What ligand-gated ion channels can tell us about the allosteric regulation of G protein-coupled receptors.

The GABA(A) receptor is the target for a number of important allosteric drugs used in medicine, including benzodiazepines and anesthetics. These modulators have variable effects on the potency and maximal response of macroscopic currents elicited by different GABA(A) receptor agonists, yet this modulation is consistent with a two-state model in which the allosteric ligand has invariant affinity constants for the active and inactive states. Analysis of the effects of an allosteric agonist, like etomidate, on the population current provides a means of estimating the gating constant of the unliganded GABA(A) receptor (∼10(-4)). In contrast, allosteric interactions at the M(2) muscarinic receptor are often inconsistent with a two-state model. Analyzing allosterism within the constraints of a two-state model, nonetheless, provides an unbiased measure of probe dependence as well as clues to the mechanism of allosteric modulation. The rather simple allosteric effect of affinity-only modulation is difficult to explain and suggests modulation of a peripheral orthosteric ligand-docking site on the M(2) muscarinic receptor.