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

ABSTRACT: 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-3?/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.

SUBMITTER: Lee DS

PROVIDER: S-EPMC7555659 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Lee Duk-Shin DS Kim Ji-Eun JE

International journal of molecular sciences 20200904 18

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 ...[more]

PMID: 32899862

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Project description:Objective: Our study aimed to explore whether gasdermin D (GSDMD)-mediated pyroptosis is involved in the mechanism of kainic acid-induced seizures. Methods: C57BL/6 mice were randomly divided into sham and epilepsy groups. The epilepsy group was intrahippocampally injected with kainic acid to induce status epilepticus (SE), and the sham group was injected with an equal volume of saline. Dimethyl fumarate (DMF) was used as the GSDMD N-terminal fragments (GSDMD-N) inhibitor and suspended in 0.5% sodium carboxymethyl cellulose (CMC) for orally administration. The epilepsy group was divided into SE + CMC and SE + DMF groups. In the SE + DMF group, DMF was orally administered for 1 week before SE induction and was continued until the end of the experiment. An equal volume of CMC was administered to the sham and SE + CMC groups. Recurrent spontaneous seizures (SRSs) were monitored for 21 days after SE. Western blot analysis and immunofluorescent staining was performed. Results: The expression of GSDMD increased at 7-21 days post-SE, and GSDMD-N expression was significantly elevated 7 days after SE in both ipsilateral and contralateral hippocampus. GSDMD-positive cells were co-labeled with astrocytes, but not neurons or microglia. Astroglial damage occurs following status epilepticus (SE). Damaged astrocytes showed typical clasmatodendrosis in the CA1 region containing strong GSDMD expression at 7-21 days post-SE, accompanied by activated microglia. In the SE + DMF group, the expression of GSDMD-N was significantly inhibited compared to that in the SE + CMC group. After administration of DMF, SRSs at 7-21 days after SE were significantly decreased, and the number of clasmatodendritic astrocytes, microglia, and the expression of inflammatory factors such as IL-1β and IL-18 were significantly attenuated. Conclusion: GSDMD-mediated pyroptosis is involved in the mechanism of kainic acid-induced seizures. Our study provides a new potential therapeutic target for seizure control.

Dataset Information

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

Publications

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

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