The Cannabinoid Receptor CB1 Modulates the Signaling Properties of the Lysophosphatidylinositol Receptor GPR55

Abstract

Background: G protein-coupled receptors (GPCR) can form heteromers and thereby alter their signaling properties. Results: GPR55 and cannabinoid 1 (CB1) receptor signaling is modulated if receptors are co-expressed. Conclusion: GPR55 signaling is inhibited in the presence of CB1 receptors; in contrast, CB1 receptor-mediated signaling is enhanced if GPR55 is co-expressed. Significance: Cross-regulation of CB1 receptor and GPR55 may affect cell function when endogenously co-expressed.

Targeting CB2-GPR55 Receptor Heteromers Modulates Cancer Cell Signaling

“…Therefore, CB 1 Rs have been shown previously to interact with other G protein-coupled receptors, including dopamine D 2 receptors (which promotes a switch in the preferential coupling from G i to G s ) (27), D 2 receptors and adenosine A 2A receptors simultaneously (producing a negative modulation of D 2 receptor function by A 2A and CB 1 R agonists) (28), opioid receptors (which produces a negative cross-talk between protomers) (29), orexin OX 1 receptors (eliciting a positive cross-talk in response to orexin and cross-antagonism) (30), and angiotensin AT 1 receptors (resulting in the potentiation of AT 1 receptor signaling) (31). More recently, coimmunoprecipitation assays in HEK293 cells have suggested that CB 1 R can form heteromers with GPR55 (32). In contrast to CB 1 R, very little is known about the possible existence and functional relevance of heteromers involving CB 2 R. A recent study has shown that CB 2 R heteromerizes with CB 1 R in neuronal cells in culture and in vivo (19).…”

A Selective Antagonist Reveals a Potential Role of G Protein–Coupled Receptor 55 in Platelet and Endothelial Cell Function

“…In addition, GPR55 has been reported to activate small GTPases (Ryberg et al, 2007;Henstridge et al, 2009;Balenga et al, 2011a) and to induce calcium release from intracellular stores (Oka et al, 2007;Henstridge et al, 2009Henstridge et al, , 2010. Further downstream, GPR55 activation leads to the activation of several transcription factors, such as nuclear factor of activated T-cells (NFAT), nuclear factor k of activated B cells (NF-kB), serum response element (SRE), cAMP response element-binding protein (CREB), and activating transcription factor 2 (Henstridge et al, 2009(Henstridge et al, , 2010Oka et al, 2010;Kargl et al, 2012a). In addition, mitogen-activated protein kinases, such as p38 and extracellular signal-regulated kinases (ERK1/2), are activated upon GPR55 stimulation (Henstridge et al, 2010;Oka et al, 2010).…”

“…The first such chemical series of synthetic GPR55 agonists to be described were the benzoylpiperazines. Importantly, benzoylpiperazines were independently identified at GlaxoSmithKline Kargl et al, 2012a) and by the National Institutes of Health (NIH) Molecular Libraries Probe Identification program (Heynen-Genel et al, 2010b;Kotsikorou et al, 2011). The latter screen used b-arrestin fluorescent protein biosensors and identified further agonists as well as antagonists (Heynen-Genel et al, 2010a,b).…”

“…Screening approaches have identified selective GPR55 agonists, such as [4-(3,4-dichloro-phenyl)-piperazin-1-yl]-(49-fluoro-4-methanesulfonyl-biphenyl-2-yl)-methanone (GSK319197A) or GSK494581A Kargl et al, 2012a), which generally appear to be inactive at CB 1 and CB 2 receptors and hence are promising tools to elucidate the pharmacologic, physiologic, and pathophysiologic functions of GPR55. The first such chemical series of synthetic GPR55 agonists to be described were the benzoylpiperazines.…”

“…The lipid ligand LPI; the CB 1 receptor inverse agonists/ antagonists SR141716A, AM251, and AM281; and selective GPR55 agonists were described to activate transcription factors in HEK-293 cells transiently or stably expressing human GPR55 (Ryberg et al, 2007;Henstridge et al, 2009Henstridge et al, , 2010Brown et al, 2011;Kargl et al, 2012a). The phytocannabinoid cannabidiol (CBD) was reported to antagonize O-1602-mediated GPR55 activation in HEK-GPR55 cells and human osteoclasts (Ryberg et al, 2007;Whyte et al, 2009).…”