When a quantum of transmitter is released into a synaptic cleft, the magnitude of the subsynaptic response depends upon how much transmitter becomes bound to receptors. Theoretical considerations lead to the conclusion that if receptor density is normally high enough that most of the quantal transmitter is captured, subsynaptic quantal responses may be insensitive to receptor blockade. The effectiveness of receptor blockers in depressing the subsynaptic response should be diminished by interference with processes that normally dispose of transmitter, but increased if receptor density is reduced. In conformity with equations derived from a simple mathematical model, the apparent potency of (+)-
tubocurarine (dTC) to depress the peak height of miniature end-plate currents (MEPCs) in mouse diaphragm was substantially reduced by
poisoning of
acetylcholinesterase (AChE) and increased by partial blockade of receptors by
immunoglobulin G from patients with
myasthenia gravis or
alpha-bungarotoxin. We calculated from the data that normally capture of quantal
acetylcholine (ACh) by receptors is approximately 75% of what it would be if there were no loss of ACh by hydrolysis or diffusion of ACh form the synaptic cleft. This fraction is increased to approximately 90% by
poisoning of AChE. Conversely, it normally requires blockade of approximately 80% of receptors-and after AChE
poisoning, approximately 90% of receptors-to reduce ACh capture (and
MEPC height) by 50%. The apparent potency of dTC to alter
MEPC time-course (after AChE
poisoning) and to depress responses to superperfused
carbachol was much greater than its apparent potency to depress
MEPC height, but corresponded closely with the potency of dTC to block receptors as calculated from the action of dTC on
MEPC height. These results indicate that the amplitude of the response to nerve-applied
acetylcholine does not give a direct measure of receptor blockade; it is, in general, to be expected that an alteration of subsynaptic receptor density may not be equally manifest in responses to exogenous and endogenous
neurotransmitter.