASK通道;含有ASK-1亚基的通道最敏感，IC 50值表明布比卡因>罗哌卡因>利多卡因的等级顺序效力。LA在具有相同等级效力的小鼠中诱导强直-阵挛性癫痫发作，但需要更高的LA剂量才能在ASK敲除小鼠中诱发癫痫发作。对于产生最长癫痫发作时间的布比卡因，ASK基因敲除小鼠的癫痫发作持续时间显著较短;布比卡因诱导的癫痫发作与野生型和ASK基因敲除小鼠中频率<5 Hz的脑电图功率增加相关。这些数据表明，增加的神经元兴奋性与LAs的ASK通道抑制有助于癫痫发作诱导。由于所有的LA都能够在ASK通道缺失的小鼠中引起癫痫发作，尽管剂量较高，结果表明其他分子靶标也必须参与这种毒性作用。
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. We characterized effects of different LAs on 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. 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 <5 Hz in both wild type and TASK knockout mice. These data suggest that increased neuronal excitability associated with TASK channel inhibition by LAs contributes to seizure induction. Since 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.