17-β-estradiol potentiates the neurotrophic and neuroprotective effects mediated by the dopamine D3/acetylcholine nicotinic receptor heteromer in dopaminergic neurons

Dopaminergic neurons express a heteromer composed of the dopamine D3 receptor and the alpha 4 beta 2 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 D3RnAChR heteromer activity is potentiated by 17-beta-estradiol which acts as a positive allosteric modulator by binding a specific domain on the alpha 4 subunit of the nicotinic receptor protomer. In mouse dopaminergic neurons, in fact, 17-beta-estradiol significantly increased the ability of nicotine and quinpirole in promoting neuron dendritic remodeling and in protecting neurons against the accumulation of alpha-synuclein induced by deprivation of glucose, with a mechanism that does not involve the classical estrogen receptors. The potentiation induced by 17 beta-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-beta-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-beta-estradiol reduces dopaminergic neuron vulnerability.