Blockade of RyRs in the ER Attenuates 6-OHDA-Induced Calcium Overload, Cellular Hypo-Excitability and Apoptosis in Dopaminergic Neurons

Huang, Lu and Xue, Ying and Feng, DaYun and Yang, RuiXin and Nie, Tiejian and Zhu, Gang and Tao, Kai and Gao, GuoDong and Yang, Qian (2017) Blockade of RyRs in the ER Attenuates 6-OHDA-Induced Calcium Overload, Cellular Hypo-Excitability and Apoptosis in Dopaminergic Neurons. Frontiers in Cellular Neuroscience, 11. ISSN 1662-5102

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Abstract

Calcium (Ca2+) dyshomeostasis induced by endoplasmic reticulum (ER) stress is an important molecular mechanism of selective dopaminergic (DA) neuron loss in Parkinson’s disease (PD). Inositol 1,4,5-triphosphate receptors (IP3Rs) and ryanodine receptors (RyRs), which are located on the ER surface, are the main endogenous Ca2+ release channels and play crucial roles in regulating Ca2+ homeostasis. However, the roles of these endogenous Ca2+ release channels in PD and their effects on the function and survival of DA neurons remain unknown. In this study, using a 6-hydroxydopamine (6-OHDA)-induced in vitro PD model (SN4741 Cell line), we found that 6-OHDA significantly increased cytoplasmic Ca2+ levels ([Ca2+]i), which was attenuated by pretreatment with 4-phenyl butyric acid (4-PBA; an ER stress inhibitor) or ryanodine (a RyRs blocker). In addition, in acute midbrain slices of male Sprague-Dawley rats, we found that 6-OHDA reduced the spike number and rheobase of DA neurons, which were also reversed by pretreatment with 4-PBA and ryanodine. TUNEL staining and MTT assays also showed that 4-PBA and ryanodine obviously alleviated 6-OHDA-induced cell apoptosis and devitalization. Interestingly, a IP3Rs blocker had little effect on the above 6-OHDA-induced neurotoxicity in DA neurons. In conclusion, our findings provide evidence of the different roles of IP3Rs and RyRs in the regulation of endogenous Ca2+ homeostasis, neuronal excitability, and viability in DA neurons, and suggest a potential therapeutic strategy for PD by inhibiting the RyRs Ca2+ channels in the ER.

Item Type: Article
Subjects: STM Open Press > Medical Science
Depositing User: Unnamed user with email support@stmopenpress.com
Date Deposited: 28 Jun 2023 04:43
Last Modified: 03 Oct 2024 03:56
URI: http://journal.submissionpages.com/id/eprint/1684

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