Blanchard S G, Elliott J, Raftery M A
Biochemistry. 1979 Dec 25;18(26):5880-5. doi: 10.1021/bi00593a019.
The effects of local anesthetics on the rate of the agonist-induced increase in ligand affinity of membrane-bound acetylcholine receptor from Torpedo californica were examined. The rate of the transition in receptor affinity was determined by following the time-dependent increase in inhibition of iodinated alpha-bungarotoxin binding caused by 1 microM carbamylcholine. At concentrations below those that directly inhibited the binding of iodinated alpha-bungarotoxin, dibucaine increased the rate of the transition to a high-affinity state and tetracaine decreased this rate. The measured rate constants were 0.026 +/- 0.008 s-1 in the presence and 0.010 +/- 0.002 s-1 in the absence of dibucaine while tetracaine decreased the rate to 0.006 +/- 0.002 s-1 as compared to a control value of 0.012 +/- 0.003 s-1. A parallel was observed between the effectiveness of a compound in increasing or decreasing the rate of the agonist-induced transition in affinity and the change in its apparent inhibition constant in the presence of carbamylcholine (increase or decrease) measured by the displacement of tritiated perhydrohistrionicotoxin. This parallel could be explained by assuming (a) that local anesthetics bound directly to the specific histrionicotoxin binding site or (b) that they bound to a different site and the observed effects were caused by conformational changes.
研究了局部麻醉药对来自加州电鳐的膜结合型乙酰胆碱受体激动剂诱导的配体亲和力增加速率的影响。受体亲和力转变的速率是通过跟踪由1微摩尔氨甲酰胆碱引起的碘化α-银环蛇毒素结合抑制的时间依赖性增加来确定的。在低于直接抑制碘化α-银环蛇毒素结合的浓度下，丁卡因增加了向高亲和力状态转变的速率，而丁哌卡因降低了该速率。在有丁卡因存在时测得的速率常数为0.026±0.008 s-1，无丁卡因时为0.010±0.002 s-1，而丁哌卡因将速率降低至0.006±0.002 s-1，相比之下对照值为0.012±0.003 s-1。观察到一种化合物在增加或降低激动剂诱导的亲和力转变速率方面的有效性与其在氨甲酰胆碱存在下（增加或降低）通过氚化全氢组胺毒素的置换测得的表观抑制常数变化之间存在平行关系。这种平行关系可以通过假设（a）局部麻醉药直接结合到特定的组胺毒素结合位点或（b）它们结合到不同的位点且观察到的效应是由构象变化引起的来解释。
