Crosstalk between Dopamine D2 receptors and cannabinoid CB1 receptors regulates CNR1 promoter activity via ERK1/2 signaling. (28th August 2013)

• Record Type: Journal Article
• Authors: Chiang, Yao‐Chang; Lo, Yan‐Ni; Chen, Jin‐Chung
• Is Part Of: Journal of neurochemistry. Volume 127:Number 2(2013:Oct.)
• Page Start: 163
• Page End: 176
• Publication Date: 2013-08-28
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.12399
• Languages: English
• ISSNs: 0022-3042

Abstract

<abstract abstract-type="main" id="jnc12399-abs-0001"> <title>Abstract</title> <p>Previously, we found that chronic methamphetamine treatment altered cannabinoid type 1 receptor (CB<sub>1</sub>R)‐dependent cAMP/PKA/dopamine and cAMP‐regulated phosphoprotein of Mr 32 000 (DARPP‐32)/T34/PP2B signaling and decreased levels of CB<sub>1</sub>R protein and mRNA in the nucleus accumbens. These findings suggested the existence of signaling interplay between mesolimbic dopamine and CB<sub>1</sub>R. In this study, we further investigate interactions between CB<sub>1</sub>R and dopamine D2 receptor (D<sub>2</sub>R) signaling. Activation of either CB<sub>1</sub>R or D<sub>2</sub>R increased extracellular signal‐regulated kinases 1 and 2 (ERK1/2) phosphorylation, while co‐stimulation of CB<sub>1</sub>R and D<sub>2</sub>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 CB<sub>1</sub>R was increased via dopamine D2 receptor short form (D<sub>2S</sub>R) by treatment with D<sub>2</sub>R agonist quinpirole in D<sub>2S</sub>R/C6 glioma cells. This effect could be suppressed by co‐treatment with the ERK1/2 inhibitor U0126. To test if D<sub>2S</sub>R could transcriptionally regulate CB<sub>1</sub>R, the 5′‐untranslated region (5′‐UTR) of the cannabinoid receptor 1 (<italic>CNR1</italic>) gene was sequenced from rat brain. Results showed that the <italic>CNR1</italic> 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<sub>2S</sub>R‐responsive promoter activity is located in the −1 to −222 region of <italic>CNR1</italic> promoter. Overall, we demonstrate previously unidentified crosstalk between D<sub>2</sub>R and CB<sub>1</sub>R via ERK1/2 signaling that enhances the expression of CB<sub>1</sub>R by modulating its promoter activity.</p> <p> <boxed-text content-type="graphic" id="jnc12399-blkfxd-0001" position="anchor" orientation="portrait"> <graphic position="anchor" mimetype="image" xlink:href="ark:/27927/pgg3j5r4nfz" orientation="portrait" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink" /> </boxed-text> </p> <p>Cannabinoid CB<sub>1</sub>R and dopamine D<sub>2</sub>R cross‐talk at ERK1/2 signal. Activation of D<sub>2S</sub>R increases the CB<sub>1</sub>R transcription, which is ERK1/2 dependent and enhances CB<sub>1</sub>R promoter activity that requires up‐stream −1 to −222 region. The results implicate pre‐synaptic D<sub>2S</sub>R could functionally regulate the retrograde cannabinoid signal in the striatum.</p> </abstract>