PT  - JOURNAL ARTICLE
AU  - Rothe, Kathrin
AU  - Solinski, Hans Jürgen
AU  - Boekhoff, Ingrid
AU  - Gudermann, Thomas
AU  - Breit, Andreas
TI  - 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
AID  - 10.1124/jpet.112.192757
DP  - 2012 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 41--52
VI  - 342
IP  - 1
4099  - http://jpet.aspetjournals.org/content/342/1/41.short
4100  - http://jpet.aspetjournals.org/content/342/1/41.full
SO  - J Pharmacol Exp Ther2012 Jul 01; 342
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.