Agonist pharmacology of neonatal and adult glycine receptor alpha subunits: identification of amino acid residues involved in taurine activation.
Agonist pharmacology of neonatal and adult glycine receptor alpha subunits: identification of amino acid residues involved in taurine activation.
复制标题
新生儿和成人甘氨酸受体α亚基的激动剂药理学：鉴定参与牛磺酸激活的氨基酸残基。
作者：
V. Schmieden;J. Kuhse;H. Betz
抑制性甘氨酸受体（GlyR）是一种在哺乳动物中枢神经系统中介导突触后抑制的五聚体氯通道蛋白。在脊髓中，不同的GlyR亚型源于配体结合α亚基的发育调节变体的顺序表达。在这里，新生α 2和成年α 1亚基在非洲爪蟾卵母细胞中异种表达时产生具有不同激动剂激活谱的GlyRs。α - 1受体可被α -丙氨酸和牛磺酸有效地门控，α - 2 GlyRs对这些激动剂仅表现出较低的相对反应，对甘氨酸能拮抗剂士的宁的抑制也表现出较低的敏感性。α 2/ α 1亚基嵌合体的构建和α 1序列胞外区域的定点诱变确定了氨基酸位置111和212是牛磺酸激活的重要决定因素。我们的研究结果表明，受体激动剂在α 1和α 2 GlyRs上存在不同的亚位，并表明这些受体蛋白的配体结合袋是由其细胞外区域的不连续结构域形成的。
The inhibitory glycine receptor (GlyR) is a pentameric chloride channel protein which mediates postsynaptic inhibition in the mammalian central nervous system. In spinal cord, different GlyR isoforms originate from the sequential expression of developmentally regulated variants of the ligand binding alpha subunit. Here, neonatal alpha 2 and adult alpha 1 subunits are shown to generate GlyRs with distinct agonist activation profiles upon heterologous expression in Xenopus oocytes. Whereas alpha 1 receptors are efficiently gated by beta‐alanine and taurine, alpha 2 GlyRs show only a low relative response to these agonists, which also display a reduced sensitivity to inhibition by the glycinergic antagonist strychnine. Construction of an alpha 2/alpha 1 subunit chimera and site‐directed mutagenesis of the extracellular region of the alpha 1 sequence identified amino acid positions 111 and 212 as important determinants of taurine activation. Our results indicate the existence of distinct subsites for agonists on alpha 1 and alpha 2 GlyRs and suggest that the ligand binding pocket of these receptor proteins is formed from discontinuous domains of their extracellular region.