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]

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