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Alcohol Regulates Gene Expression in Neurons via Activation of Heat Shock Factor 1
Leonardo Pignataro, Alexandria N. Miller, Limei Ma, Shonali Midha, Petr Protiva, Daniel G. Herrera, and Neil L. Harrison

Departments of Anesthesiology, Pharmacology, and Psychiatry, Weill Cornell Medical College, New York, New York 10021, The Stowers Institute for Medical Research, Kansas City, Missouri 64110, The Rockefeller University, New York, New York 10021, and University of Connecticut Health Center, Farmington, Connecticut 06030 Correspondence should be addressed to Neil L. Harrison, Departments of Anesthesiology and Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10021. Email: neh2001@med.cornell.edu

Drinking alcohol causes widespread alterations in gene expression that can result in long-term physiological changes. Although many alcohol-responsive genes (ARGs) have been identified, the mechanisms by which alcohol alters transcription are not well understood. To elucidate these mechanisms, we investigated Gabra4, a neuron-specific gene that is rapidly and robustly activated by alcohol (10-60 mM), both in vitro and in vivo. Here we show that alcohol can activate elements of the heat shock pathway in mouse cortical neurons to enhance the expression of Gabra4 and other ARGs. The activation of Gabra4 by alcohol or high temperature is dependent on the binding of heat shock factor 1 (HSF1) to a short downstream DNA sequence, the alcohol response element (ARE). Alcohol and heat stimulate the translocation of HSF1 from the cytoplasm to the nucleus and the induction of HSF1-dependent genes, Hsp70 and Hsp90, in cultured neurons and in the mouse cerebral cortex in vivo. The reduction of HSF1 levels using small interfering RNA prevented the stimulation of Gabra4 and Hsp70 by alcohol and heat shock. Microarray analysis showed that many ARGs contain ARE-like sequences and that some of these genes are also activated by heat shock. We suggest that alcohol activates phylogenetically conserved pathways that involve intermediates in the heat shock cascade and that sequence elements similar to the ARE may mediate some of the changes in gene expression triggered by alcohol intake, which could be important in a variety of pathophysiological responses to alcohol.