GPR55 (GPR55)

GPR55 is an orphan G protein-coupled receptor that binds certain cannabinoids and lipid mediators, and whose classification as a canonical cannabinoid receptor remains under scientific debate.

GPR55 (G protein-coupled receptor 55) is encoded by the GPR55 gene and couples primarily to the Gα13 signalling pathway, distinguishing it from the classical CB1 and CB2 cannabinoid receptors, which signal through Gαi/o. It is expressed across a range of tissues, with relatively high levels reported in the brain (particularly the striatum and cerebellum), the adrenal glands, and the gastrointestinal tract. Because it binds some cannabinoid ligands , including the endogenous lipid lysophosphatidylinositol (LPI) and, at varying affinities, phytocannabinoids such as cannabidiol and Δ9-tetrahydrocannabinol , a number of researchers have proposed it as a candidate "CB3" receptor, though this designation is not yet formally adopted by the International Union of Basic and Clinical Pharmacology (IUPHAR).

At the intracellular level, GPR55 activation triggers downstream cascades involving RhoA, cdc42, and extracellular signal-regulated kinase (ERK), which have been associated in preclinical models with processes including cytoskeletal reorganisation and cell migration. Its pharmacology is notably promiscuous: the same ligand can act as an agonist, antagonist, or neutral ligand depending on the assay system and cellular context, which has complicated efforts to build a consistent functional profile.

Some researchers have hypothesised that dysregulation of GPR55 signalling may be implicated in inflammatory states, bone metabolism, and metabolic regulation. These remain working hypotheses based largely on in vitro and rodent data; no causal role in human disease has been established, and GPR55-directed therapeutics have not progressed to approved clinical use as of 2024.

GPR55 is listed as an orphan receptor in the IUPHAR/BPS Guide to Pharmacology database. Under Australian law, substances acting on cannabinoid-related receptors are regulated through the Therapeutic Goods Administration (TGA) and scheduled under the Poisons Standard (the Standard for the Uniform Scheduling of Medicines and Poisons). Research involving GPR55 ligands in Australia is subject to standard TGA and institutional ethics frameworks.

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