title: Crosstalk between dopamine D₂ receptors and cannabinoid CB₁ receptors regulates CNR1 promoter activity via ERK1/2 signaling.
abstract: Previously, we found that chronic methamphetamine treatment altered cannabinoid type 1 receptor (CB₁R)-dependent cAMP/PKA/dopamine and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32)/T34/PP2B signaling and decreased levels of CB₁R protein and mRNA in the nucleus accumbens. These findings suggested the existence of signaling interplay between mesolimbic dopamine and CB₁R. In this study, we further investigate interactions between CB₁R and dopamine D2 receptor (D₂R) signaling. Activation of either CB₁R or D₂R increased extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation, while co-stimulation of CB₁R and D2 R evoked an additive effect on the phospho-ERK1/2 signal. This effect was mediated through a pertussis toxin-sensitive Gαi/o pathway in primary striatal cells. Furthermore, the mRNA level of CB₁R was increased via dopamine D2 receptor short form (D(2S)R) by treatment with D₂R agonist quinpirole in D(2S)R/C6 glioma cells. This effect could be suppressed by co-treatment with the ERK1/2 inhibitor U0126. To test if D(2S)R could transcriptionally regulate CB₁R, the 5'-untranslated region (5'-UTR) of the cannabinoid receptor 1 (CNR1) gene was sequenced from rat brain. Results showed that the CNR1 gene includes two exons, which contain 375 bp of 5'-UTR and are separated by a 17-kb intron. A luciferase reporter assay showed that the maximal D(2S)R-responsive promoter activity is located in the -1 to -222 region of CNR1 promoter. Overall, we demonstrate previously unidentified crosstalk between D₂R and CB₁R via ERK1/2 signaling that enhances the expression of CB₁R by modulating its promoter activity.
authors: Center for Drug Abuse and Addiction, China Medical University Hospital, Taichung, Taiwan; China Medical University, Taichung, Taiwan.
authors: Yao-Chang
authors: YC
authors: Chiang
authors: Yan-Ni
authors: YN
authors: Lo
authors: Jin-Chung
authors: JC
authors: Chen
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003511:Cyclohexanols / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis / Q000302:isolation & purification; D005260:Female; D017930:Genes, Reporter / Q000187:drug effects; D005910:Glioma / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008969:Molecular Sequence Data; D017072:Neostriatum / Q000166:cytology / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012313:RNA / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk / Q000187:drug effects*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D014162:Transfection
chemical_list: C543264:Cnr1 protein, rat; D003511:Cyclohexanols; D043884:Receptor, Cannabinoid, CB1; D017448:Receptors, Dopamine D2; D012313:RNA; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D004247:DNA
keywords: 5′-untranslated region; ERK1/2; cannabinoid CB1 receptor; dopamine D2 receptor; gene regulation; promoter structure