Membrane permeable local anesthetics modulate Na(V)1.5 mechanosensitivity.
Membrane permeable local anesthetics modulate Na(V)1.5 mechanosensitivity.
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DOI：
10.4161/chan.21202
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发表时间：
2012-07
期刊：
影响因子：
--
通讯作者：
Farrugia G
中科院分区：
文献类型：
--
作者：
Beyder A;Strege PR;Bernard C;Farrugia G
电压门控钠选择性离子通道NaV1.5在心脏和胃肠道中表达，这是机械活性器官。NaV1.5在门控其他机械敏感离子通道的刺激下是机械敏感的。局部麻醉药和抗癫痫药通过多种机制作用于NaV1.5以调节活性。本研究检查了NaV1.5机械敏感性是否受局部麻醉剂调节。在HEK-293细胞中表达NaV1.5通道，并在细胞贴附和切除的由内向外构型中测试机械敏感性。使用具有成对电压梯和短压力脉冲的新方案，两种配置中的负贴片压力（-30 mmHg）在激活（V1/2a）和失活（V1/2 i）的电压依赖性的半点中产生约-10 mV的超极化偏移。利多卡因（50 µM）抑制压力诱导的V1/2a移动，但不抑制V1/2 i。利多卡因在使用依赖性方案中抑制压力诱导的峰电流的强直性增加，但它不影响使用依赖性阻滞。局部麻醉剂苯并咪唑，不显示使用依赖性阻滞，也有效地阻断了压力诱导的V1/2a移位。利多卡因在突变的局部麻醉剂结合位点（F1760 A）抑制NaV1.5中的机械敏感性。然而，当从膜的任一侧施加时，膜不可渗透的利多卡因类似物QX-314不影响F1760 A NaV1.5的机械敏感性。这些数据表明，利多卡因抑制压力诱导的激活电压依赖性半点偏移的机制与使用依赖性阻滞的机制是分开的。膜渗透性局部麻醉剂对NaV1.5机械敏感性的调节可能需要疏水通路，并可能涉及膜-蛋白相互作用。
Voltage-gated sodium selective ion channel NaV1.5 is expressed in the heart and the gastrointestinal tract, which are mechanically active organs. NaV1.5 is mechanosensitive at stimuli that gate other mechanosensitive ion channels. Local anesthetic and antiarrhythmic drugs act upon NaV1.5 to modulate activity by multiple mechanisms. This study examined whether NaV1.5 mechanosensitivity is modulated by local anesthetics. NaV1.5 channels wereexpressed in HEK-293 cells, and mechanosensitivity was tested in cell-attached and excised inside-out configurations. Using a novel protocol with paired voltage ladders and short pressure pulses, negative patch pressure (-30 mmHg) in both configurations produced a hyperpolarizing shift in the half-point of the voltage-dependence of activation (V1/2a) and inactivation (V1/2i) by about -10 mV. Lidocaine (50 µM) inhibited the pressure-induced shift of V1/2a but not V1/2i. Lidocaine inhibited the tonic increase in pressure-induced peak current in a use-dependence protocol, but it did not otherwise affect use-dependent block. The local anesthetic benzocaine, which does not show use-dependent block, also effectively blocked a pressure-induced shift in V1/2a. Lidocaine inhibited mechanosensitivity in NaV1.5 at the local anesthetic binding site mutated (F1760A). However, a membrane impermeable lidocaine analog QX-314 did not affect mechanosensitivity of F1760A NaV1.5 when applied from either side of the membrane. These data suggest that the mechanism of lidocaine inhibition of the pressure-induced shift in the half-point of voltage-dependence of activation is separate from the mechanisms of use-dependent block. Modulation of NaV1.5 mechanosensitivity by the membrane permeable local anesthetics may require hydrophobic access and may involve membrane-protein interactions.
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影响因子：
3.3
作者：
Banderali, Umberto;Juranka, Peter F.;Morris, Catherine E.
通讯作者：
Morris, Catherine E.
影响因子：
3.8
作者：
Lundbaek, Jens A;Birn, Pia;Hansen, Anker J;Sogaard, Rikke;Nielsen, Claus;Girshman, Jeffrey;Bruno, Michael J;Tape, Sonya E;Egebjerg, Jan;Greathouse, Denise V;Mattice, Gwendolyn L;Koeppe, Roger E 2nd;Andersen, Olaf S
通讯作者：
Andersen, Olaf S
DOI：
10.1152/ajpheart.2001.280.1.h272
发表时间：
2001-01-01
影响因子：
4.8
作者：
Li, GR;Baumgarten, CM
通讯作者：
Baumgarten, CM
影响因子：
3.4
作者：
Morris, Catherine E.;Juranka, Peter F.
通讯作者：
Juranka, Peter F.
影响因子：
3.8
作者：
Fraceto, Leonardo F.;Oyama, Sergio, Jr.;Pertinhez, Thelma A.
通讯作者：
Pertinhez, Thelma A.