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Allosteric modulation of the glycine receptor activated by agonists differing in efficacy

机译：激动剂激活的甘氨酸受体的变构调节作用不同

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The glycine receptor (GlyR) is the predominant inhibitory neurotransmitter receptor in the brainstem and spinal cord but is also found in higher brain regions. GlyR function is affected by a variety of allosteric modulators including drugs of abuse, such as ethanol and inhalants and the ubiquitous divalent cation zinc. Two-electrode voltage-clamp experiments were conducted on Xenopus laevis oocytes expressing wild-type alpha 1 homomeric glycine receptors to compare the degree of enhancement produced by zinc on GlyR activated by two agonists (glycine vs. taurine) that vary markedly in their efficacies. Zinc potentiation of both glycine- and taurine-evoked currents was the same at the concentrations of agonists that produced the same currents, corresponding to 6% of the maximal effect of glycine compared to 23% of the maximal effect of taurine. Similar results were seen with 50 and 200 mM ethanol. A direct comparison of agonist concentration-response curves showed that zinc enhancement was greater, overall, for taurine-activated than glycine-activated receptors. In addition, zinc only enhanced taurine- but not glycine-activated GlyR when agonists were applied at saturating concentrations. These data suggest that zinc affects taurine affinity, as well as the probability of channel opening at sub-maximal taurine concentrations, and that the magnitude of allosteric modulation at the GlyR depends on the efficacy of the agonist tested. This has implications for mutagenesis studies in which changes in the degree of allosteric modulation observed may result from mutation-induced changes in agonist efficacy. (C) 2015 Elsevier B.V. All rights reserved.
机译：甘氨酸受体（GlyR）是脑干和脊髓中主要的抑制性神经递质受体，但也存在于较高的大脑区域。 GlyR的功能受多种变构调节剂的影响，包括滥用药物，例如乙醇和吸入剂以及普遍存在的二价阳离子锌。在表达野生型α1同型甘氨酸受体的非洲爪蟾卵母细胞上进行了两电极电压钳实验，以比较锌在两种激动剂（甘氨酸对牛磺酸）激活的GlyR上产生的增强程度，二者的功效明显不同。在产生相同电流的激动剂浓度下，甘氨酸和牛磺酸引起的电流的锌增效作用相同，相当于甘氨酸最大作用的6％，而牛磺酸最大作用的23％。用50和200 mM乙醇观察到相似的结果。激动剂浓度-反应曲线的直接比较显示，总体而言，牛磺酸激活的锌的增强作用大于甘氨酸激活的受体的增强作用。另外，当以饱和浓度施用激动剂时，锌仅增强牛磺酸而不是甘氨酸激活的GlyR。这些数据表明锌会影响牛磺酸的亲和力，以及牛磺酸浓度低于最大浓度时通道打开的可能性，并且GlyR处的变构调节幅度取决于测试的激动剂的功效。这对诱变研究具有重要意义，在诱变研究中，观察到的变构调节程度的变化可能是由突变诱导的激动剂功效变化引起的。 （C）2015 Elsevier B.V.保留所有权利。

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