1: Br J Pharmacol. 2008 Sep;155(1):24-33. Epub 2008 Jun 9.

Differential modulation of AP-1- and CRE-driven transcription by cannabinoid
agonists emphasizes functional selectivity at the CB1 receptor.

Bosier B, Hermans E, Lambert D.

Unité de Chimie Pharmaceutique et de Radiopharmacie (UCL 7340), Université
catholique de Louvain, Brussels, Belgium.

BACKGROUND AND PURPOSE: Long-term adaptations to pharmacological stimuli
frequently originate from modulation of complex intracellular signalling
pathways. We previously reported that HU210 and CP55940, two CB1 cannabinoid
receptor agonists, induced opposite effects on TH expression. Herein, we
characterized their influence on cAMP response element (CRE) and activator
protein 1 (AP-1)-mediated regulation of gene transcription. EXPERIMENTAL
APPROACH: The activity of the agonists was examined on transfected N1E-115 cells 
in which expression of the luciferase reporter gene was controlled by
transcription promoters consisting of repeats of either CRE or AP-1 elements. In 
addition, the implication of classical signalling pathways was investigated using
a variety of kinase inhibitors. KEY RESULTS: Consistent with the CB1-mediated
reduction of cAMP accumulation, both ligands decreased CRE-driven luciferase
expression with similar potencies. HU210 also exhibited a concentration-dependent
reduction of luciferase activity in cells engineered to examine AP-1-controlled
transcription, whereas such response was not obtained with CP55940. Responses
were all inhibited by SR141716A and were modified in Pertussis toxin-treated
cells, suggesting agonist-selective regulations of distinct Gi/o-dependent
mechanisms through CB1 receptor activation. Finally, PKC inhibitors efficiently
inhibited the paradoxical effect of HU210 on AP-1-mediated transcription,
indicating selective regulation of PKC-dependent responses. CONCLUSIONS AND
IMPLICATIONS: Together, our results demonstrate that two cannabinoid ligands,
commonly used as reference agonists acting on the same receptor with similar
affinities, differentially modulate gene transcription through distinct controls 
of AP-1. This could reflect activation of distinct subsets of Gi/o-proteins,
supporting the concept of functional selectivity at CB1 receptors.

PMCID: PMC2527844 [Available on 09/01/09]
PMID: 18536748 [PubMed - in process]

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