Glycine receptors (GlyRs) regulate motor control and pain processing in the central nervous system through inhibitory synaptic signaling. The subtype GlyRα3 expressed in nociceptive sensory neurons of the spinal dorsal horn is a key regulator of physiological pain perception. Disruption of spinal glycinergic inhibition is associated with chronic inflammatory pain states, making GlyRα3 an attractive target for pain treatment. GlyRα3 activity is modulated by numerous endogenous and exogenous ligands that consequently affect pain sensitization. To understand the mechanism of two such endogenous modulators, Zn 2+ and protons, we have used cryo–electron microscopy to determine structures of full-length human GlyRα3 in various functional states. Whereas acidic pH reduces peak glycine response, Zn 2+ displays biphasic modulation in a concentration-dependent manner. Our findings reveal the effector sites and also capture intermediate conformations in the gating cycle. Combined with molecular dynamics simulations and electrophysiology, this work provides important insights into GlyRα3 activation and regulation.

中文翻译：

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Zn 2+ 和 pH 调节人 GlyRα3 受体的机制


甘氨酸受体 （GlyR） 通过抑制性突触信号传导调节中枢神经系统的运动控制和疼痛处理。在脊髓背角的伤害感受感觉神经元中表达的亚型 GlyRα3 是生理性疼痛感知的关键调节因子。脊髓甘氨酸能抑制的破坏与慢性炎症性疼痛状态有关，使 GlyRα3 成为疼痛治疗的有吸引力的靶点。GlyRα3 活性受许多内源性和外源性配体的调节，从而影响疼痛敏化。为了了解两种内源性调节剂 Zn 2+ 和质子的机制，我们使用冷冻电子显微镜来确定各种功能状态下全长人 GlyRα3 的结构。酸性 pH 值会降低甘氨酸峰反应，而 Zn 2+ 以浓度依赖性方式表现出双相调节。我们的研究结果揭示了效应位点，并捕获了门控周期中的中间构象。结合分子动力学模拟和电生理学，这项工作为 GlyRα3 的激活和调节提供了重要的见解。