Paradoxical allosteric effects of competitive inhibitors on neuronal alpha 7 nicotinic receptor mutants
Paradoxical allosteric effects of competitive inhibitors on neuronal alpha 7 nicotinic receptor mutants
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DOI：
10.1097/00001756-199711100-00034
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发表时间：
1997-11-10
期刊：
影响因子：
1.7
通讯作者：
Bertrand, D
中科院分区：
文献类型：
--
作者：
Bertrand, S;DevillersThiery, A;Bertrand, D
神经元α 7乙酰胆碱受体第二跨膜结构域中的保守亮氨酸残基突变为苏氨酸（L247 T），导致受体特性的多效性改变。在这项研究中，我们研究了竞争性抑制剂对α 7-L247 T生理反应的影响。虽然α 7竞争性抑制剂二氢-β-赤藓定引起的电流与ACh诱导的电流相当，但其他抑制剂如甲基乌头碱（MLA）和α-银环蛇毒素（α-Bgt）引起α 7-L247 T对ACh激活的阻断。当在不存在ACh的情况下应用时，MLA或α-Bgt降低了细胞漏电流，表明α 7-L247 T显示出显著分数（10%）的自发开放通道。这些数据可以解释的变构模型，假设L247 T突变体具有低的异构化常数L和MLA和α-Bgt稳定的封闭，静止状态。
MUTATION of the conserved leucine residue, in the second transmembrane domain of the neuronal alpha 7 acetylcholine receptor to a threonine (L247T) causes pleiotropic alterations of receptor properties. In this study we examined the effects of competitive inhibitors on the alpha 7-L247T physiological responses. While the alpha 7 competitive inhibitor dihydro-beta-erythroidine evoked a current comparable to that induced by ACh, other inhibitors such as methyllycaconitine (MLA) and alpha-bungarotoxin (alpha-Bgt) caused a blockade of alpha 7-L247T to ACh activation. When applied in the absence of ACh, MLA or alpha-Bgt reduced the cell leakage current, showing that alpha 7-L247T displays a significant fraction (10%) of spontaneously open channels. These data can be interpreted in terms of an allosteric model, assuming that the L247T mutant possesses a low isomerization constant L and that MLA and alpha-Bgt stabilize the closed, resting state.