title: Enhancement of ischemia-induced tyrosine phosphorylation of Kv1.2 by vascular endothelial growth factor via activation of phosphatidylinositol 3-kinase.
abstract: Our studies observed that, consistent with the literature, ischemic/hypoxic insults increased the expression of voltage-gated potassium channel (Kv) 1.2 potassium channel as well as elevating the endogenous level of vascular endothelial growth factor (VEGF) in neurons of adult rat brain following middle cerebral artery occlusion and in SH-SY5Y cells after hypoxia and glucose deprivation. Concomitantly, we also observed that ischemic injury increased the tyrosine phosphorylation of Kv 1.2 in in vivo and in vitro; the introduction of exogenous VEGF could attenuate cell death in in vitro models. Furthermore, we found that the protective effect of VEGF is mediated through its up-regulative actions on the tyrosine phosphorylation of Kv 1.2, which in turn has a direct influence on cell viability after ischemic insult. In substantiation of this result, we used anti-sense methodology to suppress the expression of endogenous VEGF, which significantly inhibited the tyrosine phosphorylation of Kv 1.2 and increased cell death elicited by ischemic/hypoxic injury. Finally, the enhancement of the tyrosine phosphorylation of the channel by VEGF in neuronal cells was significantly attenuated in the presence of wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-K), or genestin, an inhibitor of tyrosine kinase, thus suggesting that the phosphorylation of Kv 1.2 induced by VEGF is mechanistically linked to the PI3-K pathway.
authors.affiliation: National Laboratory of Medical Neurobiology, Shanghai Medical College of, Fudan University, Shanghai, People's Republic of China.
authors.forename: Mei-Hong
authors.initials: MH
authors.lastname: Qiu
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Feng-Yan
authors.initials: FY
authors.lastname: Sun
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000517:prevention & control; D020925:Hypoxia-Ischemia, Brain / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000378:metabolism; D051663:Kv1.2 Potassium Channel; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010766:Phosphorylation; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011233:Precipitin Tests / Q000379:methods; D011419:Propidium / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014443:Tyrosine / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D005904:Glial Fibrillary Acidic Protein; C496969:KCNA2 protein, human; C496972:Kcna2 protein, rat; D051663:Kv1.2 Potassium Channel; D020319:Oligodeoxyribonucleotides, Antisense; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D042461:Vascular Endothelial Growth Factor A; D011419:Propidium; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D017493:Leukocyte Common Antigens; D010751:Phosphopyruvate Hydratase; D005947:Glucose