On allosteric mechanisms and acetylcholine receptors.

The original observation of Meyer Jackson ~ that nicotinic acetylcholine receptor (nAChR) channels may open spontaneously with the same intrinsic conductance and ion selectivity as the acetylcholine-gated channels provides strong support in favour of the Monod-Wyman-Changeux theory 2. It illustrates the interconversion of the protein between discrete conformations before ligand binding. In effect, the signal amplification derived from the passage of thousands of ions through the channel during a single transient opening permits the allosteric transition to be visualized at the level of a single molecule, an advantage that gated channels possess over other allosteric proteins. Such observations complement the insights obtained from correlations of function with the structures established at atomic resolution for both the T and R conformational states of haemoglobin, aspartate transcarbamoylase, phosphofructokinase and glycogen phospho~,lase ~ . The nAChR is also in accord with the Monod-Wyman-Changeux scheme by virtue of its specific oligomeric organization, which includes (at least) two binding sites for acetylcholine per molecule, with positive homotropic interactions (i.e. binding of one acetylcholine facilitates binding of the other). The sites are present on their resl~ective subunits at a distance of 20-40A from the ion channel 9-14 (supporting the notion of 'indirect' interactions between topographically distinct sites2). In addition, the divergence between curves of variation of agonist binding and channel opening as a function of agonist concentration illustrates the basic distinction of the Monod-WymanChangeux model between the 'binding function' and the 'state function '~5-~8. Yet, very early on ~g, the case of the nAChR, like that of other ligand-gated