Nigrostriatal damage preferentially decreases a subpopulation of α6β2*nAChRs in mouse, monkey, and Parkinson's disease striatum
Nigrostriatal damage preferentially decreases a subpopulation of α6β2*nAChRs in mouse, monkey, and Parkinson's disease striatum
复制标题
DOI：
10.1124/mol.107.035998
复制
发表时间：
2007-07-01
影响因子：
3.6
通讯作者：
Quik, Maryka
中科院分区：
文献类型：
--
作者：
Bordia, Tanuja;Grady, Sharon R.;Quik, Maryka
帕金森病是一种神经退行性运动障碍，其特征在于黑质多巴胺神经元的损失，以及纹状体多巴胺能神经末梢上存在的分子组分的相应下降。这些包括α 6 β 2* 烟碱乙酰胆碱受体（nAChR），其仅定位于纹状体中的多巴胺末端（* 表示可能存在另外的亚基）。在这项研究中，我们使用了一种新的α-芋螺毒素MII（α-CtxMII）类似物E11 A，以进一步研究α 6 β 2* nAChR亚型在小鼠，猴子和人类纹状体。用I-125-alpha-CtxMII进行的受体竞争研究表明，E11 A抑制曲线为双相，表明存在两种不同的α 6 β 2* nAChR亚型。这些包括非常高（飞摩尔）和高（皮摩尔）亲和力位点，其中类似于40%的位点处于非常高亲和力形式。值得注意的是，在α 4 nAChR缺失突变小鼠中仅检测到高亲和力形式。由于I-125-alpha-CtxMII主要与小鼠纹状体中的α 6 α 4 β 2 β 3和α 6 β 2 β 3 nAChR亚型结合，因此这些数据表明α 4敲除小鼠中丢失的群体是α 6 α 4 β 2 β 3亚型。接下来，我们研究了黑质纹状体损伤对两种动物模型和帕金森病中这两种纹状体α 6 β 2* 群体的影响。在用1-甲基-4苯基-1，2，3，6-四氢吡啶（MPTP）处理的小鼠、用MPTP处理的猴子和帕金森病患者的纹状体中，存在非常高亲和力的亚型的优先损失。这些数据表明，表达α 6 α 4 β 2 β 3群体的多巴胺能末梢选择性地易受黑质纹状体损伤。后者nAChR亚型，确定与α-CtxMII E11 A，因此可能提供了一个独特的标记多巴胺能终端特别敏感的黑质纹状体变性帕金森氏病。
Parkinson's disease is a neurodegenerative movement disorder characterized by a loss of substantia nigra dopamine neurons, and corresponding declines in molecular components present on striatal dopaminergic nerve terminals. These include the alpha 6 beta 2* nicotinic acetylcholine receptors (nAChRs), which are localized exclusively on dopamine terminals in striatum (*denotes the presence of possible additional subunits). In this study, we used a novel alpha-conotoxin MII (alpha-CtxMII) analog E11A to further investigate alpha 6 beta 2* nAChR subtypes in mouse, monkey, and human striatum. Receptor competition studies with I-125-alpha-CtxMII showed that E11A inhibition curves were biphasic, suggesting the presence of two distinct alpha 6 beta 2* nAChR subtypes. These include a very high (femtomolar) and a high (picomolar) affinity site, with similar to 40% of the sites in the very high affinity form. It is noteworthy that only the high-affinity form was detected in alpha 4 nAChR-null mutant mice. Because I-125-alpha-CtxMII binds primarily to alpha 6 alpha 4 beta 2 beta 3 and alpha 6 beta 2 beta 3 nAChR subtypes in mouse striatum, these data suggest that the population lost in the alpha 4 knockout mice was the alpha 6 alpha 4 beta 2 beta 3 subtype. We next investigated the effect of nigrostriatal lesioning on these two striatal alpha 6 beta 2* populations in two animal models and in Parkinson's disease. There was a preferential loss of the very high affinity subtype in striatum of mice treated with 1-methyl-4phenyl-1,2,3,6- tetrahydropyridine (MPTP), monkeys treated with MPTP, and patients with Parkinson's disease. These data suggest that dopaminergic terminals expressing the alpha 6 alpha 4 beta 2 beta 3 population are selectively vulnerable to nigrostriatal damage. This latter nAChR subtype, identified with alpha-CtxMII E11A, may therefore provide a unique marker for dopaminergic terminals particularly sensitive to nigrostriatal degeneration in Parkinson's disease.