MOLECULAR MECHANISM OF LOCAL ANESTHETIC ACTION

我的研究的长期目标是了解当地如何 麻醉剂阻断神经传导。 该项目已将 强调区分当地的具体影响， 麻醉剂对神经膜的非特异性作用。 的 将通过检查药物-Na通道来研究特异性作用 相互作用和非特异性效应将通过使用 疏水离子作为一般膜性质的探针。 两种类型的 实验将在电压钳位鱿鱼轴突与 具体目的：（1）确定钠失活机制在 药物通道相对于静止的阻断作用， 使用依赖性块通过使用不同的代理商，以消除钠失活。 (2)为了确定激活门在调节 使用依赖性块（a），通过比较 使用依赖性阻断Na通道的激活，和（B） 通过比较从使用依赖性阻断恢复的电压依赖性， 与激活钠离子通道的能力相当。 (3)确定 局部麻醉剂阻滞作用的效力和电压依赖性， 存在不同浓度的不同种类的永久离子 在链霉蛋白酶处理过的轴突中。 这些结果将使用 提供多离子发生的势垒模型。 (4)来定义 外部或内部的H+离子在调节恢复的作用， 使用依赖块。 (5)为了确定局部麻醉剂的作用， 其他膜扰动剂对诱导的人工门控电流的影响 并将这些影响与它们对钠离子的影响进行比较 门控电流 我们对产生局部麻醉作用的机制的理解将 也提供了一个了解如何抗癫痫和抗惊厥 作用是由那些表现出局部麻醉作用的药剂引起的。

The long-term objective of my research is to understand how do local anesthetics block the nerve conduction. The proposed project has placed the emphasis on discriminating between the specific effect of local anesthetics from their non-specific effects on nerve membranes. The specific effect will be studied by examining the drug-Na channel interactions and the non-specific effects will be investigated by using hydrophobic ions as probes of general membrane properties. Both types of experiments will be performed in voltage-clamped squid axons with the specific aims: (1) to determine the role of Na inactivation machinery in the drug channel blocking action with respect to the resting and use-dependent blocks by using different agents to remove Na inactivation. (2) To determine the role of the activation gate in modulating use-dependent block (a) by comparing the voltage dependence of use-dependent block to that for the activation of the Na channels, and (b) by comparing the voltage dependence for recovery from use-dependent block to that for the activation of the Na channels. (3) To determine the potency and voltage dependency of local anesthetic blocking action in the presence of different species of permenant ions at various concentrations in pronase-treated axons. These results will be interpreted using a barrier model with a provision for multi-ion occcupancy. (4) To define the role of external or internal H+ ions in modulating the recovery from use-dependent block. (5) To determine the effects of local anesthetics and other membrane perturbating agents on the artificial gating current induced by hydrophobic ions and compare these effects to their effects on the Na gating currents. Our understanding of mechanisms for producing local anesthetic action will also provide an understanding of how antiarrhythmic and anticonvulsant action is brought about by those agents exhibiting local anesthetic action.