Glutamate 172, essential for modulation of L247T α7 ACh receptors by Ca2+, lines the extracellular vestibule
Glutamate 172, essential for modulation of L247T α7 ACh receptors by Ca2+, lines the extracellular vestibule
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DOI：
10.1152/ajpcell.00204.2002
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发表时间：
2002-11-01
影响因子：
5.5
通讯作者：
Rosenberg, RL
中科院分区：
文献类型：
--
作者：
Eddins, D;Sproul, AD;Rosenberg, RL
神经元型α(7)烟碱型ACh受体(NAChRs)对钙离子、Ba2+和Sr2+具有通透性和可调性。这些永久的二价阳离子与缓慢脱敏(LT)-T-247α(7)nAChRs相互作用，以增加ACh的效力和最大疗效，增加二氢-β-红景天碱(DHbetaE)的效力，并增强激动剂非依赖性活性。将谷氨酸172(E-172)突变为谷氨酰胺或半胱氨酸可消除二价阳离子的这些影响。针对水可及硫醇的半胱氨酸修饰剂2-(三甲基铵)乙基甲烷硫磺酸(MTSET)对(EC)-C-172/(LT)-T-247α(7)nAChRs的ACh诱发电流有90%的抑制作用，表明E-172是可被离子激活的。这些数据与α(7)受体的模型是一致的，该模型来自Lymneea stagnalis的ACh结合蛋白(AChBP)的晶体结构，在该模型中，E-172向细胞外前庭的管腔投射。观察到E-172是(LT)-T-247α(7)nAChRs二价阳离子调节所必需的，并可被离子渗透，这表明该残基参与了离子渗透与受体活性调节的耦合。
Neuronal alpha(7) nicotinic ACh receptors (nAChRs) are permeable to and modulated by Ca2+, Ba2+, and Sr2+. These permeant divalent cations interact with slowly desensitizing (LT)-T-247 alpha(7) nAChRs to increase the potency and maximal efficacy of ACh, increase the efficacy of dihydro-beta-erythroidine (DHbetaE), and increase agonist-independent activity. Mutation of glutamate 172 (E-172)to glutamine or cysteine eliminated these effects of permeant divalent cations. 2-(Trimethylammonium) ethyl methanethiosulfonate (MTSET), a cysteine-modifying reagent directed at water-accessible thiols, inhibited ACh-evoked currents of (EC)-C-172/(LT)-T-247 alpha(7) nAChRs by >90%, demonstrating that E-172 was accessible to permeant ions. The data are consistent with a model of alpha(7) receptors, derived from the crystal structure of the ACh binding protein (AChBP) from Lymnaea stagnalis, in which E-172 projects toward the lumen of the extracellular vestibule. The observations that E-172 was essential for divalent cation modulation of (LT)-T-247 alpha(7) nAChRs and was accessible to permeating ions suggest that this residue participates in coupling ion permeation with modulation of receptor activity.