The main objective of the proposed research is to elucidate the mechanism of action of drugs and chemicals on neuromuscular transmission. Skeletal neuromuscular junctions are used as a model for synapse. Special emphasis is placed on the interactions of these agents on end-plate membranes as examined by advanced electrophysiological techniques including voltage clamp, noise analysis and single channel recording. Specific projects are concerned with the mechanism where guanidine and other ammonium derivatives block end-plate ionic channels, the mechanism whereby local and general anesthetics and alcohols modify the kinetics of the agonist-induced activation of end-plate receptor/channel, and chemical dissection of end-plate receptor/channel using protein specific reagents as tools. This data will be integrated to construct an overall picture of the end-plate receptor/channel with respect to its dimension, ionic selectivity, reacting molecular groups and kinetics. This study is expected to provide a clue to the molecular mechanisms of action of drugs and the basis for improvement of therapeutic agents.