Department of Pharmacology, School of Medicine, University of California, Irvine, California, USA.
Prog Mol Biol Transl Sci. 2013;115:291-347. doi: 10.1016/B978-0-12-394587-7.00007-5.
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.
GABA(A) 受体是许多医学上使用的重要变构药物的靶标，包括苯二氮䓬类药物和麻醉剂。这些调节剂对不同 GABA(A) 受体激动剂引起的宏观电流的效力和最大反应有不同的影响，但这种调节与二态模型一致，其中变构配体对活性和非活性状态的亲和力常数不变。分析变构激动剂（如依托咪酯）对群体电流的影响提供了一种估计未配体 GABA(A) 受体门控常数（约 10(-4)) 的方法。相比之下，M(2) 毒蕈碱受体的变构相互作用通常不符合二态模型。尽管如此，在二态模型的限制内分析变构作用提供了对探针依赖性的无偏测量以及对变构调节机制的线索。亲和力调节的这种相当简单的变构效应很难解释，并提示 M(2) 毒蕈碱受体上的外周正位配体结合位点的调节。
