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Ethanol activates midkine and anaplastic lymphoma kinase signaling in neuroblastoma cells and in the brain

2015; Wiley; Volume: 135; Issue: 3 Linguagem: Inglês

10.1111/jnc.13252

1471-4159

Donghong He, Hu Chen, Hisako Muramatsu, Amy W. Lasek,

Fibroblast Growth Factor Research

Abstract Alcohol engages signaling pathways in the brain. Midkine ( MDK ) is a neurotrophic factor that is over‐expressed in the prefrontal cortex of alcoholics. MDK and one of its receptors, anaplastic lymphoma kinase ( ALK ), also regulate behavioral responses to ethanol in mice. The goal of this study was to determine whether MDK and ALK expression and signaling are activated by ethanol. We found that ethanol treatment of neuroblastoma cells increased MDK and ALK expression. We also assessed activation of ALK by ethanol in cells and found that ALK and ALK ‐dependent extracellular signal‐regulated kinase ( ERK ) and signal transducer and activator of transcription 3 (STAT3) phosphorylation increased rapidly with ethanol exposure. Similarly, treatment of cells with recombinant MDK protein increased ALK , ERK and STAT3 phosphorylation, suggesting that ethanol may utilize MDK to activate ALK signaling. In support of this, transfection of cells with MDK si RNA s attenuated ALK signaling in response to ethanol. Ethanol also activates ERK signaling in the brain. We found that inhibition of ALK or knockout of MDK attenuated ethanol‐induced ERK phosphorylation in mouse amygdala. These results demonstrate that ethanol engages MDK and ALK signaling, which has important consequences for alcohol‐induced neurotoxicity and the regulation of behaviors related to alcohol abuse. image We propose that ethanol (a) increases transcription of the anaplastic lymphoma kinase ( ALK ) and midkine ( MDK ) genes and (b) rapidly activates extracellular signal‐regulated kinase (pERK1/2) and signal transducer and activator of transcription 3 (pSTAT3) through MDK and ALK. Activation of ALK and MDK signaling by ethanol may alter behavioral responses to ethanol with implications for the development of alcohol use disorders.