Comparison of taurine- and glycine-induced conformational changes in the M2-M3 domain of the glycine receptor
Comparison of taurine- and glycine-induced conformational changes in the M2-M3 domain of the glycine receptor
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DOI：
10.1074/jbc.m400548200
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发表时间：
2004-05-07
影响因子：
4.8
通讯作者：
Lynch, JW
中科院分区：
文献类型：
--
作者：
Han, NLR;Clements, JD;Lynch, JW
在嗜离子性谷氨酸受体中，部分激动剂诱导的整体构象变化小于完全激动剂诱导的构象变化。然而，在五聚体配体门控离子通道受体家族中，部分激动作用的结构基础尚不清楚。本研究探讨了完全和部分激动剂是否会诱导甘氨酸受体氯通道（GlyR）的不同构象变化。先前的替代半胱氨酸可接近性分析表明，甘氨酸结合诱导同源α - 1 GlyR的M2-M3结构域中从Arg（271）到Lys（276）的所有残基的表面可接近性增加。在这里，我们比较了完全激动剂甘氨酸和部分激动剂牛磺酸诱导的表面可接近性变化。在含有A272C、S273C、L274C或P275C突变的GlyRs中，半胱氨酸特异性化合物甲乙硫磺酸乙基三甲基铵的反应速率取决于受体被激活的强度，但不依赖于激动剂。R271C和K276C突变型GlyRs的反应速率无法进行比较，因为甲乙硫磺酸乙基三甲基铵不能改变饱和牛磺酸或同等低浓度甘氨酸诱导的极小电流。结果表明，结合的牛磺酸和甘氨酸分子对M2-M3结构域施加相同的构象变化。因此，我们得出结论，甘氨酸的更高功效是由于稳定普通激活构型的能力增加。
In the ionotropic glutamate receptor, the global conformational changes induced by partial agonists are smaller than those induced by full agonists. However, in the pentameric ligand-gated ion channel receptor family, the structural basis of partial agonism is not understood. This study investigated whether full and partial agonists induce different conformation changes in the glycine receptor chloride channel ( GlyR). A substituted cysteine accessibility analysis demonstrated previously that glycine binding induced an increase in surface accessibility of all residues from Arg(271) to Lys(276) in the M2-M3 domain of the homomeric alpha1 GlyR. Here we compare the surface accessibility changes induced by the full agonist, glycine, and the partial agonist, taurine. In GlyRs incorporating the A272C, S273C, L274C, or P275C mutation, the reaction rate of the cysteine-specific compound, methanethiosulfonate ethyltrimethylammonium, depended on how strongly the receptors were activated but was agonist-independent. Reaction rates could not be compared in the R271C and K276C mutant GlyRs because methanethiosulfonate ethyltrimethylammonium did not modify the extremely small currents induced by saturating taurine or equivalent low glycine concentrations. The results indicate that bound taurine and glycine molecules impose identical conformational changes to the M2-M3 domain. We therefore conclude that the higher efficacy of glycine is due to an increased ability to stabilize a common activated configuration.