Activation of G-Protein-Coupled Receptor 30 Protects Neurons against Excitotoxicity through Inhibiting Excessive Autophagy Induced by Glutamate

Yue, Jiao; Wang, Xin‐shang; Feng, Bin; Hu, Li‐ning; Yang, Liu-kun; Lu, Liang; Zhang, Kun; Wang, Yatao

doi:10.1021/acschemneuro.9b00287

Cited by 20 publications

(10 citation statements)

References 55 publications

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“…Many studies have confirmed that autophagy plays an important role in cardiac function and metabolism [ 24 , 25 ], and G1 shows a protective effect by regulating autophagy intensity in the nervous system [ 29 , 30 ]. In order to verify whether the cardiac protection of the G1 treatment in our study was related to autophagy, we detected the expression of LC3 and P62, which are reported as markers of autophagy [ 14 ].…”

Section: Resultsmentioning

confidence: 99%

“…G1 treated female mice also exhibited increased energy expenditure, lower body fat content, and reduced fasting cholesterol, glucose, insulin, and inflammatory markers [ 16 ]. Yue et al demonstrated that GPR30 activation reduced glutamate-induced excessive autophagy in neurons and protected neurons against excitotoxicity [ 29 ]. Wang et al reported that activation of GPR30 by G1 played a neuroprotection role via the regulation of astrocyte autophagy and supported astrocytic GPR30 as a potential drug target against ischemic brain damage [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

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GPR30 Alleviates Pressure Overload-Induced Myocardial Hypertrophy in Ovariectomized Mice by Regulating Autophagy

Zhang

Wang

et al. 2023

IJMS

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The incidence of heart failure mainly resulting from cardiac hypertrophy and fibrosis increases sharply in post-menopausal women compared with men at the same age, which indicates a cardioprotective role of estrogen. Previous studies in our group have shown that the novel estrogen receptor G Protein Coupled Receptor 30 (GPR30) could attenuate myocardial fibrosis caused by ischemic heart disease. However, the role of GPR30 in myocardial hypertrophy in ovariectomized mice has not been investigated yet. In this study, female mice with bilateral ovariectomy or sham surgery underwent transverse aortic constriction (TAC) surgery. After 8 weeks, mice in the OVX + TAC group exhibited more severe myocardial hypertrophy and fibrosis than mice in the TAC group. G1, the specific agonist of GPR30, could attenuate myocardial hypertrophy and fibrosis of mice in the OVX + TAC group. Furthermore, the expression of LC3II was significantly higher in the OVX + TAC group than in the OVX + TAC + G1 group, which indicates that autophagy might play an important role in this process. An in vitro study showed that G1 alleviated AngiotensionII (AngII)-induced hypertrophy and reduced the autophagy level of H9c2 cells, as revealed by LC3II expression and tandem mRFP-GFP-LC3 fluorescence analysis. Additionally, Western blot results showed that the AKT/mTOR pathway was inhibited in the AngII group, whereas it was restored in the AngII + G1 group. To further verify the mechanism, PI3K inhibitor LY294002 or autophagy activator rapamycin was added in the AngII + G1 group, and the antihypertrophy effect of G1 on H9c2 cells was blocked by LY294002 or rapamycin. In summary, our results demonstrate that G1 can attenuate cardiac hypertrophy and fibrosis and improve the cardiac function of mice in the OVX + TAC group through AKT/mTOR mediated inhibition of autophagy. Thus, this study demonstrates a potential option for the drug treatment of pressure overload-induced cardiac hypertrophy in postmenopausal women.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

GPR30 Alleviates Pressure Overload-Induced Myocardial Hypertrophy in Ovariectomized Mice by Regulating Autophagy

Zhang

Wang

et al. 2023

IJMS

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“…As mentioned, the role of GPER1 in protecting brain neurons from hypoxia and ischemia remains controversial. It has been suggested that GPER1-mediated neuroprotection relies on the inhibition of apoptosis and excessive autophagy via the modulation of the PI3K-Akt-mTOR signaling pathway [ 79 ]. Since the role of autophagy in hypoxia/ischemia-induced brain pathology is ambiguous, the involvement of GPER1 in neuroprotection or neurotoxicity may be a result of interference with the autophagy process that determines the stroke duration and damage area.…”

Section: Neuroprotection Mediated By Membrane Ersmentioning

confidence: 99%

Emerging Evidence on Membrane Estrogen Receptors as Novel Therapeutic Targets for Central Nervous System Pathologies

Wnuk

Przepiórska

Pietrzak

et al. 2023

IJMS

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Nuclear- and membrane-initiated estrogen signaling cooperate to orchestrate the pleiotropic effects of estrogens. Classical estrogen receptors (ERs) act transcriptionally and govern the vast majority of hormonal effects, whereas membrane ERs (mERs) enable acute modulation of estrogenic signaling and have recently been shown to exert strong neuroprotective capacity without the negative side effects associated with nuclear ER activity. In recent years, GPER1 was the most extensively characterized mER. Despite triggering neuroprotective effects, cognitive improvements, and vascular protective effects and maintaining metabolic homeostasis, GPER1 has become the subject of controversy, particularly due to its participation in tumorigenesis. This is why interest has recently turned toward non-GPER-dependent mERs, namely, mERα and mERβ. According to available data, non-GPER-dependent mERs elicit protective effects against brain damage, synaptic plasticity impairment, memory and cognitive dysfunctions, metabolic imbalance, and vascular insufficiency. We postulate that these properties are emerging platforms for designing new therapeutics that may be used in the treatment of stroke and neurodegenerative diseases. Since mERs have the ability to interfere with noncoding RNAs and to regulate the translational status of brain tissue by affecting histones, non-GPER-dependent mERs appear to be attractive targets for modern pharmacotherapy for nervous system diseases.

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“…It can be speculated that it is depend on the types of cells, physiological functions, and types of stress stimuli that determine which types of G-protein subunits can activate mTORC1. The activation of G protein-coupled receptor 30 (GPR30, an estrogen membrane receptor) mainly regulates the PI3K–AKT–mTOR signaling pathway to inhibit excessive autophagy induced by glutamate and protect neurons from excitotoxicity [ 195 ]. The lysosomal GPR137B can interact with Rag GTPases to regulate mTORC1 in the absence of amino acids; however, autophagy is abnormal and lysosomes are damaged when GPR137B is knocked out, indicating that GPR137B can control the location and activity of mTORC1 and maintain lysosome morphology [ 196 ].…”

Section: Gpcrs-mediated Autophagymentioning

confidence: 99%

The dual roles of autophagy and the GPCRs-mediating autophagy signaling pathway after cerebral ischemic stroke

et al. 2022

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Ischemic stroke, caused by a lack of blood supply in brain tissues, is the third leading cause of human death and disability worldwide, and usually results in sensory and motor dysfunction, cognitive impairment, and in severe cases, even death. Autophagy is a highly conserved lysosome-dependent process in which eukaryotic cells removal misfolded proteins and damaged organelles in cytoplasm, which is critical for energy metabolism, organelle renewal, and maintenance of intracellular homeostasis. Increasing evidence suggests that autophagy plays important roles in pathophysiological mechanisms under ischemic conditions. However, there are still controversies about whether autophagy plays a neuroprotective or damaging role after ischemia. G-protein-coupled receptors (GPCRs), one of the largest protein receptor superfamilies in mammals, play crucial roles in various physiological and pathological processes. Statistics show that GPCRs are the targets of about one-fifth of drugs known in the world, predicting potential values as targets for drug research. Studies have demonstrated that nutritional deprivation can directly or indirectly activate GPCRs, mediating a series of downstream biological processes, including autophagy. It can be concluded that there are interactions between autophagy and GPCRs signaling pathway, which provides research evidence for regulating GPCRs-mediated autophagy. This review aims to systematically discuss the underlying mechanism and dual roles of autophagy in cerebral ischemia, and describe the GPCRs-mediated autophagy, hoping to probe promising therapeutic targets for ischemic stroke through in-depth exploration of the GPCRs-mediated autophagy signaling pathway.

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Activation of G-Protein-Coupled Receptor 30 Protects Neurons against Excitotoxicity through Inhibiting Excessive Autophagy Induced by Glutamate

Cited by 20 publications

References 55 publications

GPR30 Alleviates Pressure Overload-Induced Myocardial Hypertrophy in Ovariectomized Mice by Regulating Autophagy

GPR30 Alleviates Pressure Overload-Induced Myocardial Hypertrophy in Ovariectomized Mice by Regulating Autophagy

Emerging Evidence on Membrane Estrogen Receptors as Novel Therapeutic Targets for Central Nervous System Pathologies

The dual roles of autophagy and the GPCRs-mediating autophagy signaling pathway after cerebral ischemic stroke

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