Interaction of local anesthetics with Torpedo californica membrane-bound acetylcholine receptor

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Abstract
The effects of local anesthetics on the rate of the agonist-induced increase in ligand affinity of membrane-bound acetylcholine receptor from T. 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 .mu.M 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 in the presence and 0.010 .+-. 0.002/s in the absence of dibucaine, while tetracaine decreased the rate to 0.006 .+-. 0.002/s as compared to a control value of 0.012 .+-. 0.003/s. A parallel was seen 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 [3H]perhydrohistrionicotoxin. Apparently local anesthetics either bind directly to the specific histrionicotoxin binding site or to a different site and the observed effects may be caused by conformational changes.