Abstract：
Dopaminergic neurons express a heteromer composed of the dopamine D3 receptor and the α4β2 nicotinic acetylcholine receptor, the D3R-nAChR heteromer, activated by both nicotine and dopamine D2 and D3 receptors agonists, such as quinpirole, and crucial for dopaminergic neuron homeostasis. We now report that D3R-nAChR heteromer activity is potentiated by 17-β-estradiol which acts as a positive allosteric modulator by binding a specific domain on the α4 subunit of the nicotinic receptor protomer. In mouse dopaminergic neurons, in fact, 17-β-estradiol significantly increased the ability of nicotine and quinpirole in promoting neuron dendritic remodeling and in protecting neurons against the accumulation of α-synuclein induced by deprivation of glucose, with a mechanism that does not involve the classical estrogen receptors. The potentiation induced by 17-β-estradiol required the D3R-nAChR heteromer since either nicotinic receptor or dopamine D3 receptor antagonists and interfering TAT-peptides, but not the estrogen receptor antagonist fulvestrant, specifically prevented 17-β-estradiol effects. Evidence of estrogens neuroprotection, mainly mediated by genomic mechanisms, have been provided, which is in line with epidemiological data reporting that females are less likely to develop Parkinson\'s Disease than males. Therefore, potentiation of D3R-nAChR heteromer activity may represent a further mechanism by which 17-β-estradiol reduces dopaminergic neuron vulnerability.
摘要：
多巴胺能神经元表达由多巴胺D3受体和α4β2烟碱乙酰胆碱受体组成的异聚体，D3R-nAChR异聚体，由尼古丁和多巴胺D2和D3受体激动剂激活，比如喹吡罗,对多巴胺能神经元稳态至关重要。我们现在报道，D3R-nAChR异聚体活性被17-β-雌二醇增强，该17-β-雌二醇通过结合烟碱受体原聚体α4亚基上的特异性结构域而充当正变构调节剂。在小鼠多巴胺能神经元中，事实上,17-β-雌二醇显着增加尼古丁和喹吡罗促进神经元树突重塑和保护神经元免受葡萄糖剥夺诱导的α-突触核蛋白积累的能力，具有不涉及经典雌激素受体的机制。17-β-雌二醇诱导的增强作用需要D3R-nAChR异聚体，因为烟碱受体或多巴胺D3受体拮抗剂并干扰TAT肽，但不是雌激素受体拮抗剂氟维司群，特异性预防17-β-雌二醇效应。雌激素神经保护的证据，主要由基因组机制介导，已经提供了,这与流行病学数据报告一致，女性患帕金森病的可能性低于男性。因此,D3R-nAChR异聚体活性的增强可能代表了17-β-雌二醇降低多巴胺能神经元脆弱性的另一种机制。
