کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5534343 | 1551124 | 2017 | 11 صفحه PDF | دانلود رایگان |
- Dopamine induces [Zn2Â +]i elevation in culture neurons via cAMP-NO signaling.
- NO interacts with the metallothionein to release Zn2Â +.
- Chelate [Zn2Â +]i elevation rescues neurons from dopamine-induced cell death.
- [Zn2Â +]i elevation is a pre-requisite for dopamine-induced autophagic flux.
Zinc ion (Zn2Â +), the second most abundant transition metal after iron in the body, is essential for neuronal activity and also induces toxicity if the concentration is abnormally high. Our previous results show that exposure of cultured cortical neurons to dopamine elevates intracellular Zn2Â + concentrations ([Zn2Â +]i) and induces autophagosome formation but the mechanism is not clear. In this study, we characterized the signaling pathway responsible for the dopamine-induced elevation of [Zn2Â +]i and the effect of [Zn2Â +]i in modulating the autophagy in cultured rat embryonic cortical neurons. N,N,Nâ²,Nâ²-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), a membrane-permeable Zn2Â + chelator, could rescue the cell death and suppress the autophagosome puncta number induced by dopamine. Dopamine treatment increased the lipidation level of the endogenous microtubule-associated protein 1A/1B-light chain 3 (LC3 II), an autophagosome marker. TPEN added 1Â h before, but not after, dopamine treatment suppressed the dopamine-induced elevation of LC3 II level. Inhibitors of the dopamine D1-like receptor, protein kinase A (PKA), and NOS suppressed the dopamine-induced elevation of [Zn2Â +]i. PKA activators and NO generators directly increased [Zn2Â +]i in cultured neurons. Through cell fractionation, proteins with m.w. values between 5 and 10Â kD were found to release Zn2Â + following NO stimulation. In addition, TPEN pretreatment and an inhibitor against PKA could suppress the LC3 II level increased by NO and dopamine, respectively. Therefore, our results demonstrate that dopamine-induced elevation of [Zn2Â +]i is mediated by the D1-like receptor-PKA-NO pathway and is important in modulating the cell death and autophagy.
Journal: Molecular and Cellular Neuroscience - Volume 82, July 2017, Pages 35-45