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The Journal of Neuroscience, April 21, 2004, 24(16):4052-4060; doi:10.1523/JNEUROSCI.5449-03.2004

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Neurobiology of Disease
Dual Neuroprotective Signaling Mediated by Downregulating Two Distinct Phosphatase Activities of PTEN

Ke Ning,^1,2,3 Lin Pei,^4,5 Mingxia Liao,^1,2,3 Baosong Liu,^1,2,3 Yunzhou Zhang,⁶ Wen Jiang,⁶ John G. Mielke,¹ Lei Li,^1,2,3 Yonghong Chen,^1,2,3 Youssef H. El-Hayek,^1,2,3 Michael G. Fehlings,^1,3 Xia Zhang,⁶ Fang Liu,^4,5 James Eubanks,^1,3 and Qi Wan^1,2,3

¹Division of Cellular and Molecular Biology, Toronto Western Research Institute, University Health Network, Toronto, Canada M5T 2S8, Departments of ²Physiology, ³Surgery, and ⁴Psychiatry, University of Toronto, Toronto, Canada M5S 1A8, ⁵Centre for Addiction and Mental Health, Clarke Division, Toronto, Canada M5T 1R8, and ⁶Neuropsychiatry Research Unit, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5E4

The tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a lipid and protein phosphatase. We report here that PTEN physically associates with the NR1 and NR2B subunits of NMDA receptors (NMDARs) in rat hippocampus. Downregulating the protein expression of PTEN inhibits the function of extrasynaptic NMDARs and decreases NMDAR surface expression, suggesting a crucial role for endogenous PTEN in the modulation of NMDAR-mediated neuronal function. Reducing PTEN expression also enhances Akt/Bad phosphorylation in hippocampal neurons. Importantly, suppressing lipid and protein phosphatase activity of PTEN, respectively, activates Akt and inhibits extrasynaptic NMDAR activity and thereby protects against ischemic neuronal death in vitro and in vivo. Thus, our study reveals a dual neuroprotective mechanism by which Akt/Bad and extrasynaptic NMDARs are regulated via downregulation of two distinct PTEN phosphatase activities and present the possibility of PTEN as a potential therapeutic target for stroke treatment.

Key words: phosphatase; NMDA receptor; cerebral ischemia; neuroprotection; stroke; synapse

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Received Dec 10, 2003; revised March 8, 2004; accepted March 8, 2004.

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