title: PTEN degradation after ischemic stroke: a double-edged sword.
abstract: Tumor suppressor phosphatase and tensin homolog (PTEN) is highly expressed in neurons and PTEN inhibition has been reported to be neuroprotective against ischemic stroke in experimental models. On the other hand, PTEN deletion has been shown to lead to cognitive impairment. In the current study, we examined the expression and functions of PTEN in an ischemic stroke rodent model. We found rapid S-nitrosylation and degradation of PTEN after cerebral ischemia/reperfusion injury. PTEN degradation leads to activation of Akt. PTEN partial deletion or PTEN inhibition increased the expression of GABAA receptor (GABAAR) γ2 subunit and enhanced GABAA receptor current. After cerebral ischemia, increased expression of GABAAR γ2 subunit was observed in the ischemia region and the penumbra area. We also observed PTEN loss in astrocytes after cerebral ischemia. Astrocytic PTEN partial knockout increased astrocyte activation and exacerbated ischemic damage. We speculated that ischemic stroke induced neuronal PTEN degradation, hence enhanced GABAA receptor-medicated neuronal activity inhibition which could attenuate excitotoxicity and provide neuroprotection during the acute phase after stroke, while inhibiting long-term functional recovery and contributing to vascular cognitive impairment after stroke. On the other hand, ischemic stroke induced astrocytic PTEN loss and enhanced ischemic damage and astrogliosis. Taken together, our study indicates that ischemic stroke induces rapid PTEN degradation in both neurons and astrocytes which play both protective and detrimental action in a spatiotemporal- and cell-type-dependent manner. Our study provides critical insight for targeting PTEN signaling pathway for stroke treatment.
authors.affiliation: Department of Pharmacology and Neuroscience, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, United States.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Neuroscience, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, United States.
authors.forename: R
authors.initials: R
authors.lastname: Huang
authors.affiliation: Department of Pharmacology and Neuroscience, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, United States.
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, United States.
authors.forename: L-J
authors.initials: LJ
authors.lastname: Yan
authors.affiliation: Department of Physiology and Pharmacology, Center for Neuroscience, West Virginia University Health Science Center, 1 Medical Center Drive, Morgantown, WV 26506, United States.
authors.forename: J W
authors.initials: JW
authors.lastname: Simpkins
authors.affiliation: Department of Pharmacology and Neuroscience, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, United States. Electronic address: shaohua.yang@unthsc.edu.
authors.forename: S-H
authors.initials: SH
authors.lastname: Yang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism*; D002460:Cell Line; D006624:Hippocampus / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D011963:Receptors, GABA-A / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism; D015398:Signal Transduction; D020521:Stroke / Q000378:metabolism*
chemical_list: D011963:Receptors, GABA-A; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat
keywords: GABA; PTEN; degradation; gliosis; nitrosylation; stroke