Department of Anesthesiology (A.L.G., D.J.S., C.R.K., A.D.J., A.S.E., G.A.) and Taylor Family Institute for Innovative Psychiatric Research (A.S.E., G.A.), Washington University School of Medicine, St. Louis, Missouri.
Department of Anesthesiology (A.L.G., D.J.S., C.R.K., A.D.J., A.S.E., G.A.) and Taylor Family Institute for Innovative Psychiatric Research (A.S.E., G.A.), Washington University School of Medicine, St. Louis, Missouri
Mol Pharmacol. 2018 May;93(5):468-476. doi: 10.1124/mol.117.111435. Epub 2018 Feb 8.
GABA receptors activated by the transmitter GABA are potentiated by several allosterically acting drugs, including the intravenous anesthetic propofol. Propofol can also directly activate the receptor, albeit at higher concentrations. Previous functional studies have identified amino acid residues whose substitution reduces potentiation of GABA-activated receptors by propofol while enhancing the ability of propofol to directly activate the receptor. One interpretation of such observations is that the mutation has specific effects on the sites or processes involved in potentiation or activation. We show here that divergent effects on potentiation and direct activation can be mediated by increased constitutive open probability in the mutant receptor without any specific effect on the interactions between the allosteric drug and the receptor. By simulating GABA receptor activity using the concerted transition model, we demonstrate that the predicted degree of potentiation is reduced as the level of constitutive activity increases. The model further predicts that a potentiating effect of an allosteric modulator is a computable value that depends on the level of constitutive activity, the amplitude of the response to the agonist, and the amplitude of the direct activating response to the modulator. Specific predictions were confirmed by electrophysiological data from the binary 13 and concatemeric ternary 212L+21 GABA receptors. The corollaries of reduced potentiation due to increased constitutive activity are isobolograms that conform to simple additivity and a loss of separation between the concentration-response relationships for direct activation and potentiation.
GABA 受体被递质 GABA 激活，可被几种变构作用药物增强，包括静脉麻醉药异丙酚。异丙酚也可以直接激活受体，尽管需要更高的浓度。先前的功能研究已经确定了氨基酸残基，其取代可降低异丙酚对 GABA 激活的受体的增强作用，同时增强异丙酚直接激活受体的能力。这种观察结果的一种解释是，该突变对变构药物与受体相互作用的增强或激活部位或过程具有特异性影响。我们在这里表明，在突变受体中增加组成型开放概率可以介导对增强和直接激活的不同影响，而对变构药物与受体之间的相互作用没有任何特定影响。通过使用协调跃迁模型模拟 GABA 受体活性，我们证明随着组成型活性的增加，预测的增强程度降低。该模型进一步预测，变构调节剂的增强作用是一个可计算的值，取决于组成型活性水平、激动剂的反应幅度和调节剂的直接激活反应幅度。通过来自二元 13 和串联三聚体 212L+21 GABA 受体的电生理数据证实了具体预测。由于组成型活性增加而导致的增强作用降低的推论是符合简单加性的等对数图，并且直接激活和增强作用的浓度反应关系之间的分离丧失。
