Fast desensitization of the nicotinic receptor at the mouse neuromuscular junction.

1 When low concentrations of carbachol (2-20 muM) were applied by local superfusion to mouse diaphragm endplates, there occurred a rapid decrease (within seconds) in the height of miniature endplate currents (m.e.p.cs) in addition to the increase of muscle membrane conductance.2 With 2, 5, 10 and 20 muM carbachol, m.e.p.c. heights were diminished by 5, 10, 30 and 50% respectively. A subsequent slow decrease in height took place at a rate corresponding to that reported for the slow desensitization produced by bath-applied carbachol (see Adams, 1975).3 The effect of carbachol on m.e.p.c. height was not affected by poisoning of acetylcholinesterase (AChE). After poisoning of AChE, 4 muM acetylcholine (ACh) depressed m.e.p.c. height by 23%.4 At 20 muM carbachol, both the onset and offset of the effect on m.e.p.c. height lagged behind the subsynaptic conductance change, and the calculated change of subsynaptic agonist concentration, by about 3 s; the onset rate was at least ten times faster than expected for slow desensitization.5 When the conductance responses produced by carbachol were corrected for fast desensitization, the slope of the log-response log-dose line (Hill coefficient) was increased from 1.7 to 2.0.6 The Hill coefficient for fast desensitization was 1.4. The data were compatible with a cyclic model for fast desensitization, with receptor activation not a prerequisite for desensitization of receptors.7 The failure of AChE poisoning to affect m.e.p.c. height during desensitization suggests that desensitized receptor associated with exogenous agonist can continue to bind quantal ACh.