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-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.
Highlights
Astrocytes are the most abundant glial cells, which play vital roles in controlling extracellular ion/glutamate homeostasis, brain–blood barrier, energy metabolism, and synaptic function
Western blot study demonstrated the upregulations of heat shock protein 25 (HSP25), phospho (p)-HSP25, and lysosome-associated membrane protein 1 (LAMP1) expression in isolated astrocytes obtained from P2X7 receptor (P2X7R) KO mice without affecting p-HSP25/HSP25 ratio after kainic acid (KA) injection, as compared to WT mice
Since LAMP1 is important for the autophagolysosomal pathway [17], these findings indicate that KA-induced upregulation of HSP25 expIrnet.sJs.iMonol. mScia. y202e0x, e21r,t6a47s6troglial autophagy in P2X7R KO mice, independent of seizure activ4 iotfy2.1
Summary
Astrocytes are the most abundant glial cells, which play vital roles in controlling extracellular ion/glutamate homeostasis, brain–blood barrier, energy metabolism, and synaptic function. We have reported that clasmatodendrosis is lysosome-associated membrane protein 1 (LAMP1)-mediated astroglial autophagy [6]. Autophagy is critical for energy homeostasis and cell survival, since it clears the damaged proteins and organelles and provides cellular energy and building blocks for biosynthesis by enabling the recycle of the degraded cellular components. Excessive autophagy leads to cell death, which shows extensive cytoplasmic vacuolization and culminating with phagocytic uptake and consequent lysosomal degradation [7]. Upregulated HSP25 itself evokes endoplasmic reticulum stress and exerts 5 adenosine monophosphate-activated protein kinase (AMPK)/unc-51 like autophagy activating kinase 1 (ULK1)-mediated autophagic pathways independent of mammalian target of rapamycin (mTOR) activity in astrocytes [6]
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