The Multiple Waves of Cannabinoid 1 Receptor Signaling

Abstract

The cannabinoid 1 receptor (CB 1 R) 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, CB 1 Rs 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 b-arrestins. The third and final wave occurs at intracellular compartments and could be elicited by G proteins or b-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 CB 1 R. 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 b-arrestins. Here, we review our current knowledge on CB 1 R signaling, with particular emphasis on the mechanisms and cascades mediated by b-arrestins downstream from the CB 1 R.

Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease

“…Evidence of promiscuous coupling to different G proteins, signaling roles mediated by β-arrestins and signaling from intracellular compartments (Figure 1B) adds yet another level of complexity making these receptors, like other GPCRs, pluridimentional (Bosier et al, 2010). For our recent review on the multiple waves of receptor signaling see Nogueras-Ortiz and Yudowski (2016). CB 1 receptors exhibit constitutive activity indicative of G protein activation in the absence of agonists and this could mediate their highly polarized localization to axonal and presynaptic compartments (Bouaboula et al, 1997; Nie and Lewis, 2001; Rozenfeld, 2011).…”

“…Interestingly, these location-specific signaling events appear to be widespread among several GPCRs. For example, the LH receptor, β2 adrenergic receptor and the CB 2 receptor can signal from intracellular compartments either by β-arrestins or G proteins via a “super-complex” ultimately resulting in three different spatio-temporal signaling waves (Brailoiu et al, 2014; Irannejad and von Zastrow, 2014; Lyga et al, 2016; Nogueras-Ortiz and Yudowski, 2016; Thomsen et al, 2016). Constitutive activation also plays a role in their trafficking (Leterrier et al, 2006; McDonald et al, 2007).…”

Cannabinoid CB1and CB2Receptor Signaling and Bias

“…54 The Gα i/o protein-independent pERK1/2 activation might arise from the recruitment of β-arrestin-1 as mutation of phosphorylation sites in the CB 1 C-terminal (S426A/S430A) has been suggested to result in β-arrestin-1-mediated pERK activation, 55 which in general occurs later than the G protein-mediated activation. 56 Similarly, as discussed below, ORG27569, an allosteric modulator of CB 1 , has been suggested by some studies 57,58 but not others 59,60 to activate β-arrestin-1-mediated pERK1/2 signaling through CB 1 .…”

Different pharmaceutical preparations of Δ9‐tetrahydrocannabinol differentially affect its behavioral effects in rats

“…However, further studies are needed to investigate the underlying molecular mechanisms. Interestingly, it has been reported that the activation of presynaptic G protein coupled CB 1 Rs results in the modulation of multiple cellular responses through three distinct signaling waves (for review, see Nogueras‐Ortiz and Yudowski). The first wave—mediated by heterotrimeric Gα i/o proteins—is transient (<10 minutes) and starts after the ligand binds to the receptor.…”

“…This induces within seconds a decrease in cAMP levels, a decrease in Ca 2+ , and an increase in K + conductance, resulting in a decreased transmitter release. Depending on the nature of the transmitter, this causes short‐term suppression of inhibition or excitation . The second signaling wave starts with the ligand‐induced receptor phosphorylation leading to receptor desensitization and the recruitment of β‐arrestins.…”