Cross-talk between an activator of nuclear receptors-mediated transcription and the D1 dopamine receptor signaling pathway.
Nuclear receptors are transcription factors that usually interact, in a ligand-dependent manner, with specific DNA sequences located within promoters of target genes. The nuclear receptors can also be controlled in a ligand-independent manner via the action of membrane receptors and cellular signaling pathways. 5-Tetradecyloxy-2-furancarboxylic acid (TOFA) was shown to stimulate transcription from the MMTV promoter via chimeric receptors that consist of the DNA binding domain of GR and the ligand binding regions of the PPARbeta or LXRbeta nuclear receptors (GR/PPARbeta and GR/LXRbeta). TOFA and hydroxycholesterols also modulate transcription from NF-kappaB- and AP-1-controlled reporter genes and induce neurite differentiation in PC12 cells. In CV-1 cells that express D(1) dopamine receptors, D(1) dopamine receptor stimulation was found to inhibit TOFA-stimulated transcription from the MMTV promoter that is under the control of chimeric GR/PPARbeta and GR/LXRbeta receptors. Treatment with the D(1) dopamine receptor antagonist, SCH23390, prevented dopamine-mediated suppression of transcription, and by itself increased transcription controlled by GR/LXRbeta. Furthermore, combined treatment of CV-1 cells with TOFA and SCH23390 increased transcription controlled by the GR/LXRbeta chimeric receptor synergistically. The significance of this in vitro synergy was demonstrated in vivo, by the observation that SCH23390 (but not haloperidol)-mediated catalepsy in rats was potentiated by TOFA, thus showing that an agent that mimics the in vitro activities of compounds that activate members of the LXR and PPAR receptor families can influence D1 dopamine receptor elicited responses.
Schmidt
Azriel
A
Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, PA 19486, USA.
Vogel
Robert
R
Rutledge
Su Jane
SJ
Opas
Evan E
EE
Rodan
Gideon A
GA
Friedman
Eitan
E
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D004298:Dopamine / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008251:Macaca; D008297:Male; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051381:Rats; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
D018492:Dopamine Antagonists; D017447:Receptors, Dopamine D1; D018808:Transcription Factor AP-1; D004298:Dopamine