Local anesthetic inhibition of baseline potassium channels with two pore domains in tandem
Local anesthetic inhibition of baseline potassium channels with two pore domains in tandem
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DOI：
10.1097/00000542-199904000-00024
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发表时间：
1999-04-01
期刊：
影响因子：
8.8
通讯作者：
Gray, AT
中科院分区：
文献类型：
--
作者：
Kindler, CH;Yost, CS;Gray, AT
背景：最近，一个新的钾通道结构家族被发现，其特征是在其主要氨基酸序列中有两个串联的孔区。这些串联孔结构域钾通道不受电压的控制，似乎参与了基线膜电导的控制。方法：向非洲爪哇卵母细胞注射5种克隆的串联孔域基础钾通道(TASK、TREK-1、TOK1、ORK1和TWIK-1)的cRNA，并用双电极电压钳和电流钳技术检测几种局麻药对异源通道的影响。结果：布比卡因(1mar)对所研究的所有串联孔钾通道均有抑制作用，其中TASK抑制作用最强，抑制作用的强弱与局麻药的辛醇缓冲分配系数成正比TASK的半数抑制浓度分别为709mU M甲比卡因、222mM利多卡因、51mM R(+)-罗比卡因、53mM S(-)-罗比卡因、668mV丁卡因、41mM布比卡因和39mM伊多卡因。与注射生理盐水的对照卵母细胞相比，局麻药(1mU)显著地使TASK注射的卵母细胞的静息膜电位去极化(丁卡因22+/-6 mV vs.7+/-1 mV和布比卡因31+/-7 mV vs.6+/-4 mV)，结论：局麻药抑制串联孔结构域基线钾通道，并可使表达这些通道的细胞的静息膜电位去极化，但抑制这些通道是否导致传导阻断或局麻药的不良反应仍有待确定。
Background: Recently, a new structural family of potassium channels characterized by two pore domains in tandem within their primary amino acid sequence was identified. These tandem pore domain potassium channels are not gated by voltage and appear to be involved in the control of baseline membrane conductances. The goal of this study was to identify mechanisms of local anesthetic action on these channels.Methods: Oocytes of Xenopus laevis were Injected with cRNA from five cloned tandem pore domain baseline potassium channels (TASK,TREK-1, TOK1, ORK1, and TWIK-1), and the effects of several local anesthetics on the heterologously expressed channels were assayed using two-electrode voltage-clamp and current-clamp techniques.Results: Bupivacaine(1 mar) inhibited all studied tandem pore potassium channels, with TASK inhibited most potently, The potency of inhibition was directly correlated with the octanol: buffer distribution coefficient of the local anesthetic, with the exception of tetracaine, to which TASK is relatively insensitive, The approximate 50% inhibitory concentrations of TASK were 709 mu M mepivacaine, 222 mu M lidocaine, 51 mu M R(+)-ropivacaine, 53 mu M S(-)-ropivacaine, 668 mu M tetracaine, 41 mu M bupivacaine, and 39 mu M etidocaine, Local anesthetics (1 mu) significantly depolarized the resting membrane potential of TASK cRNA-injected oocytes compared with saline-injected control oocytes (tetracaine 22 +/- 6 mV vs. 7 +/- 1 mV, respectively, and bupivacaine 31 +/- 7 mV vs. 6 +/- 4 mV),Conclusions: Local anesthetics inhibit tandem pore domain baseline potassium channels, and they could depolarize the resting membrane potential of cells expressing these channels, Whether inhibition of these channels contributes to conduction blockade or to the adverse effects of local anesthetics remains to be determined.