Diffusion of acetylcholine in the synaptic cleft of normal and myasthenia gravis human endplates

Abstract

When acetylcholinesterase (AChE) is inactivated the time constant of decay of the miniature endplate current (τ_m.e.p.c.) depends on the lifetime of the endplate channel and on the speed of clearance of acetylcholine (ACh) from the synaptic cleft^1–3. The latter will be influenced by the binding of ACh to receptors, hence by their density and by the proportion of the ACh packet which attaches to them. By comparing τ_m.e.p.c at various levels of receptor density, for example, following curare treatment, it is possible to estimate the proportion, p, of the ACh packet which normally attaches to the receptors¹. We have estimated p at the normal human endplate and compared this with myasthenia gravis (MG) affected human endplates where, as a result of reduced receptor density, there is a reduction in miniature endplate potential (m.e.p.p.)⁴ and m.e.p.c. amplitudes^5,6, α-bungarotoxin (α-Btx) binding^7,8 and ACh-sensitivity⁹. The properties of the ACh-induced channels are similar at normal and MG endplates^5,10 and it is unlikely that normal or MG channel properties are markedly altered by the various drug treatments used here^11,12. Therefore, at treated normal and at MG endplates any reduction in the time constant of decay of m.e.p.cs indicates that the speed of clearance of the ACh from the cleft is increased. In the experiments reported here the proportion of the ACh packet which binds is estimated to be about 0.5 at normal human endplates. At MG endplates in the absence of cholinesterase activity m.e.p.cs decay more rapidly than normal and the proportion of the ACh packet attaching is reduced.