title: Angiopoietin-1 blocks neurotoxic zinc entry into cortical cells via PIP2 hydrolysis-mediated ion channel inhibition.
abstract: Excessive entry of zinc ions into the soma of neurons and glial cells results in extensive oxidative stress and necrosis of cortical cells, which underlies acute neuronal injury in cerebral ischemia and epileptic seizures. Here, we show that angiopoietin-1 (Ang1), a potent angiogenic ligand for the receptor tyrosine kinase Tie2 and integrins, inhibits the entry of zinc into primary mouse cortical cells and exerts a substantial protective effect against zinc-induced neurotoxicity. The neuroprotective effect of Ang1 was mediated by the integrin/focal adhesion kinase (FAK) signaling axis, as evidenced by the blocking effects of a pan-integrin inhibitory RGD peptide and PF-573228, a specific chemical inhibitor of FAK. Notably, blockade of zinc-permeable ion channels by Ang1 was attributable to phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate. Collectively, these data reveal a novel role of Ang1 in regulating the activity of zinc-permeable ion channels, and thereby protecting cortical cells against zinc-induced neurotoxicity.
authors.affiliation: Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea; Neural Injury Research Lab, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Joon Seo
authors.initials: JS
authors.lastname: Lim
authors.affiliation: Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea. Electronic address: gykoh@kaist.ac.kr.
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.affiliation: Neural Injury Research Lab, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea; Department of Neurology, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea. Electronic address: jkko@amc.seoul.kr.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Koh
mesh_terms: D042683:Angiopoietin-1 / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006868:Hydrolysis / Q000187:drug effects; D016023:Integrins / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D010455:Peptides / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D015363:Quinolones / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology; D013997:Time Factors; D015032:Zinc / Q000633:toxicity*
chemical_list: C521108:6-(4-(3-(methylsulfonyl)benzylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one; D042683:Angiopoietin-1; D004791:Enzyme Inhibitors; C587174:FAK peptide; D016023:Integrins; D007473:Ion Channels; D010455:Peptides; D019269:Phosphatidylinositol 4,5-Diphosphate; D015363:Quinolones; D017382:Reactive Oxygen Species; D013450:Sulfones; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D015032:Zinc
keywords: Angiopoietin-1; Astrocyte; Cell death; Integrin; Neuron; Phosphatidylinositol 4,5-bisphosphate (PIP(2)); Zinc