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Effects of drugs on miniature end-plate currents at the mouse neuromuscular junction Pennefather, Peter


Digital averaging and analysis of miniature endplate currents (MEPCs) from mouse diaphragm was used to characterize the normal MEPC and its modification by a variety of drugs. Under normal conditions the decay of MEPCs showed consistent deviations from a simple exponential consisting in a progressive increase of rate constant, followed by a slow tail. Receptor blockade by d-tubocurarine (dTC), a-bungarotoxin, and other agents thought to occupy ACh-binding sites reduced MEPC amplitude, accelerated MEPC decay by about 30% (making it about equal to decay rate of channels opened by exogenous acetylcholine), and eliminated the early deviations from an exponential decay; dTC also abolished the late tail. Examination of the interaction of acetylcholinesterase (AChE) poisoning and receptor blockade on MEPC height and time course indicated that normally most quantal ACh is captured by receptors and, as predicted by theoretical consideration, a rather large degree of receptor blockade is necessary to reduce MEPC height. MEPC tails were exaggerated by AChE poisoning and exogenous ACh or carba-chol. The latter agents reduced MEPC height in a fashion inconsistent with blockade of ACh binding and concurrent modulation of the tail suggested an important role of desensitized receptors in tail generation. A number of other drug actions are also described quantitatively: (a) channel prolongation, typical of alcohols but also found with ketones and some amines; (b) 'channel plugging', typical of local anaesthetics but also found with many other agents, including long chain alcohols, and (c) an action to reduce MEPC size without reducing net response to exogenous agonist typical of volatile anaesthetics, associated with increase rather than decrease of ACh binding to receptor. Criteria for distinguishing different modes of modification of receptor function are discussed.

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