A novel nicotinic acetylcholine receptor subtype in basal forebrain cholinergic neurons with high sensitivity to amyloid peptides.
A novel nicotinic acetylcholine receptor subtype in basal forebrain cholinergic neurons with high sensitivity to amyloid peptides.
复制标题
DOI：
10.1523/jneurosci.3952-08.2009
复制
发表时间：
2009-01-28
期刊：
影响因子：
--
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Liu Q;Huang Y;Xue F;Simard A;DeChon J;Li G;Zhang J;Lucero L;Wang M;Sierks M;Hu G;Chang Y;Lukas RJ;Wu J
含有α7亚基的烟碱乙酰胆碱受体（nAChRs）被认为是以同聚体形式组装。α7-nAChR的功能与学习记忆有关，在阿尔茨海默病（Alzheimer's disease，AD）患者中发现了α7-nAChR的改变。在这里，我们报告的结果一致的一种新的，自然发生的nAChR亚型在啮齿动物，基底前脑胆碱能神经元。在这些细胞中，α7亚基与β2亚基共表达、共定位和共组装。与来自腹侧被盖区神经元的同源α7-nAChRs相比，来自内侧隔/斜角带（MS/DB）的胆碱能神经元上的功能性的、可能是异源的α7β2-nAChRs对烟碱激动剂的全细胞电流反应动力学相对较慢，并且对含有β2亚基的nAChR选择性拮抗剂二氢-β-赤藓定（DHβE）更敏感。有趣的是，据推测，异聚体α7β2-nAChR对病理相关浓度的寡聚体淀粉样蛋白β1-42（Aβ1-42）的功能抑制高度敏感，但对单体或纤维形式的淀粉样蛋白β1-42（Aβ1-42）不敏感。缓慢的全细胞电流动力学、对DHβE的敏感性以及寡聚体Aβ1-42的特异性拮抗作用也是异聚体α7β2-nAChRs的特征，但不是在非洲爪蟾卵母细胞中异源表达的同源体α7-nAChRs的特征。此外，胆碱诱导的电流具有更快的动力学和较低的敏感性Aβ时，从MS/DB神经元来源于nAChR β2亚基敲除小鼠，而不是从野生型小鼠。基底前脑胆碱能神经元上存在新型、功能性、异聚体α7β2-nAChR及其对低浓度寡聚体Aβ1-42阻断的高敏感性表明，胆碱能信号传导缺陷可能发生在AD发病机制的早期，并可能成为疾病治疗的靶点。
Nicotinic acetylcholine receptors (nAChRs) containing α7 subunits are thought to assemble as homomers. α7-nAChR function has been implicated in learning and memory, and alterations of α7-nAChR have been found in patients with Alzheimer’s disease (AD). Here we report findings consistent with a novel, naturally-occurring nAChR subtype in rodent, basal forebrain cholinergic neurons. In these cells, α7 subunits are co-expressed, co-localize and co-assemble with β2 subunit(s). Compared to homomeric α7-nAChRs from ventral tegmental area neurons, functional, presumably heteromeric α7β2-nAChRs on cholinergic neurons freshly dissociated from medial septum/diagonal band (MS/DB) exhibit relatively slow kinetics of whole-cell current responses to nicotinic agonists and are more sensitive to the β2 subunit-containing nAChR-selective antagonist, dihydro-β-erythroidine (DHβE). Interestingly, presumed, heteromeric α7β2-nAChRs are highly sensitive to functional inhibition by pathologically-relevant concentrations of oligomeric, but not monomeric or fibrillar forms of amyloid β1-42 (Aβ1-42). Slow whole-cell current kinetics, sensitivity to DHβE, and specific antagonism by oligomeric Aβ1-42 also are characteristic of heteromeric α7β2-nAChRs, but not of homomeric α7-nAChRs, heterologously expressed in Xenopus oocytes. Moreover, choline-induced currents have faster kinetics and less sensitivity to Aβ when elicited from MS/DB neurons derived from nAChR β2 subunit knockout mice rather than from wild-type mice. The presence of novel, functional, heteromeric α7β2-nAChRs on basal forebrain cholinergic neurons and their high sensitivity to blockade by low concentrations of oligomeric Aβ1-42 suggests possible mechanisms for deficits in cholinergic signaling that could occur early in the etiopathogenesis of AD and might be targeted by disease therapies.