Blockade of RyRs in the ER Attenuates 6-OHDA-Induced Calcium Overload, Cellular Hypo-Excitability and Apoptosis in Dopaminergic Neurons.
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)-inducedin vitroPD 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.
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
Lu
L
Huang
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
Ying
Y
Xue
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
DaYun
D
Feng
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
RuiXin
R
Yang
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
Tiejian
T
Nie
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
Gang
G
Zhu
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
Kai
K
Tao
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
GuoDong
G
Gao
Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University Xi'an, China.
Qian
Q
Yang
4; 5-triphosphate receptors; 6-hydroxydopamine; ER stress; Inositol 1; Parkinson’s disease; calcium; ryanodine receptors