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Ethanol Induces Apoptosis in Cerebellar Granule Neurons by Inhibiting Insulin‐Like Growth Factor 1 Signaling
Author(s) -
Zhang Frank X.,
Rubin Raphael,
Rooney Thomas A.
Publication year - 1998
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.1471-4159.1998.71010196.x
Subject(s) - protein kinase a , protein kinase c , protein kinase inhibitor , kinase , microbiology and biotechnology , biology , chemistry , endocrinology , medicine
The ability of ethanol to interfere with insulin‐like growth factor 1 (IGF‐1)‐mediated cell survival was examined in primary cultured cerebellar granule neurons. Cells underwent apoptosis when switched from medium containing 25 m M K + to one containing 5 m M K + . IGF‐1 protected granule neurons from apoptosis in medium containing 5 m M K + . Ethanol inhibited IGF‐1‐mediated neuronal survival but did not inhibit IGF‐1 receptor binding or the neurotrophic action of elevated K + , and failed to potentiate cell death in the presence of 5 m M K + . Inhibition of neuronal survival by ethanol was not reversed by increasing the concentration of IGF‐1. Significant inhibition by ethanol (15–20%) was observed at 1 m M and was half‐maximal at 45 m M . The inhibition of IGF‐1 protection by ethanol corresponded to a marked reduction in the phosphorylation of insulin receptor substrate 1, the binding of phosphatidylinositol 3‐kinase (PI 3‐kinase), and a block of IGF‐1‐stimulated PI 3‐kinase activity. The neurotrophic response of IGF‐1 was also inhibited by the PI 3‐kinase inhibitor LY294002, the protein kinase C inhibitor chelerythrine chloride, and the protein kinase A inhibitor KT5720, but unaffected by the mitogen‐activated protein kinase kinase inhibitor PD 98059. These data demonstrate that ethanol promotes cell death in cerebellar granule neurons by inhibiting the antiapoptotic action of IGF‐1.