Expression profiling of neural cells reveals specific patterns of ethanol-responsive gene expression.
Adaptive changes in gene expression are thought to contribute to dependence, addiction and other behavioral responses to chronic ethanol abuse. DNA array studies provide a nonbiased detection of networks of gene expression changes, allowing insight into functional consequences and mechanisms of such molecular responses. We used oligonucleotide arrays to study nearly 6000 genes in human SH-SY5Y neuroblastoma cells exposed to chronic ethanol. A set of 42 genes had consistently increased or decreased mRNA abundance after 3 days of ethanol treatment. Groups of genes related to norepinephrine production, glutathione metabolism, and protection against apoptosis were identified. Genes involved in catecholamine metabolism are of special interest because of the role of this pathway in mediating ethanol withdrawal symptoms (physical dependence). Ethanol treatment elevated dopamine beta-hydroxylase (DBH, EC 1.14.17.1) mRNA and protein levels and increased releasable norepinephrine in SH-SY5Y cultures. Acute ethanol also increased DBH mRNA levels in mouse adrenal gland, suggesting in vivo functional consequences for ethanol regulation of DBH. In SH-SY5Y cells, ethanol also decreased mRNA and secreted protein levels for monocyte chemotactic protein 1, an effect that could contribute to the protective role of moderate ethanol consumption in atherosclerotic vascular disease. Finally, we identified a subset of genes similarly regulated by both ethanol and dibutyryl-cAMP treatment in SH-SY5Y cells. This suggests that ethanol and cAMP signaling share mechanistic features in regulating a subset of ethanol-responsive genes. Our findings offer new insights regarding possible molecular mechanisms underlying behavioral responses or medical consequences of ethanol consumption and alcoholism.
Thibault
C
C
The Ernest Gallo Clinic and Research Center and Department of Neurology, University of California, San Francisco, California, USA.
Lai
C
C
Wilke
N
N
Duong
B
B
Olive
M F
MF
Rahman
S
S
Dong
H
H
Hodge
C W
CW
Lockhart
D J
DJ
Miles
M F
MF
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002352:Carrier Proteins / Q000096:biosynthesis; D002492:Central Nervous System Depressants / Q000494:pharmacology; D004299:Dopamine beta-Hydroxylase / Q000096:biosynthesis; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008811:Mice, Inbred DBA; D018945:Monocyte Chemoattractant Proteins / Q000096:biosynthesis; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D050484:Norepinephrine Plasma Membrane Transport Proteins; D027981:Symporters; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D002492:Central Nervous System Depressants; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018945:Monocyte Chemoattractant Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; C493228:Slc6a2 protein, mouse; D027981:Symporters; C064045:delta protein; D000431:Ethanol; D003994:Bucladesine; D004299:Dopamine beta-Hydroxylase