GPR55 – The Third Cannabinoid Receptor ?

How this receptor could explain off-target effects of cannabinoids

The effects of cannabis on the body and mind are mediated through cannabinoid receptors. These specialized proteins – called cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) – bind with chemical messengers (from inside or outside of the body) and trigger a cascade of signals within the cell. These molecular changes quickly spread and create your cannabis “experience.”

CB1 and CB2 receptors are part of the G protein-coupled receptor (GPCR)family. Although they share similarities, CB1 receptors are mainly found in the brain, while CB2 receptors are mainly located in the immune system.¹ While both endogenous cannabinoids (such as anandamide and 2-arachidonoylglycerol) and exogenous cannabinoids (such as THC and CBD) bind CB1 and CB2 receptors,each receptor contributes differently to their effects on the body. ²This complex pharmacology results in the “entourage effect” – where the full effects of the plant can only be achieved when its wide range of cannabinoids and terpenes are processed together.³

Decades of research into the mechanisms underlying the effects of cannabis have revealed some gaps. While most of the effects of cannabinoids on anti-inflammatory, anxiolytic, and other properties have been attributed to actions of the CB1 and CB2 receptors, its other effects have been a bit more difficult to explain.For example, cannabinoids works to reduce pain through the transient receptor potential vanilloid type 1 – without affecting CB1 or CB2.⁴

GPR55, which belongs to the same family of receptors as CB1 and CB2 and was first identified in 1999,is highly expressed in the brain. ⁵Researchers proposed that GPR55 is a novel cannabinoid receptor after demonstrating that it both binds to and is activated by cannabinoids.⁶ However, the mechanism by which GPR55 triggers cellular and molecular changes in response to these cannabinoids differs from that of CB1 and CB2. ⁷In addition, GPR55 also responds to a non-cannabinoid substance, l-α-lysophosphatidylinositol (LI). For these reasons, the status of GPR55 as the “third” CB receptor remains controversial.⁸

Pre-clinical studies have indicated a role of GPR55 in cancer, and additional research may perhaps zone in further on the mechanism by which cannabis appears to target cancer cells. Both GPR55 and LI have been implicated in a wide range of cancer types, including skin, breast, and gastrointestinal cancers. ⁹ Studies have shown that GPR55 promotes cell cancer growth, and several reports have indicated that anti-GPR55 agents may be successful at reducing cancer cell activity.^10-13

Further study of GPR55 is crucial – not only to determine if it does indeed hold a place amongst CB1 and CB2 but also to explore its benefits. So, while cannabis scientists continue the debate on the proper nomenclature for GPR55, cancer biologists may provide us with new information on this potential therapeutic target.

References

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7. Lauckner, J.E., Jensen, J.B., Chen, H-Y., Lu, H-C., Hille, B., Mackie, K., “GPR55 Is a Cannabinoid Receptor That Increases Intracellular Calcium and Inhibits M Current”,Proc Natl Acad Sci USA, 2008, Volume 105.(impact factor: 9.661; citations: 464)
8. Henstridge, C.M., “Off-Target Cannabinoid Effects Mediated by GPR55”, Pharmacology, 2012, Volume 89.(impact factor: 1.538; citations: 45)
9. Shore, D.M., Reggio, P.H., “The Therapeutic Potential of Orphan GPCRs, GPR35 and GPR55”, Front Pharmacol, 2015, Volume 6.(impact factor: 3.831; citations: 38)
10. Hu, G., Ren, G., Shi, Y, “The Putative Cannabinoid Receptor GPR55 Promotes Cancer Cell Proliferation”, Oncogene, 2011, Volume 30.(impact factor: 6.854; citations: 33)
11. Wnorowski, A., et al., “Concurrent Activation of β2-adrenergic Receptor and Blockage of GPR55 Disrupts Pro-Oncogenic Signaling in Glioma Cells”, Cell Signal, 2017, Volume 36.(impact factor: 3.937; citation: 1)
12. Bernier, M., et al., “GPR55 Receptor Antagonist Decreases Glycolytic Activity in PANC-1 Pancreatic Cancer Cell Line and Tumor Xenografts”, Int J Cancer, 2017,Volume 141.(impact factor: 6.513; citations unavailable)
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