The Multiple Waves of Cannabinoid 1 Receptor Signaling

Abstract

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.

Graphical abstract

Fig. 1.

Cannabinoid receptor signals in three waves. (A) Activation of CB₁Rs results in the modulation of multiple cellular responses through three distinct signaling waves. The first wave, mediated by G proteins, is observed within seconds and up to few minutes after receptor activation. Receptor activation also results in phosphorylation by GRKs. This post-translational modification leads to receptor desensitization and the recruitment of β-arrestins, scaffold proteins of the endocytic machinery that initiate clathrin-mediated endocytosis. In addition to the endocytic machinery, receptor bound β-arrestins can also recruit and activate signaling proteins, resulting in a second signaling wave with distinct kinetic and signaling profile. These events are initiated at the plasma membrane and can continue after receptor endocytosis into intracellular compartments. After receptor internalization, a third signaling wave has been described that is characterized by the activation of effectors associated with both G proteins and β-arrestins. (B) Proposed time course of G protein– and β-arrestin–mediated responses. G protein signaling has a fast initial response, whereas β-arrestins are somewhat slower but sustained over time. Kinetics of third waves can be initiated within minutes (modified from Luttrell and Gesty-Palmer, 2010).

Fig. 2.

β-Arrestin effectors downstream from CB₁R. Brief summary of published results utilizing different cellular and tissue models suggests that β-arrestin 1 mediates most of the signaling whereas β-arrestin 2 mediates receptor desensitization and internalization in vitro and in vivo. Signaling from CB₁R/β-arrestin 1 results in regulation of gene transcription and protein synthesis, which suggests that long-term effects of CB₁R activation are mediated by β-arrestins (see text for more detail).