FAST DESENSITIZATION OF THE NICOTINIC RECEPTOR AT THE MOUSE NEUROMUSCULAR JUNCTION

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Abstract
1 When low concentrations of carbachol (2–20 μm) 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 μm 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 μm acetylcholine (ACh) depressed m.e.p.c. height by 23%. 4 At 20 μm 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.

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