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Article

P2 × 7 Receptor Inhibits Astroglial Autophagy via Regulating FAK- and PHLPP1/2-Mediated AKT-S473 Phosphorylation Following Kainic Acid-Induced Seizures

Department of Anatomy and Neurobiology, Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon 24252, Korea
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Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(18), 6476; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186476
Received: 22 July 2020 / Revised: 25 August 2020 / Accepted: 3 September 2020 / Published: 4 September 2020
(This article belongs to the Collection Neuroinflammatory Processes in Neurodegenerative Diseases)
Recently, we have reported that blockade/deletion of P2X7 receptor (P2X7R), an ATP-gated ion channel, exacerbates heat shock protein 25 (HSP25)-mediated astroglial autophagy (clasmatodendrosis) following kainic acid (KA) injection. In P2X7R knockout (KO) mice, prolonged astroglial HSP25 induction exerts 5′ adenosine monophosphate-activated protein kinase/unc-51 like autophagy activating kinase 1-mediated autophagic pathway independent of mammalian target of rapamycin (mTOR) activity following KA injection. Sustained HSP25 expression also enhances AKT-serine (S) 473 phosphorylation leading to astroglial autophagy via glycogen synthase kinase-3β/bax interacting factor 1 signaling pathway. However, it is unanswered how P2X7R deletion induces AKT-S473 hyperphosphorylation during autophagic process in astrocytes. In the present study, we found that AKT-S473 phosphorylation was increased by enhancing activity of focal adhesion kinase (FAK), independent of mTOR complex (mTORC) 1 and 2 activities in isolated astrocytes of P2X7R knockout (KO) mice following KA injection. In addition, HSP25 overexpression in P2X7R KO mice acted as a chaperone of AKT, which retained AKT-S473 phosphorylation by inhibiting the pleckstrin homology domain and leucine-rich repeat protein phosphatase (PHLPP) 1- and 2-binding to AKT. Therefore, our findings suggest that P2X7R may be a fine-tuner of AKT-S473 activity during astroglial autophagy by regulating FAK phosphorylation and HSP25-mediated inhibition of PHLPP1/2-AKT binding following KA treatment. View Full-Text
Keywords: Bif-1; FAK inhibitor 14; LAMP1; p70S6K; PRAS40; Raptor; Rictor; siRNA Bif-1; FAK inhibitor 14; LAMP1; p70S6K; PRAS40; Raptor; Rictor; siRNA
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MDPI and ACS Style

Lee, D.-S.; Kim, J.-E. P2 × 7 Receptor Inhibits Astroglial Autophagy via Regulating FAK- and PHLPP1/2-Mediated AKT-S473 Phosphorylation Following Kainic Acid-Induced Seizures. Int. J. Mol. Sci. 2020, 21, 6476. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186476

AMA Style

Lee D-S, Kim J-E. P2 × 7 Receptor Inhibits Astroglial Autophagy via Regulating FAK- and PHLPP1/2-Mediated AKT-S473 Phosphorylation Following Kainic Acid-Induced Seizures. International Journal of Molecular Sciences. 2020; 21(18):6476. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186476

Chicago/Turabian Style

Lee, Duk-Shin; Kim, Ji-Eun. 2020. "P2 × 7 Receptor Inhibits Astroglial Autophagy via Regulating FAK- and PHLPP1/2-Mediated AKT-S473 Phosphorylation Following Kainic Acid-Induced Seizures" Int. J. Mol. Sci. 21, no. 18: 6476. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186476

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