ETHANOL ENHANCES GROWTH-FACTOR ACTIVATION OF MITOGEN-ACTIVATED PROTEIN-KINASES BY A PROTEIN-KINASE C-DEPENDENT MECHANISM

Excessive alcohol consumption alters neuronal growth and causes striki ng elongation of axons and dendrites in several brain regions. This co uld result from increased sensitivity to neurotrophic factors, since e thanol markedly enhances nerve growth factor (NGF)- and basic fibrobla st growth factor (bFGF)-stimulated neurite outgrowth in the neural cel l line PC12. The mechanism by which ethanol enhances growth factor res ponses was investigated by examining activation of mitogen-activated p rotein kinases (MAP kinases), a key event in growth factor signaling. Ethanol (100 mM) increased NGF- and bFGF-induced activation of MAP kin ases. This increase, like ethanol-induced increases in neurite outgrow th, was prevented by down regulation of beta, delta, and epsilon prote in kinase C (PKC) isozymes. Since chronic ethanol exposure specificall y upregulates delta and epsilon PKC, these findings suggest that ethan ol promotes neurite growth by enhancing growth Factor signal transduct ion through a delta or epsilon PKC-regulated pathway.