Ethanol enhances growth factor activation of mitogen-activated protein kinases by a protein kinase C-dependent mechanism

Abstract

Excessive alcohol consumption alters neuronal growth and causes striking elongation of axons and dendrites in several brain regions. This could result from increased sensitivity to neurotrophic factors, since ethanol markedly enhances nerve growth factor (NGF)- and basic fibroblast growth factor (bFGF)-stimulated neurite outgrowth in the neural cell line PC12. The mechanism by which ethanol enhances growth factor responses was investigated by examining activation of mitogen-activated protein kinases (MAP kinases), a key event in growth factor signaling. Ethanol (100 mM) increased NGF- and bFGF-induced activation of MAP kinases. This increase, like ethanol-induced increases in neurite outgrowth, was prevented by down regulation of beta, delta, and epsilon protein kinase C (PKC) isozymes. Since chronic ethanol exposure specifically upregulates delta and epsilon PKC, these findings suggest that ethanol promotes neurite growth by enhancing growth factor signal transduction through a delta or epsilon PKC-regulated pathway.