SUMMARY1. Characteristics of receptor-channel activation and desensitization have been compared at voltage-clamped snake slow and twitch fibre end-plates maintained in an isotonic potassium propionate solution.2. Miniature end-plate current (m.e.p.c.) decay was slower and less voltage dependent at slow fibre end-plates than at twitch fibre end-plates. The peak m.e.p.c. amplitude versus voltage relationship and reversal potential were similar at the two end-plate types.3. Acetylcholine-induced noise and m.e.p.c.s were recorded at slow fibre end-plates. At most slow fibres the spectral density was not adequately fitted by a single Lorentzian function. Rather, the observed spectral density was greater at high frequencies than the values predicted using the m.e.p.c. decay rate. The noise could be well described by the sum of two Lorentzian functions, one of which corresponded to a single Lorentzian function with the corner frequency determined by the m.e.p.c. decay rate.4. The shape of the carbachol concentration-peak end-plate current relationship was similar at both slow and twitch fibre end-plates. However, for all concentrations tested, the peak carbachol-induced end-plate current (e.p.c.carb ) value was markedly less at slow fibre end-plates than at twitch fibre end-plates. 5. The onset of desensitization was determined using two methods. The first concerned analysis of the time course of decay of the e.p.c.carb from a peak value during the sustained application of agonist. The second involved a double-perfusion technique in which a 'desensitizing' dose was applied for varying intervals before the application of a second 'test' dose of carbachol. With both methods the development of desensitization at both end-plate types was dependent on carbachol concentration and duration of exposure. At each end-plate type the time course of desensitization onset often exhibited two components; one with a time constant of seconds and a slower component having time constants in the range of tens to hundreds of seconds. E. A. CONNOR AND OTHERS6. The slope of the relationship between carbachol concentration and equilibrium desensitization at slow and twitch fibre end-plates was close to two, suggesting that two molecules of agonist are probably bound during the development of desensitization. However, for all concentrations tested, desensitization developed more rapidly and to a greater extent at twitch fibre end-plates than at slow fibre end-plates.7. The voltage dependence of the 3 min steady-state desensitization produced by 108 jSM-carbachol was very similar (--0.0250 mV-1) at both fibre types. However, the 3 min steady-state level of desensitization was consistently greater at corresponding voltages for twitch fibre end-plates than at slow fibre end-plates. It was also observed at twitch fibre end-plates exposed to 216,M-carbachol that the fast component of desensitization and 3 min steady-state level of desensitization could exhibit different voltage dependencies. This is consistent with the view that the fast and slow ...

SUMMARYThe presynaptic influence of lanthanum on neuromuscular transmission was studied in the isolated sciatic nerve-sartorius muscle preparation of the frog, Rana pipiens. Twitch tension output from indirectly stimulated muscles progressively decreased with increasing concentrations of La3+ from 0.01 t o 1.0 mM and was abolished in the presence of 0.5 mM and 1 mM LaR+ after approximately 50 min and 15 min, respectively. Studies on directly stimulated muscle indicated that the inhibition by La3 + of tension development during indirect stimulation was not primarily of myogenic origin. The decrease in indirectly stimulated twitch tension by 0.5 mM La3+ was reduced by pretreatment in 10 mM Ca2+, but was not overcome by 1 mM TEA or 5 mM guanidine. In contrast, blockade produced by 8.2 mM Mg2 + was alleviated by TEA or guanidine. In Mgz+ poisoned preparations, microperfusion of 0.001 mM La3+ decreased m by 70% (5 fibers). In curarized preparations, the presence of 0.001 mM La3+ caused the EPP t o decrease by 57% (3 fibers), and 0.5 mM Mgn+ decreased the EPP by 61% (4 fibers). Although the EPP amplitude was reduced by La3+, the MEPP frequency was markedly potentiated in the presence of 0.001 to 0.5 mM La3 +. The potentiation of MEPP frequency by LaY+ appeared to be enhanced in the absence of calcium and reduced by pretreatment in a 10 mM Ca2+ Ringer solution. I t is suggested that Laa+ blocks transmission presynaptically by decreasing the quanta1 content of the EPP, and that it is a more efficient blocker of evoked release than Mg2+.

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I The effects of the ionophore X-537A were studied on carbamylcholine (carbachol)-induced desensitization and on tension development in relaxed potassium-depolarized frog sartorius muscles. 2 X-537A accelerated carbachol-induced desensitization in Ca2+-deficient solutions without having any effect on the conductance of the membrane in the absence of carbachol or on the extent of the carbachol-induced increase in conductance. 3 In Ca2+-deficient solution, the acceleration of desensitization by the ionophore was concentrationdependent. No effect was observed with concentrations less than 5,M and maximal acceleration was evident with 10 gM. 4 The influence of X-537A on desensitization was time-dependent. At 20 AM X-537A, there was a marked acceleration of desensitization by the end of 5 min exposure. An additional gradual acceleration occurred during a 5 to 30 min treatment. No acceleration of desensitization was evident when X-537A was simultaneously applied with carbachol to the end-plate region without prior exposure to the ionophore. 5 Desensitization also was accelerated by 30 min exposure to 20 gM X-537A in solutions containing Ca2+ or deficient in both Mg2+ and Ca2+; the rate being increased 2.8-fold in Ca2+-containing solutions, 2.9-fold in Ca2+-deficient solutions containing Mg2+, and 2.5-fold in divalent cation-deficient solutions. 6 Tension development gradually occurred in relaxed potassium-depolarized muscle preparations exposed to 20 gM X-537A. The onset of tension development occurred only after approximately 25 min of exposure both in preparations kept in Ca2+-deficient or Ca2+-containing solutions. By the end of 90 min in the ionophore, the tension developed was approximately 12% and 23% of the initial potassium contracture in those preparations maintained in the Ca2+-deficient or Ca2+-containing solutions, respectively. 7 We assume that the increase in desensitization rate following exposure to X-537A results from an elevation of the intracellular Ca2+ concentration. That muscle tension gradually increased during exposure to the ionophore supports this conclusion. The acceleration of desensitization by X-537A in the absence of external Ca2+ supports the view that the site of calcium acceleration is not on the external surface of the end-plate membrane either at or near the agonist-recognition site but rather on the inner surface.

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