1: Biochem Pharmacol. 2009 Jan 15;77(2):216-27. Epub 2008 Oct 17. Concomitant activation of adenylyl cyclase suppresses the opposite influences of CB(1) cannabinoid receptor agonists on tyrosine hydroxylase expression. Bosier B, Hermans E, Lambert DM. Unité de Chimie Pharmaceutique et de Radiopharmacie, Université catholique de Louvain, Brussels, Belgium. The CB(1) cannabinoid receptor shows complex interactions with intracellular signalling partners, and responses to cannabinoid ligands are likely to be influenced by concomitant inputs modifying the overall tone of signalling cascades. This appears even more relevant as we previously evidenced opposite regulations of tyrosine hydroxylase (TH) expression by the two common cannabinoid agonists HU 210 and CP 55,940. Therefore, we studied the consequences of manipulating adenylyl cyclase activity with forskolin on the regulation of TH gene transcription in neuroblastoma cells (N1E-115). Reporter gene experiments performed with the luciferase sequence cloned under the control of modified fragments of the TH gene promoter revealed that the AP-1 consensus sequence is essential for cannabinoid-mediated regulation of TH expression. Consistently, inhibition of PKC totally blocked the responses mediated by both HU 210 and CP 55,940. In addition, forskolin which boosts adenylyl cyclase activity remarkably modified the responses to the cannabinoid agonists. Thus, in these conditions, both agonists efficiently reduced TH gene promoter activity, a response requiring functional PKA/CRE-dependent signallings. Finally, the modulations of the promoter were inhibited in pertussis toxin treated cells, suggesting that responses to both agonists are mediated through G(i/o)-dependent mechanisms. Emphasising on the importance of functional selectivity at GPCRs, these data demonstrate that the concomitant activation of adenylyl cyclase by forskolin strongly influences the biochemical responses triggered by distinct cannabinoid agonists. Together our results suggest that the physiological modulation of TH expression by cannabinoid agonists in dopaminergic neurons would be influenced by additional endogenous inputs. PMID: 18992715 [PubMed - indexed for MEDLINE] Related Links Agonist selective modulation of tyrosine hydroxylase expression by cannabinoid ligands in a murine neuroblastoma cell line. [J Neurochem. 2007] PMID:17540007 Differential modulation of AP-1- and CRE-driven transcription by cannabinoid agonists emphasizes functional selectivity at the CB1 receptor. [Br J Pharmacol. 2008] PMID:18536748 Reciprocal influences of CB1 cannabinoid receptor agonists on ERK and JNK signalling in N1E-115 cells. [FEBS Lett. 2008] PMID:18950629 Suppression of the humoral immune response by cannabinoids is partially mediated through inhibition of adenylate cyclase by a pertussis toxin-sensitive G-protein coupled mechanism. [Biochem Pharmacol. 1994] PMID:7986201 Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses. [J Pharmacol Exp Ther. 1998] PMID:9864268