title: 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.
abstract: 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.
authors.affiliation: Walther-Straub-Institut of Pharmacology and Toxicology, Ludwig-Maximilians University of Munich, Goethestrasse 33, 80336 Munich, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Rothe
authors.forename: Hans Jürgen
authors.initials: HJ
authors.lastname: Solinski
authors.forename: Ingrid
authors.initials: I
authors.lastname: Boekhoff
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.forename: Andreas
authors.initials: A
authors.lastname: Breit
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D051765:Early Growth Response Transcription Factors / Q000235:genetics / Q000378:metabolism; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D050801:Ternary Complex Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D051765:Early Growth Response Transcription Factors; D012333:RNA, Messenger; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D026362:Serum Response Factor; D050801:Ternary Complex Factors; D050807:ets-Domain Protein Elk-1; D009020:Morphine