Synaptic actions of acetylcholine: problems for future research

Acetylcholine is currently believed to act on postsynaptic membranes by binding to a specific membrane receptor protein and inducing a conformational change that opens a channel for ion fluxes. This conformational change is viewed as rate limiting, with the agonist binding-dissociation step being very fast. The open channel has a conductance of 27 pS, and the gating molecule responsible for the channel opening and closing undergoes a dipole moment change of 50 D in making the open-closed transition. Although this picture accounts quantitatively for many aspects of acetylcholine action, certain of the underlying assumptions are untested, and the view is incomplete or unsatisfactory in several other ways. Four goals for future research, then, are: 1) To determine whether conformational change or agonist dissociation is the rate limiting step; present interpretations assume the conformation change is rate limiting, but available data are equally consistent with the alternative assumption. 2) To discover the nature and significance of direct anticholinesterase actions on the channel gating process; evidence is available that some direct actions occur, but these have not yet been studied. 3) To fit the process of desensitization into the present picture of acetylcholine actions. 4) To merge the pictures of acetylcholine-receptor interactions that are being developed concurrently by physiologists and biochemists. Achieving this goal should eventually lead to an understanding of how intrinsic proteins regulate membrane ionic fluxes.