“The cannabinoid 1 receptor (CB1R) is one of the most abundant G protein-coupled receptor (GPCR) in the CNS with key roles during neurotransmitter release and synaptic plasticity. Upon ligand activation, CB1Rs may signal in three different spatiotemporal waves.
The first wave is transient (<10 minutes) and is initiated by heterotrimeric G proteins followed by a second wave (>10 minutes) mediated by beta-arrestins. A final third wave occurs at intracellular compartments and could be elicited by G proteins or beta-arrestins.
This functional complexity presents multiple challenges, from the correct classification of receptor ligands to the identification of the signaling pathways regulated by each wave and their underlying molecular mechanisms and physiological impact.
Simultaneously, it provides new opportunities to harness the therapeutic potential of the cannabinoid system.
Over the last several years, we have significantly expanded our understanding of the mechanisms and pathways downstream from CB1R. The identification of mutations in the receptor that can bias signaling to specific pathways and the use of siRNA technology in combination with toxins have been key tools to identify which signaling cascades are controlled by G proteins or beta-arrestins.
Here, we review our current knowledge of the multiple waves of CB1R signaling with particular emphasis on the mechanisms and cascades mediated by beta-arrestins downstream from the CB1R.”