CB1 cannabinoid receptor agonists-induced dual regulation of tyrosine hydroxylase expression in N1E-115 cells
(2006) 10th euron PhD student meeting — Location: Maastricht, the Netherlands (21.September.2006)
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- Abstract
- Functional interactions between catecholamines and cannabinoid transmission systems could explain the influence of 9-THC on several central activities including modulation of motor and emotional behaviours. Many studies have reported the lack of co-localisation of CB1 cannabinoid receptors with tyrosine hydroxylase (TH), the rate-limiting enzyme implicated in catecholamines biosynthesis. Hence, it is generally suggested that cannabinoids could mediate regulation of neurotransmission by modulating presynaptic influences on catecholaminergic neurons. In contrast, other immunohistochemical investigations have demonstrated expression of CB1 cannabinoid receptors in TH containing cells of the mesocorticolimbic system, suggesting a possible direct control cannabinoid system on catecholamines synthesis. We recently identified the expression of functional CB1 cannabinoid receptors on the murine neuroblastoma cell line N1E-115, a widely used model for the study of catecholamines synthesis. In the present study we examined the influence of structurally different cannabinoid ligands on TH expression in this model. The expression of TH was examined by Western blot analysis of protein extracts from N1E-115 cells previously exposed to cannabinoid agonists. The regulation of TH gene transcription was examined using a rodent TH promoter luciferase reporter assay in transiently transfected cells. Analysis of Western blot studies indicated that exposure of the cells for 5 to 24h to the cannabinoid agonist HU210 (100 nM-10 µM) resulted in a significant reduction of TH expression. In contrast, such treatments with a second cannabinoid agonist, CP55940, elicited no change, suggesting an agonist dependent effect. Besides, the use of the luciferase-based assay revealed that HU210 mediated an inhibition of TH gene transcription while CP55940 induced an increase in the transcriptional activity. Both responses were inhibited by SR141716A, a CB1 selective inverse agonist/antagonist, confirming the involvement of CB1 cannabinoid receptors. This system was used for evaluating the properties of variety of cannabinoid ligands from different chemical families. Contrasting with the inhibitory response mediated by the majority of tested compounds that behaved like HU210, the members of the family of non-classical cannabinoid ligands (CP55940, CP47947, CP55243) were found to markedly increase the activity of the reporter gene. Together, the present data indicate that cannabinoid receptors present in this neuroblastoma cell line operate a direct modulation of TH expression through the regulation of its gene transcription. In addition, the existence of different responses to chemically distinct agonists suggests an agonist-mediated differential coupling of the CB1 cannabinoid receptor to multiple signalling pathways.
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Bosier, B., & et al. (2006). CB1 cannabinoid receptor agonists-induced dual regulation of tyrosine hydroxylase expression in N1E-115 cells. 10th euron PhD student meeting, Maastricht, the Netherlands. https://hdl.handle.net/2078.5/159207