Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P21554 (cannabinoid receptor)
 3,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cannabinoid receptor 1 (CB(1)) and CB(2) cannabinoid receptors, associated with drugs of abuse, may provide a means to treat pain, mood, and addiction disorders affecting widespread segments of society. Whether the orphan G-protein coupled receptor GPR55 is also a cannabinoid receptor remains unclear as a result of conflicting pharmacological studies. GPR55 has been reported to be activated by exogenous and endogenous cannabinoid compounds but surprisingly also by the endogenous non-cannabinoid mediator lysophosphatidylinositol (LPI). We examined the effects of a representative panel of cannabinoid ligands and LPI on GPR55 using a beta-arrestin-green fluorescent protein biosensor as a direct readout of agonist-mediated receptor activation. Our data demonstrate that AM251 and SR141716A (rimonabant), which are cannabinoid antagonists, and the lipid LPI, which is not a cannabinoid receptor ligand, are GPR55 agonists. They possess comparable efficacy in inducing beta-arrestin trafficking and, moreover, activate the G-protein-dependent signaling of protein kinase CbetaII. Conversely, the potent synthetic cannabinoid agonist CP55,940 acts as a GPR55 antagonist/partial agonist. CP55,940 blocks GPR55 internalization, the formation of beta-arrestin GPR55 complexes, and the phosphorylation of ERK1/2; CP55,940 produces only a slight amount of protein kinase CbetaII membrane recruitment but does not stimulate membrane remodeling like LPI, AM251, or rimonabant. Our studies provide a paradigm for measuring the responsiveness of GPR55 to a variety of ligand scaffolds comprising cannabinoid and novel compounds and suggest that at best GPR55 is an atypical cannabinoid responder. The activation of GPR55 by rimonabant may be responsible for some of the off-target effects that led to its removal as a potential obesity therapy.
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PMID:Atypical responsiveness of the orphan receptor GPR55 to cannabinoid ligands. 1972 26

Given the vast therapeutic potential of the endocannabinoid system, the revelation of a novel cannabinoid-sensitive target was treated with great excitement. The orphan G-protein coupled receptor 55 (GPR55) was initially touted as a novel cannabinoid target in early industrial patent literature. Consequently, numerous studies have revealed GPR55 expression in a diverse array of cells and tissues, regulating various physiological and pathological processes. Although a confusing cannabinoid profile has prevented its classification as a cannabinoid receptor, the therapeutic potential of the receptor cannot be denied, with roles in cancer progression, bone resorption and analgesia. This commentary aims to summarize GPR55 expression data and speculate on potential therapeutic exploitation of this enigmatic orphan receptor.
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PMID:Off-target cannabinoid effects mediated by GPR55. 2243 74

The orphan G-protein coupled receptor GPR55 was shown to bind to certain cannabinoid compounds which led to its initial classification as the third type of cannabinoid receptor. Later studies showed that lysophosphatidylinositol (LPI) also activated GPR55, in particular 2-arachidonoyl-LPI was proposed to be its endogenous ligand. However, the results of pharmacological studies regarding GPR55 have been quite inconsistent. Despite its contradictory pharmacological profile, GPR55 has been implicated in various disease states including inflammatory and neuropathic pain, metabolic bone diseases, and cancer. Herein, we report the ligand binding properties of GPR55 by applying homology modeling and automated docking algorithms in order to understand its pharmacological profile. The 3D homology model of GPR55 was built based on the adenosine A(2A) receptor crystal structure. Docking studies of several types of reported ligands were carried out afterwards. The results indicated that both hydrogen bonding and hydrophobic interactions contributed significantly for its ligand binding and the amino acid residue Lys80 seemed to be the anchor residue for receptor recognition. In addition, its putative agonist and antagonist appeared to recognize different domains of the receptor corresponding to their reported pharmacological activities.
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PMID:A homology modeling study toward the understanding of three-dimensional structure and putative pharmacological profile of the G-protein coupled receptor GPR55. 2322 Feb 81