Activation of G protein‐coupled receptor 30 protects neurons by regulating autophagy in astrocytes. Issue 1 (19th August 2019)

• Record Type: Journal Article
• Authors: Wang, Xin‐Shang; Yue, Jiao; Hu, Li‐Ning; Tian, Zhen; Zhang, Kun; Yang, Le; Zhang, Hui‐Nan; Guo, Yan‐Yan; Feng, Bin; Liu, Hai‐Yan; Wu, Yu‐Mei; Zhao, Ming‐Gao; Liu, Shui‐Bing
• Is Part Of: Glia. Volume 68:Issue 1(2020)
• Page Start: 27
• Page End: 43
• Publication Date: 2019-08-19
• Subjects: astrocyte -- autophagy -- GPR30 -- neuroprotection -- p38 MAPK; Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.23697
• Languages: English
• ISSNs: 0894-1491

Abstract

Abstract: Ischemic stroke leads to neuronal damage induced by excitotoxicity, inflammation, and oxidative stress. Astrocytes play diverse roles in stroke and ischemia‐induced inflammation, and autophagy is critical for maintaining astrocytic functions. Our previous studies showed that the activation of G protein‐coupled receptor 30 (GPR30), an estrogen membrane receptor, protected neurons from excitotoxicity. However, the role of astrocytic GPR30 in maintaining autophagy and neuroprotection remained unclear. In this study, we found that the neuroprotection induced by G1 (GPR30 agonist) in wild‐type mice after a middle cerebral artery occlusion was completely blocked in GPR30 conventional knockout (KO) mice but partially attenuated in astrocytic or neuronal GPR30 KO mice. In cultured primary astrocytes, glutamate exposure induced astrocyte proliferation and decreased astrocyte autophagy by activating mammalian target of rapamycin (mTOR) and c‐Jun N‐terminal kinase (JNK) and inhibiting p38 mitogen‐activated protein kinase (MAPK) pathway. G1 treatment restored autophagy to its basal level by regulating the p38 pathway but not the mTOR and JNK signaling pathways. Our findings revealed a key role of GPR30 in neuroprotection via the regulation of astrocyte autophagy and support astrocytic GPR30 as a potential drug target against ischemic brain damage. Main Points: Astrocytic GPR30 was involved in the neuroprotection. Autophagic deficiency of astrocytes induced by glutamate promoted inflammatory cytokine release. GPR30 activation restored autophagy balance in astrocytes by regulating the p38 MAPK pathway.