M3 Receptor Pathway Stimulates Rapid Transcription of the CB1 Receptor Activation through Calcium Signalling and the CNR1 Gene Promoter.

In this study, we have investigated a possible mechanism that enables CB ₁ /M ₃ receptor cross-talk, using SH-SY5Y cells as a model system. Our results show that M ₃ receptor activation initiates signaling that rapidly upregulates the CNR1 gene, resulting in a greatly potentiated CB ₁ receptor response to agonists. Calcium homeostasis plays an essential intermediary role in this functional CB ₁ /M ₃ receptor cross-talk. We show that M ₃ receptor-triggered calcium release greatly increases CB ₁ receptor expression via both transcriptional and translational activity, by enhancing CNR1 promoter activity. The co-expression of M ₃ and CB ₁ receptors in brain areas such as the nucleus accumbens and amygdala support the hypothesis that the altered synaptic plasticity observed after exposure to cannabinoids involves cross-talk with the M ₃ receptor subtype. In this context, M ₃ receptors and their interaction with the cannabinoid system at the transcriptional level represent a potential pharmacogenomic target not only for the develop of new drugs for addressing addiction and tolerance. but also to understand the mechanisms underpinning response stratification to cannabinoids.