Discovery and Potential of GPR55 in the Endocannabinoid System
Ongoing research has long suggested that additional endocannabinoid receptor sites may exist beyond the known CB1 and CB2 receptors (M. Begg et al., 2005). Among these, GPR55—sometimes proposed as CB3—was initially regarded as an orphan receptor due to its structural similarities to other cannabinoid receptors, though its endogenous ligand remains unidentified.
The History and Distribution of GPR55
Human G protein-coupled receptor GPR55 was first identified and cloned by researchers at the University of Toronto, with its gene linked to chromosome 2q37 (M. Sawzdargo et al., 1999). mRNA transcripts of GPR55 were initially detected in brain regions like the caudate nucleus and putamen and have since been found in tissues such as the testis, spleen, lymph nodes, thymus, and intestines (T. Tanikawa et al., 2022). As a seven-transmembrane G-protein-coupled receptor (NIH, 2023), GPR55 shares minimal amino acid similarity with CB1 (13.5%) and CB2 (14.4%) receptors (H. Sharir et al., 2010), hinting at its distinct functional profile.
Functionality of GPR55 and Therapeutic Implications
GPR55 is known to bind and be activated by various endocannabinoids, phytocannabinoids, and synthetic cannabinoids, although its exact modulatory mechanisms and functional outcomes are still under investigation. Key findings on CBD’s interaction with GPR55 include:
- Impact on Fragile X Syndrome: CBD demonstrated therapeutic effects in Fragile X syndrome by modulating GPR55 activity in an in vivo model (A. Manduca et al., 2024).
- Cancer Research: CBD was shown to reverse hepatocellular carcinoma cell proliferation via GPR55 downregulation (S. Tan et al., 2024).
- Inverse Agonism: Recent studies found CBD acts as an inverse agonist at GPR55 (F. Patricio et al., 2022).
- Epilepsy and Neuroprotection: CBD’s interaction with GPR55 is linked to an inhibition of excitotoxicity, which has implications for epilepsy treatment (J. S. Kaplan et al., 2017).
- Excitotoxicity and Glutamate Modulation: GPR55 activates intracellular Ca2+ release in neurons, altering excitability and promoting glutamate release, making GPR55 antagonists a potential novel treatment approach for excitotoxicity (J. E. Lauckner et al., 2008).
- Antagonistic Effects: CBD lacks functional activation at GPR55, though it acts as an antagonist to certain GPR55 agonists, such as CP55940 (E. Ryberg et al., 2007).
These findings suggest that GPR55 modulation, particularly through cannabinoids like CBD, offers promising therapeutic pathways across multiple conditions, from neurodegenerative diseases to cancer and epilepsy.
