Journal
NEUROSCIENCE RESEARCH
Volume 131, Issue -, Pages 52-62Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neures.2017.09.002
Keywords
MCU; Pyk2; Mitochondria; Ca2+; Ischemic stroke; HUK
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Funding
- NSFC from the National Natural Science Foundation of China [81571160]
- Second Hospital of Hebei Medical University Research Fund [2h2201506]
- Key project of medical research in Hebei Province [20150668]
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Mitochondrial dysfunction caused by Ca2+ overload plays an important role in ischemia-induced brain damage. Mitochondrial calcium uniporter (MCU), located on the mitochondrial inner membrane, is the major channel responsible for mitochondrial Ca2+ uptake. Activated proline-rich tyrosine kinase 2 (Pyk2) can directly phosphorylate MCU, which enhances mitochondrial Ca2+ uptake in cardiomyocytes. It has been suggested that the Pyk2/MCU pathway may be a novel therapeutic target in stress -induced cellular apoptosis. In this study, we explored the role of the Pyk2/MCU pathway in the ischemic brain following a stroke injury. We found that the Pyk2/MCU pathway is activated in a rat cerebral ischemia model, and is responsible for mitochondrial dysfunction and neuronal apoptosis. Inhibiting the Pyk2/MCU pathway with a Pyk2 inhibitor (PF-431396) prevented mitochondrial Ca2+ overload, mitochondrial injury, proapoptotic protein release, and cell death. Interestingly, human urinary kallidinogenase (HUK) alleviated neuronal ischemic injury by inhibiting the Pyk2/MCU pathway, suggesting that the Pyk2/MCU pathway may be a protective target for ischemic stroke treatment. (C) 2017 Published by Elsevier Ireland Ltd.
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