It has been accepted for many years that acetylcholine (ACh) undergoes two kinds of reactions at the motor end-plate: it combines with a receptor molecule (which leads to an increase of ion permeability in the end-plate membrane), and it combines with a hydrolytic enzyme situated side-by-side with the receptor. Both reactions probably proceed in two steps and involve the formation of unstable intermediate compounds before the hydrolysis, or the depolarizing reaction, occurs (see, for example, Augustinsson, 1948; Ariens, 1954;Stephenson, 1956; del Castillo & Katz, 1957 b However, the picture of two simple, parallel events at the end-plate fails to account for an important secondary effect ofACh and its depolarizing analogues, namely the profound desensitization which develops when the drug concentration is maintained for a sufficiently long time. Recent experiments (Thesleff, 1955) have shown that the neuromuscular block produced by ACh and by its stable counterparts (C10, succinylcholine) is due mainly to desensitization, that is, a condition in which the end-plate has become refractory to depolarizing agents, and from which it recovers only slowly after complete withdrawal of the drug. It has been suggested that this change arises from gradual transformation of the drug-receptor compound into an inactive form. In order to obtain some information on the kinetics of desensitization and recovery processes, we have used the ionophoretic micromethods described by Nastuk (1953) and by del Castillo & Katz (1955a). It seemed possible that the time course of the events might come well within the practical range of this method, and the results described in this paper have borne out this expectation.

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SUMMARY1. The hypothesis is put forward that a residue of the 'active calcium' which enters the terminal axon membrane during the nerve impulse is responsible for short-term facilitation.2. This suggestion has been tested on the myoneural junction by varying the local calcium concentration so that during the first of two nerve impulses [Ca]. is either much lower than, or raised to a level approaching that, during the second impulse. Facilitation is much larger in the latter case, which is in accordance with the 'calcium hypothesis'.3. A short pulse of depolarization focally applied to the junction is followed by a brief period of very intense facilitation. This can be seen in the tetrodotoxin-treated preparation, e.g. by lengthening the depolarization from 1 to 2 msec which can cause a more than fifty-fold increase in transmitter release. This large 'early facilitation' (which presumably occurs also during the course of a normal action potential) is discussed in relation to the 'calcium hypothesis'.

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1. When a steady dose of acetylcholine (ACh) is applied to an end‐plate, the resulting depolarization is accompanied by a significant increase in voltage noise. 2. The characteristic properties of this ACh noise (amplitude and time course) are examined under various experimental conditions. The voltage noise is analysed on the assumption that it arises from statistical fluctuations in reaction rate, and in the frequency of the elementary current pulses (‘shot effects’) produced by the action of ACh molecules. 3. The elementary ACh current pulse (amplitude approximately 10−11 A), arises from a conductance change of the order of 10−10 Ω−1 which lasts for approximately 1 ms (at 20° C), and produces a minute depolarization, of the order of 0·3 μV. It is associated with a net charge transfer of nearly 10−14 C, equivalent to approximately 5 × 104 univalent ions. 4. At low temperature, and during chronic denervation, the duration of the elementary current pulse increases, and the elementary voltage change becomes correspondingly larger. 5. Curare has little or no effect on the characteristics of the elementary event. 6. A comparative study of ACh and carbachol actions shows that carbachol produces considerably briefer, and therefore less effective, current pulses than ACh.