Department of Anesthesiology, Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, USA.
J Gen Physiol. 2025 Jan 6;157(1). doi: 10.1085/jgp.202413644. Epub 2024 Nov 25.
The maximal probability of being in an active state (PA,max) is a measure of gating efficacy for a given agonist acting on a given receptor channel. In macroscopic electrophysiological recordings, PA,max is typically estimated by comparing the amplitude of the current response to a saturating concentration of a test agonist to that of a reference agonist with known PA. Here, we describe an approach to estimate the PA,max for low-efficacy agonists at subsaturating concentrations. In this approach, the amplitude of the response to a high-efficacy control agonist applied alone is compared with the amplitude of the response to a control agonist coapplied with the low-efficacy test agonist that binds to the same site(s). If the response to the combination is larger than the response to the control agonist alone, then the PA,max of the test agonist is greater than the PA of the control response. Conversely, if the response to the control agonist is reduced upon exposure to the test agonist, then the PA,max of the test agonist is smaller than the PA of the control response. The exact PA,max of the test agonist can be determined by testing its effect at different concentrations of the control agonist to estimate the PA at which the effect changes direction. The main advantage of this approach lies in the ability to use low, subsaturating concentrations of the test agonist. The model-based predictions are supported by observations from activation of heteromeric and homomeric GABAA receptors by combinations of high- and low-efficacy orthosteric agonists.
最大激活概率 (PA,max) 是衡量给定激动剂作用于特定受体通道的门控效率的指标。在宏观电生理学记录中，PA,max 通常通过比较测试激动剂的饱和浓度下的电流响应幅度与具有已知 PA 的参考激动剂的电流响应幅度来估计。在这里，我们描述了一种用于估计亚饱和浓度下低效能激动剂的 PA,max 的方法。在这种方法中，单独应用高效能对照激动剂的响应幅度与对照激动剂与结合到相同位点的低效能测试激动剂共同应用的响应幅度进行比较。如果组合的响应大于对照激动剂单独的响应，则测试激动剂的 PA,max 大于对照反应的 PA。相反，如果对照激动剂暴露于测试激动剂时响应降低，则测试激动剂的 PA,max 小于对照反应的 PA。可以通过测试测试激动剂在不同浓度的对照激动剂下的作用来确定其确切的 PA,max，以估计作用方向发生变化的 PA。这种方法的主要优点在于能够使用低浓度的亚饱和测试激动剂。该模型预测得到了由高和低效能的正位激动剂组合激活异源和同源 GABAA 受体的观察结果的支持。
