An analysis of the action of a false transmitter at the neuromuscular junction.

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Abstract
The action of monoethylcholine (MECh) on neuromuscular transmission was studied by electrophysiological methods. End-plate potentials (EPP) in curarized rat muscle were unaffected or slightly increased in amplitude by MECh (0.1-1 mM). Stimulation at 3 Hz for about 30 min in the presence of MECh caused a progressive decline in EPP amplitude, and a shortening of the EPP time course. These changes were reversed by addition of choline to the medium. Similar changes in amplitude, but no change in time course, occurred when the preparation was stimulated in the presence of hemicholinium or triethylcholine. Extracellular recordings of miniature end-plate potentials (MEPP) in frog muscle showed that stimulation in the presence of MECh caused the time constant of the exponential decay of the MEPP to decrease by 42%. The amplitude of intracellular MEPP was reduced by 45%. These changes were miximal by the time about 3 .times. 105 quanta were released. Voltage clamp experiments in rat muscle in which miniature end-plate currents (MEPC) were recorded showed that stimulation in the presence of MECh reduced the amplitude (by 33%) and the decay time constant (by 42%). Analysis of end-plate current fluctuations produced by local application of acetylcholine (ACh) and acetylmonoethylcholine (AMECh) to voltage clamped rat end-plates showed that the amplitude of the elementary current events was the same for both compounds, whereas the average channel lifetime was 44% shorter for AMECh than for ACh. The voltage-sensitivity of the channel lifetime (measured from end-plate current fluctuations) was the same for ACh and AMECh. The voltage-sensitivity of the MEPC decay time constant was the same as that found from noise measurements. The shortened MEPC (false MEPC) occurring after stimulation in the presence of MECh also showed the same voltage-sensitivity. Both normal and false MEPC were prolonged by neostigmine by almost the same factor; false MEPC were thus shorter than normal MEPC even when cholinesterase was inactivated. Experiments with progressive curarization of neostigmine-treated end-plates suggested that the fraction of transmitter molecules bound was smaller for false than for normal MEPC. The difference implies that the false transmitter has 1/4 of the affinity of ACh for the receptors. Stimulation in the presence of MECh apparently gives rise to a false transmitter, presumably AMECh, which has a lower affinity for receptors than ACh, and gives rise to ionic channels with a shorter average lifetime than those activated by Ach.