ALLOSTERIC PROTEINS AFTER 30 YEARS - THE BINDING AND STATE FUNCTIONS OF THE NEURONAL ALPHA-7 NICOTINIC ACETYLCHOLINE-RECEPTORS

A key statement of the 1965 Monod-Wyman-Changeux (MWC) model for allos teric proteins concerns the distinction between the ligand-binding fun ction ((Y) over bar) and the relevant state function ((R) over bar). S equential models predict overlapping behavior of the two functions. In contrast, a straightforward experimental consequence of the MWC model is that for an oligomeric protein the parameters which characterize t he two functions should differ significantly. Two situations, where (R ) over bar > (Y) over bar and the system is hyper-responsive or where (R) over bar < (Y) over bar and the system is hypo-responsive, have be en encountered. Indeed, the hyper-responsive pattern was first observe d for the enzyme aspartate transcarbamoylase, by comparing (Y) over ba r with (R) over bar monitored by a change in sedimentation. Extensions of the theory to ligand-gated channels led to the suggestion that, on the one hand, hyper-responsive properties also occur with high-affini ty mutants. On the other hand, native channels of the acetylcholine ne uronal alpha 7 receptor and low-affinity mutants of the glycine recept or can be interpreted in terms of the hypo-responsive pattern. For the ligand-gated channels, whereas (R) over bar is detected directly by i on flux, ligand binding has rarely been measured and the formation of desensitized states may complicate the analysis. However, stochastic m odels incorporating both binding and channel opening for single molecu les predict differences that should be measurable with new experimenta l approaches, particularly fluorescence correlation spectroscopy.