Bordia Tanuja, Grady Sharon R, McIntosh J Michael, Quik Maryka
The Parkinson's Institute, 1170 Morse Ave, Sunnyvale, CA 94089-1605, USA.
Mol Pharmacol. 2007 Jul;72(1):52-61. doi: 10.1124/mol.107.035998. Epub 2007 Apr 4.
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 alpha6beta2() 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 alpha6beta2() nAChR subtypes in mouse, monkey, and human striatum. Receptor competition studies with (125)I-alpha-CtxMII showed that E11A inhibition curves were biphasic, suggesting the presence of two distinct alpha6beta2() nAChR subtypes. These include a very high (femtomolar) and a high (picomolar) affinity site, with approximately 40% of the sites in the very high affinity form. It is noteworthy that only the high-affinity form was detected in alpha4 nAChR-null mutant mice. Because (125)I-alpha-CtxMII binds primarily to alpha6alpha4beta2beta3 and alpha6beta2beta3 nAChR subtypes in mouse striatum, these data suggest that the population lost in the alpha4 knockout mice was the alpha6alpha4beta2beta3 subtype. We next investigated the effect of nigrostriatal lesioning on these two striatal alpha6beta2(*) 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-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), monkeys treated with MPTP, and patients with Parkinson's disease. These data suggest that dopaminergic terminals expressing the alpha6alpha4beta2beta3 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.
帕金森病是一种神经退行性运动障碍，其特征是黑质多巴胺能神经元丧失，以及纹状体多巴胺能神经末梢上的分子成分相应减少。这些成分包括α6β2（）烟碱型乙酰胆碱受体（nAChRs），其仅定位于纹状体中的多巴胺能末梢（（）表示可能存在其他亚基）。在本研究中，我们使用一种新型α-芋螺毒素MII（α-CtxMII）类似物E11A，进一步研究小鼠、猴和人类纹状体中的α6β2（）nAChR亚型。用（125）I-α-CtxMII进行的受体竞争研究表明，E11A抑制曲线呈双相性，提示存在两种不同的α6β2（）nAChR亚型。其中包括一个非常高（飞摩尔）亲和力位点和一个高（皮摩尔）亲和力位点，约40%的位点为非常高亲和力形式。值得注意的是，在α4 nAChR基因敲除突变小鼠中仅检测到高亲和力形式。由于（125）I-α-CtxMII主要与小鼠纹状体中的α6α4β2β3和α6β2β3 nAChR亚型结合，这些数据表明在α4基因敲除小鼠中丧失的群体是α6α4β2β3亚型。接下来，我们在两种动物模型和帕金森病患者中研究了黑质纹状体损伤对这两种纹状体α6β2（*）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处理的猴以及帕金森病患者的纹状体中，非常高亲和力亚型优先丧失。这些数据表明，表达α6α4β2β3群体的多巴胺能末梢对黑质纹状体损伤具有选择性易损性。因此，用α-CtxMII E11A鉴定的后一种nAChR亚型可能为帕金森病中对黑质纹状体变性特别敏感的多巴胺能末梢提供一种独特的标志物。
