Most working proteins, including metabolic enzymes, transcription regulators,
and membrane receptors, transporters, and ion channels, share the property
of
allosteric coupling. The term ‘allosteric’ means that these
proteins mediate
indirect interactions between sites that are physically separated on the
protein. In
the example of ligand-gated ion channels, the binding of a suitable ligand
elicits
local conformational changes at the binding site, which are coupled to
further
conformational changes in regions distant from the binding site. The physical
motions finally arrive at the site of biological activity: the ion-permeating
pore.
The conformational changes that lead from the ligand binding to the actual
opening of the pore comprise ‘gating’. In 1956, del Castillo
and Katz suggested
that the competition between different ligands at nicotinic acetylcholine
receptors
(nAChRs) could be explained by formation of an intermediate, ligand-bound,
yet
inactive state of the receptor, which separates the active
state of the receptor from
the initial binding of the ligand (del Castillo & Katz, 1957). This
‘binding-then-gating’, two-step model went beyond the
then-prevailing drug-receptor model
that assumes a single bimolecular binding reaction, and paralleled
Stephenson's
conceptual dichotomy of ‘affinity’ and ‘efficacy’
(Stephenson, 1956). In 1965
Monod, Wyman and Changeux presented a simple allosteric model (the MWC
model) (Monod et al. 1965) that explained the cooperative
binding of oxygen to
haemoglobin; it was adopted as an important paradigm for ligand-gated channels
soon after its initial formulation (Changeux et al. 1967; Karlin,
1967; Colquhoun, 1973).