The Journal of Neuroscience, September 15, 2002, 22(18):7941-7947
A Novel Signaling Pathway of Nitric Oxide on Transcriptional
Regulation of Mouse 
Opioid Receptor Gene
Sung Wook
Park,
Jinhua
Li,
Horace H.
Loh, and
Li-Na
Wei
Department of Pharmacology, University of Minnesota Medical School,
Minneapolis, Minnesota 55455
Nitric oxide (NO) suppressed the transcription of the mouse 
opioid receptor (KOR) gene, mediated by a rapid downregulation of
c-myc gene expression. KOR was constitutively
expressed in postnatal day 19 (P19) embryonal carcinoma stem cells and
is suppressed by NO donors [sodium nitroprusside (SNP),
3-morpholinosydnonimine-1, and S-nitrosoglutathione] in
P19 stem cells within 4 hr. The suppression was reversed by
2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, an NO
scavenger, but could not be blocked by dithiothreitol, ruling out
S-nitrosylation as the underlying mechanism. The
suppressive effect of NO on KOR occurred at the level of gene
transcription, mediated by E boxes located in promoters I and II of
this gene. Protein-DNA complexes that formed on these E boxes
contained c-myc; c-myc expression was
suppressed by NO in P19 stem cells within 2 hr of treatment.
Furthermore, chromatin immunoprecipitation demonstrated reduced
c-myc binding to the E boxes and hypoacetylation of
histone H3 on the chromatin of endogenous KOR promoters in P19 stem
cells treated with SNP. It is proposed that NO regulates KOR at the
level of gene transcription, mediated by a rapid suppression of
c-myc gene expression and its binding to KOR promoters,
and followed by chromatin hypoacetylation of and reduced transcription from KOR promoters in P19 stem cells. A novel pathway mediating the
potential interplay between NO and opioid systems is discussed.
Key words:
nitric oxide; opioid receptor; c-Myc; gene
regulation; transcription; P19
Copyright © 2002 Society for Neuroscience 0270-6474/02/22187941-07$05.00/0
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