GABA and glycine act as inhibitory neurotransmitters in the CNS. Inhibitory neurotransmission is mediated via activation of ionotropic GABA_A and glycine receptors. We used a modeling approach to explain the opposite effects of the general anesthetic etomidate (ETM) and fenamate mefenamic acid (MFA) on GABA- and glycine-activated currents recorded in isolated cerebellar Purkinje cells and hippocampal pyramidal neurons, respectively. These drugs potentiated GABA_ARs but blocked GlyRs. We built a homology model of α1β GlyR based on the cryo-EM structure of open α1 GlyR, used the α1β3γ2 GABA_AR structure from the PDB, and applied Monte-Carlo energy minimization to optimize models of receptors and ligand-receptor complexes. In silico docking suggests that ETM/MFA bind at the transmembrane β( +)/α( −) intersubunit interface in GABA_AR. Our models predict that the bulky side chain of the highly conserved Arg^19′ residue at the plus interface side wedges the interface and maintains the conducting receptor state. We hypothesized that MFA/ETM binding at the β( +)/α( −) interface leads to prolongation of receptor life-time in the open state. Having analyzed different GABA_AR and GlyR structures available in the PDB, we found that mutual arrangement of the Arg^19′ and Gln^−26′ side chains at the plus and minus interface sides, respectively, plays an important role when the receptor switches from the open to closed state. We show that this process is accompanied by narrowing of the intersubunit interfaces, leading to extrusion of the Arg^19′ side chain from the interface. Our models allow us to explain the lack of GlyR potentiation in our electrophysiological experiments.

GABA 和甘氨酸在 CNS 中充当抑制性神经递质。抑制性神经传递是通过激活离子型 GABA _A和甘氨酸受体介导的。我们使用建模方法来解释全身麻醉药依托咪酯 (ETM) 和芬那酸甲芬那酸 (MFA) 分别对分离的小脑浦肯野细胞和海马锥体神经元中记录的 GABA 和甘氨酸激活电流的相反影响。这些药物增强 GABA _A Rs 但阻断 GlyRs。我们基于开放α1 GlyR的冷冻电镜结构建立了α1β GlyR的同源模型，使用了α1β3γ2 GABA _A来自 PDB 的 R 结构，并应用蒙特卡罗能量最小化来优化受体和配体-受体复合物的模型。计算机对接表明 ETM/MFA 在 GABA _A R的跨膜 β(+)/α(-) 亚基间界面处结合。我们的模型预测，正界面侧楔形处高度保守的 Arg ^19'残基的庞大侧链界面并保持导电受体状态。我们假设β(+)/α(-)界面处的MFA/ETM结合导致开放状态下受体寿命的延长。在分析了 PDB 中可用的不同 GABA _A R 和 GlyR 结构后，我们发现 Arg ^19'和 Gln ^{-26' 的}相互排列当受体从打开状态切换到关闭状态时，正负界面侧的侧链分别起重要作用。我们表明，这个过程伴随着亚基间界面的变窄，导致 Arg ^19'侧链从界面中挤出。我们的模型使我们能够解释在我们的电生理实验中缺乏 GlyR 增强。