Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri.
Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri; The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, Missouri.
Biophys J. 2024 Jul 16;123(14):1954-1967. doi: 10.1016/j.bpj.2023.09.014. Epub 2023 Sep 26.
The properties of a potentiator are typically evaluated by measuring its ability to enhance the magnitude of the control response. Analysis of the ability of drugs to potentiate responses from receptor channels takes place in the context of particular models to extract parameters for functional effects. In the often-used coagonist model, the agonist generating control activity and the potentiator enhancing the control activity make additive energetic contributions to stabilize the active state of the receptor. The energetic contributions are fixed and, once known, enable calculation of predicted receptor behavior at any concentration combination of agonist and potentiator. Here, we have examined the applicability of the coagonist model by measuring the relationship between the magnitude of receptor potentiation and the level of background activity. Ternary αβγ GABA receptors were activated by GABA or the allosteric agonist propofol, or by a gain-of-function mutation, and etiocholanolone- or propofol-mediated potentiation of peak responses was measured. We show that the free energy change contributed by the modulators etiocholanolone or propofol is reduced at higher levels of control activity, thereby being in disagreement with basic principles of the coagonist model. Possible mechanisms underlying this discrepancy are discussed.
增效剂的特性通常通过测量其增强对照反应幅度的能力来评估。在特定模型的背景下分析药物增强受体通道反应的能力，以提取功能效应的参数。在常用的共激动剂模型中，产生对照活性的激动剂和增强对照活性的增效剂对稳定受体的活性状态做出附加的能量贡献。这些能量贡献是固定的，一旦知道，就可以计算在激动剂和增效剂的任何浓度组合下预测的受体行为。在这里，我们通过测量受体增强的幅度与背景活性水平之间的关系来检查共激动剂模型的适用性。用 GABA 或变构激动剂异丙酚或功能获得性突变激活三元 αβγ GABA 受体，并测量峰反应的 etiocholanolone 或异丙酚介导的增强作用。我们表明，调节剂 etiocholanolone 或异丙酚贡献的自由能变化在对照活性水平较高时降低，因此与共激动剂模型的基本原则不一致。讨论了这种差异的可能机制。
