The orphan receptor GPR55 is a novel cannabinoid receptor

Abstract

Background: The endocannabinoid system functions through two well characterized receptor systems, the CB 1 and CB 2 receptors. Work by a number of groups in recent years has provided evidence that the system is more complicated and additional receptor types should exist to explain ligand activity in a number of physiological processes. Experimental approach: Cells transfected with the human cDNA for GPR55 were tested for their ability to bind and to mediate GTPgS binding by cannabinoid ligands. Using an antibody and peptide blocking approach, the nature of the Gprotein coupling was determined and further demonstrated by measuring activity of downstream signalling pathways.Key results: We demonstrate that GPR55 binds to and is activated by the cannabinoid ligand CP55940. In addition endocannabinoids including anandamide and virodhamine activate GTPgS binding via GPR55 with nM potencies. Ligands such as cannabidiol and abnormal cannabidiol which exhibit no CB 1 or CB 2 activity and are believed to function at a novel cannabinoid receptor, also showed activity at GPR55. GPR55 couples to Ga13 and can mediate activation of rhoA, cdc42 and rac1. Conclusions: These data suggest that GPR55 is a novel cannabinoid receptor, and its ligand profile with respect to CB 1 and CB 2 described here will permit delineation of its physiological function(s).

The orphan G protein-coupled receptor GPR55 promotes cancer cell proliferation via ERK

“…GPR55 promotes cancer cell proliferation C Andradas et al pointing out that GPR55, as other members of the lysophospholipid GPCR families, exerts its actions, at least in part, through G 12/13 and G q proteins (Ryberg et al, 2007;Lauckner et al, 2008;Henstridge et al, 2009), which signal oncogenic effects (Dorsam and Gutkind, 2007;Worzfeld et al, 2008). It is therefore tempting to speculate that LPI, through GPR55, would behave similar to their close relatives lysophosphatidic acid and sphingosine-1-phosphate in terms of involvement in cancer biology.…”

“…Nonetheless, all the functions described so far for LPI on GPR55 come from experiments in which LPI was exogenously added to the cultured cells, and therefore evidence for the role of the naturally occurring lipid in more physiological settings is still missing. It has also been shown that several cannabinoid-type compounds modulate this receptor (Ryberg et al, 2007;Lauckner et al, 2008;WaldeckWeiermair et al, 2008;Henstridge et al, 2009Henstridge et al, , 2010Kapur et al, 2009;Yin et al, 2009). However, the inconsistencies among the pharmacological results obtained so far (some compounds being active in some reports and inactive in others, some being agonists in some studies and antagonists in others, and so on) do not entirely clarify whether GPR55 is an actual cannabinoid receptor (Brown and Robin Hiley, 2009;Ross, 2009).…”

“…However, the inconsistencies among the pharmacological results obtained so far (some compounds being active in some reports and inactive in others, some being agonists in some studies and antagonists in others, and so on) do not entirely clarify whether GPR55 is an actual cannabinoid receptor (Brown and Robin Hiley, 2009;Ross, 2009). GPR55 mRNA is highly expressed in the brain, the adrenal glands, parts of the gastrointestinal tract, spleen, tonsils, testes, thymus (Sawzdargo et al, 1999;Ryberg et al, 2007;Oka et al, 2010), large dorsal root ganglion neurons (Lauckner et al, 2008), osteoclasts (Whyte et al, 2009), certain microglial cells (Pietr et al, 2009), endothelial cells and mesenteric arterial smooth muscle cells (Daly et al, 2010), but very little is known about the physiological role of the receptor in these or other tissues. To date, GPR55 has been implicated in the control of pain, specifically in the mechanical hyperalgesia induced by inflammatory and neuropathic pain (Staton et al, 2008), and in the control of bone formation (Whyte et al, 2009).…”

“…Its wide distribution throughout the body suggests, however, that GPR55 might be involved in many other biological functions. As some GPCRs have a prominent role in cancer cell biology (Dorsam and Gutkind, 2007) and, more specifically, GPR55 has been shown to couple to G 12/13 and G q proteins (Ryberg et al, 2007;Lauckner et al, 2008;Henstridge et al, 2009), which drive oncogenic signaling (Dorsam and Gutkind, 2007;Worzfeld et al, 2008), we sought to analyze the physiopathological relevance of this receptor in the context of cancer.…”

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

“…To date, two cannabinoid receptors have been identified by molecular cloning, CB 1 and CB 2 receptors (Howlett et al, 2002;Matsuda et al, 1990;Munro et al, 1993), however the existence of additional CB receptors have also been proposed (Brown, 2007;Pacher et al, 2005;Ryberg et al, 2007). Anandamide is a partial or full agonist of CB 1 receptors, depending on the tissue and biological response measured.…”