RT Journal Article
SR Electronic
T1 Morphine Activates the E Twenty Six-Like Transcription Factor-1/Serum Response Factor Pathway via Extracellular Signal-Regulated Kinases 1/2 in F11 Cells Derived from Dorsal Root Ganglia Neurons
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 41
OP 52
DO 10.1124/jpet.112.192757
VO 342
IS 1
A1 Rothe, Kathrin
A1 Solinski, Hans Jürgen
A1 Boekhoff, Ingrid
A1 Gudermann, Thomas
A1 Breit, Andreas
YR 2012
UL http://jpet.aspetjournals.org/content/342/1/41.abstract
AB Morphine-induced signaling via opioid receptors (ORs) in dorsal root ganglia (DRG) neurons, the spinal cord, and various brain regions has been shown to modulate gene activity. Hitherto, little attention has been paid to extracellular signal-regulated kinases-1/2 (ERK-1/2)-mediated activation of the serum response factor (SRF) and ternary complex factors (TCFs) such as the E twenty six-like transcription factor-1 (ELK-1) in this context. Using TCF/SRF-dependent reporter gene constructs, a specific ERK-1/2 inhibitor and a dominant-negative ELK-1 mutant, we show herein that morphine activates ELK-1 via ERK-1/2 in DRG-derived F11 cells endogenously expressing μ and δ ORs. Previous studies with glioma cell lines such as NG108-15 cells attributed morphine-induced gene expression to the activation of the cAMP-responsive element binding protein (CREB). Thus, we also analyzed morphine-dependent activation of CREB in F11 and NG108-15 cells. In contrast to the CREB stimulation found in NG108-15 cells, we observed an inhibitory effect of morphine in F11 cells, indicating cell type-specific regulation of CREB by morphine. To obtain data about putative target genes of morphine-induced ELK-1/SRF activation, we analyzed mRNA levels of 15 ELK-1/SRF-dependent genes in cultured rat DRG neurons and F11 cells. We identified the early growth response protein-4 (EGR-4) as the strongest up-regulated gene in both cell types and observed ELK-1 activity-dependent activation of an EGR-4-driven reporter in F11 cells. Overall, we reveal an important role of ELK-1 for morphine-dependent gene induction in DRG-derived cells and propose that ELK-1 and EGR-4 contribute to the effects of morphine on neuronal plasticity.