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In silico patent searching reveals a new cannabinoid receptor

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Increasing evidence suggests that some cannabinoids mediate their effects independently of the known cannabinoid CB1 and CB2 receptors. Two recently published patents indicate that several cannabinoid receptor ligands also bind to the orphan G-protein-coupled receptor GPR55. This receptor is reported to be expressed in several tissues and might function in lipid or vascular biology. Thus, GPR55 might represent a new cannabinoid receptor.

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Search for novel cannabinoid receptors reveals GPR55 as a candidate

Many aspects of the cannabinoid system have yet to be elucidated but, interestingly, two patents 1, 2 indicate that the G-protein-coupled receptor (GPCR) GPR55 [3] is a novel cannabinoid receptor. There has been recent interest in the potential medicinal properties of cannabinoids (e.g. the introduction of the cannabinoid receptor antagonist rimonabant as an anti-obesity drug 4, 5) and their activity in neurobiology [4]. To date, two cannabinoid receptor (CB1 and CB2) targets for cannabinoid

Structure of GPR55

Different sequences have been reported for human GPR55 (termed here as GPR551 1, 3, GPR552 [9] and GPR55A [2]). These might represent distinct molecules [2], polymorphisms, or cloning or sequencing errors (Figure 1), but are not due to alternative splicing because the gene encoding GPR55 lacks introns. The amino acid sequence of the GPR55A variant [2] differs from the original sequence (GPR551) [3], notably by the presence of a LRSPRKIFGIC amino acid stretch that encompasses the second

Tissue distribution of GPR55

Human GPR55 transcripts have been isolated from brain and spleen, and specific mRNA is expressed in the caudate nucleus and putamen, but not in the hippocampus, thalamus, pons, cerebellum, frontal cortex of the brain or in the liver [3]. In rats, mRNA transcripts of the GPR55 orthologue have been detected in spleen and intestine, and in situ hybridization has indicated some expression in the hippocampus, thalamic nuclei and regions of the midbrain [3]. Taqman quantitative polymerase chain

Cannabinoid activity at GPR55

The second patent reports that Δ9-tetrahydrocannabinol (the psychoactive component of cannabis), several endocannabinoids (including anandamide and 2-arachidonoyl glycerol) and palmitoylethanolamide bind to GPR55 and are potent stimulants (EC50=1–20 nM) [2]. Other cannabinoids that exhibited weak receptor stimulation include abnormal-cannabidiol (EC50≈3000 nM). JWH133 (CB2 receptor agonist) and WIN55212 failed to stimulate GPR55 [2], which contrasts with the binding of WIN55212 to a

Controversy over the function of GPR55

Given the apparently strong binding of the cannabinoid receptor ligand CP55940 to GPR55 [2], it is perhaps surprising that brain and splenic binding of [3H]CP55940 has not been reported in autoradiographic studies in cannabinoid receptor-deficient mice 12, 13. Similarly, abstracts and patents express conflicting views on whether CP55940 is an inverse agonist [14] or an agonist at GPR55 2, 15, and the extent to which rimonabant stimulates GPR55 2, 15. This might reflect technical aspects of how

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