The Multiple Waves of Cannabinoid 1 Receptor Signaling

The cannabinoid 1 receptor (CB₁R) is one of the most abundant G protein-coupled receptors (GPCRs) in the central nervous system, with key roles during neurotransmitter release and synaptic plasticity. Upon ligand activation, CB₁Rs may signal in three different spatiotemporal waves. The first wave, which is transient (<10 minutes) and initiated by heterotrimeric G proteins, is followed by a second wave (>5 minutes) that is mediated by β-arrestins. The third and final wave occurs at intracellular compartments and could be elicited by G proteins or β-arrestins. This complexity presents multiple challenges, including the correct classification of receptor ligands, the identification of the signaling pathways regulated by each wave, and the underlying molecular mechanisms and physiologic impacts of these waves. Simultaneously, it provides new opportunities to harness the therapeutic potential of the cannabinoid system and other GPCRs. Over the last several years, we have significantly expanded our understanding of the mechanisms and pathways downstream from the CB₁R. The identification of receptor mutations that can bias signaling to specific pathways and the use of siRNA technology have been key tools to identifying which signaling cascades are controlled by G proteins or β-arrestins. Here, we review our current knowledge on CB₁R signaling, with particular emphasis on the mechanisms and cascades mediated by β-arrestins downstream from the CB₁R.