ACTIONS OF TUBOCURARINE AT THE FROG NEUROMUSCULAR-JUNCTION
ACTIONS OF TUBOCURARINE AT THE FROG NEUROMUSCULAR-JUNCTION
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DOI：
10.1113/jphysiol.1979.sp012888
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发表时间：
1979-01-01
影响因子：
5.5
通讯作者：
SHERIDAN, RE
中科院分区：
文献类型：
--
作者：
COLQUHOUN, D;DREYER, F;SHERIDAN, RE
通过平衡剂量比测量、电流起伏测量和电压跳跃松弛测量，重新考察了管库拉林对电压钳制蛙肌终板的作用。平衡测量结果可以解释为，Tubocurarine具有竞争性阻断作用，其Kd值为0.34µm，不依赖于膜电位，并且具有额外的电压依赖性阻断作用。在Tubocurarine存在的情况下，可以看到2个动力学成分。更快的离子通道关闭速度与正常离子通道关闭速度相似，但比正常离子通道关闭速度快得多。另一种慢得多(S 1-3)，在松弛实验中，它与快速松弛的方向相反。竞争性阻断(或关闭通道的阻断)与Tubocurarine对开放离子通道的强烈电压依赖性阻断相结合是该药物可能的作用机制。得到了通道阻塞的速率常数的估计值(以及它们与电压的关系)。根据这些估计，Tubocurarine与开放通道的结合的Kd值似乎为.apprx。在-70 mV时为0.12微米，在-120毫伏时为0.02微米。讨论了实验及其解释中的几个潜在的误差来源。特别是与突触裂隙小体积内的扩散有关的问题，即由于结合的变化导致裂隙浓度的变化，以及拮抗剂和非激动剂进入突触裂隙的离子电泳流。
The action of tubocurarine on voltage-clamped frog muscle end-plates was re-examined by equilibrium dose-ratio measurements, current fluctuation measurements and voltage-jump relaxation measurements. The equilibrium measurements can be interpreted as implying that tubocurarine has a competitive blocking action, with a Kd of 0.34 .mu.M, which is not dependent on membrane potential, and an additional voltage-dependent blocking action. In the presence of tubocurarine 2 kinetic components can be seen. The faster one is similar to, but rather faster than, the normal ion channel closing rate. The other is much slower (1-3 s), and, in relaxation experiments it is in the opposite direction to the fast relaxation. A combination of competitive block (or block of shut channels), with a strongly voltage-dependent block of open ion channels by tubocurarine is a possible mechanism of action of the drug. Estimates of the rate constants for channel blocking (and their voltage dependence) are derived. From these estimates the Kd for the binding of tubocurarine to open channels appears to be .apprx. 0.12 .mu.M at -70 mV and 0.02 .mu.M at -120 mV. Several potential sources of error in the experiments and in their interpretation are discussed. Particularly problems associated with diffusion in the small volume of the synaptic cleft, i.e., changes in cleft concentration consequent on changes in binding, and ionophoretic flux of antagonist and agaonist into the synaptic cleft.