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.