Autophagy is a protecting intracellular pathway to transmit unnecessary or dysfunctional components to the lysosome for degeneration. Autophagic imbalance is connected with neurodegeneration. Neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, and Huntington's disease are closely related to excitotoxicity and neuronal loss. Activation of G-protein-coupled receptor 30 (GPR30), an estrogen membrane receptor, protects neurons from excitotoxicity-induced cell death. However, whether autophagy is involved in the neuroprotective effect of GPR30 activation is not well-known. In this study, methyl thiazolyl tetrazolium (MTT), Western blot, monodansylcadaverine (MDC) staining, and immunofluorescent staining were employed to detect the role of autophagy in cultured primary cortical neurons after glutamate exposure and G1 treatment. Pretreatment of G1 (GPR30 specific agonist) reduced neuronal loss through inhibiting excessive autophagy induced by glutamate exposure, which was blocked by GPR30 antagonist G15, phosphatidylinositol-3-kinase (PI3K), and the mammalian target of rapamycin (mTOR) inhibitors. These data suggest that GPR30 protects neurons from cell loss primarily by modulating PI3K-AKT-mTOR signaling pathway. In addition, G1 alone did not affect the basal autophagy and cell viability. We conclude that GPR30 activation reduces glutamate-induced excessive autophagy in neurons and protects neurons against excitotoxicity.
Keywords: GPR30; autophagy; excitotoxicity; glutamate; mTOR; neuron.