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Insulin‐Like Growth Factor I Prevents the Development of Sensitivity to Kainate Neurotoxicity in Cerebellar Granule Cells
Author(s) -
Leski Michael L.,
Valentine Stacey L.,
Baer Jesse D.,
Coyle Joseph T.
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0751548.x
Subject(s) - wortmannin , neurotoxicity , kainate receptor , p70 s6 kinase 1 , biology , endocrinology , medicine , growth factor , insulin like growth factor , kainic acid , glutamate receptor , chemistry , kinase , phosphatidylinositol , biochemistry , protein kinase b , phosphorylation , receptor , ampa receptor , toxicity
This study reports that insulin‐like growth factor I (IGF‐I) prevents cerebellar granule cells from developing sensitivity to kainate neurotoxicity. Sensitivity to kainate neurotoxicity normally develops 5‐6 days after switching cultures to a serum‐free medium containing 25 m M K + . Addition of either IGF‐I or insulin to the serum‐free medium at the time of the switch prevented the development of sensitivity to kainate, whereas brain‐derived neurotrophic factor, neurotrophin‐3, neurotrophin‐4, and nerve growth factor did not. The dose‐response curves indicated IGF‐I was more potent than insulin, favoring the assignment of the former as the physiological protective agent. The phosphatidylinositol 3‐kinase (PI 3‐K) inhibitors wortmannin (10‐100 n M ) and LY 294002 (0.3‐1 μ M ) abolished the protection afforded by IGF‐I. The p70 S6 kinase (p70 S6k ) inhibitor rapamycin (5‐50 n M ) also abolished the protection afforded by IGF‐I. The activities of both enzymes decreased in cultures switched to serum‐free medium but increased when IGF‐I was included; wortmannin (100 n M ) lowered the activity of PI 3‐K from 2 to 5 days after medium switch, whereas rapamycin (50 n M ) prevented the increase observed for p70 S6k activity over the same interval. The mitogen‐activated protein kinase kinase inhibitor U 0126 and the mitogen‐activated protein kinase inhibitor SB 203580 did not abolish IGF‐I protection. Kainate neurotoxicity was not prevented by Joro spider toxin; therefore, the development of kainate neurotoxicity could not be explained by the formation of calcium‐permeable α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptors. These results indicate that IGF‐I functions through a signal transduction pathway involving PI 3‐K and p70 S6k to prevent the development of sensitivity to kainate neurotoxicity in cerebellar granule cells.