title: Activation and inhibition of transient receptor potential TRPM3-induced gene transcription.
abstract: OBJECTIVE
  Transient receptor potential-3 (TRPM3) channels function as Ca2+ permeable cation channels. While the natural ligands for these channels are still unknown, several compounds have been described that either activate or inhibit TRPM3 channel activity. experimental approach: We assessed TRPM3-mediated gene transcription, which relies on the induction of intracellular signalling to the nucleus following activation of TRPM3 channels. Activator protein-1 (AP-1) and Egr-1-responsive reporter genes were integrated into the chromatin of the cells. This strategy enabled us to analyse gene transcription of the AP-1 and Egr-1-responsive reporter genes that were packed into an ordered chromatin structure.
  
  
  RESULTS
  The neurosteroid pregnenolone sulfate strikingly up-regulated AP-1 and Egr-1 transcriptional activity, while nifedipine and D-erythro-sphingosine, also putative activators of TRPM3 channels, exhibited either no or TRPM3-independent effects on gene transcription. In addition, pregnenolone sulfate robustly enhanced the transcriptional activation potential of the ternary complex factor Elk-1. Pregnenolone sulfate-induced activation of gene transcription was blocked by treatment with mefenamic acid and, to a lesser extent, by the polyphenol naringenin. In contrast, progesterone, pregnenolone and rosiglitazone reduced AP-1 activity in the cells, but had no inhibitory effect on Egr-1 activity in pregnenolone sulfate-stimulated cells.
  
  
  CONCLUSIONS
  Pregnenolone sulfate is a powerful activator of TRPM3-mediated gene transcription, while transcription is completely inhibited by mefenamic acid in cells expressing activated TRPM3 channels. Both compounds are valuable tools for further investigating the biological functions of TRPM3 channels.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lesch
authors.forename: Sandra
authors.initials: S
authors.lastname: Rubil
authors.forename: Gerald
authors.initials: G
authors.lastname: Thiel
mesh_terms: D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D008528:Mefenamic Acid / Q000494:pharmacology; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D011284:Pregnenolone / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D050053:TRPM Cation Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C497325:EGR1 protein, human; C494112:ELK1 protein, human; D051766:Early Growth Response Protein 1; D049990:Membrane Transport Modulators; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D050053:TRPM Cation Channels; C475667:TRPM3 protein, human; D018808:Transcription Factor AP-1; D050807:ets-Domain Protein Elk-1; C018370:pregnenolone sulfate; D008528:Mefenamic Acid; D011284:Pregnenolone