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1、Role of the amino acid glycine in inhibitory抑制的 and excitatory 兴奋的neurotransmission. Models of the extracellular ligand binding domains of the pentameric五聚物 GlyR and the tetrameric四聚物 NMDAR N-甲基-D-天冬氨酸受体. The glycine binding site of the GlyR is located between two adjacent subunits, whereas agonist
2、binding to the NMDAR occurs within two extracellular domains of a single subunit (LAUBE et al., 2019; 2019).甘氨酸是中枢神经系统中主要的抑制性神经递质 , 它与特定的突触后受体结合后 , 开启受体内部的氯 离 子 通 道 , 实 施 其 抑 制 作 用. 士 的 宁(strychnine) 能特异性阻断甘氨酸与其受体的结合. A model for activity-dependent GlyR clustering at developing postsynaptic membrane
3、 specializationsA glycinergic presynaptic terminal and a segment of the plasma membrane of a GlyR-expressing postsynaptic neuron are shown at different stages of synaptogenesis.Kneussel M , Betz H J Physiol 2000;525:1-92000 by The Physiological SocietyA, immature stage: GlyRs are randomly distribute
4、d in the plasma membrane of the postsynaptic cell, whereas gephyrin is cytoplasmically localized.aaaB, initiation of gephyrin cluster formation桥蛋白成簇构造: release of glycine from the presynaptic terminal gates neighbouring GlyRs. This results in a depolarizing去极化 Cl efflux流出 (downward arrows) that acti
5、vates nearby voltage-dependent Ca2+ channels. The resultant local microdomain of elevated Ca2+ concentration triggers the membrane apposition and aggregation 加入以及聚集of gephyrin at sites of GlyR activation.aaC, maturation stage成熟阶段: the growing submembraneous gephyrin aggregate traps additional GlyRs
6、underneath the presynaptic terminal and immobilizes固定 the receptors in the developing postsynaptic membrane by anchoring them to the subsynaptic cytoskeleton. Due to a change in Cl equilibrium potential, GlyR activation triggers Cl influx causing hyperpolarization (upward arrows), and thus inhibitio
7、n of neuronal firing. This model is based on data by Kirsch & Betz (2019) and does not include G protein-mediated signalling pathways that may also contribute to the clustering process (Kins et al. 2000).Gly对细胞内钙的激动剂诱导的增加的抑制的假定机理，经由IP3/Ca2+ pathway。受体介导的PLC激活使IP3增加，有助于大量活性Ca2+从内质网中释放经由IP3受体。细胞内Ca2+的
8、变化激活电压依赖Ca2+门控通道，导致细胞外Ca2+的大量内流，进而作为第二信使激活NADPH氧化酶，结果通过活化NF-B使多种细胞因子的表达。 简单的说，PGE2, ROS, and cytokines的产生对肝脏是有害的。Gly减弱细胞内信号以及细胞因子的生成，通过对电压依赖Ca2+门控通道的超极化诱导抑制。. Ga, activated G-protein; ER, endoplasmic reticulum; PLC, phospholipase C; IP3, inositol 1,4,5-triphosphate; PIP2, phosphatidylinositol 4,5- b
9、iphosphate; PLA2, phospholipase A2; NF-B, nuclear factor kappa B; IB, inhibitory kappa B; AA, arachidonic acid; PGE2, prostaglandin E2; LTB4, leukotriene B4; DAG, diacyl glycerol; NADPH, nicotinamide adenine dinucleotide phosphate; VoC, voltage-dependent calcium channel; ReC, receptor-mediated calcium channel.
