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

Several tryptophan (Trp) residues are conserved in G protein-coupled receptors (GPCRs). Relatively little is known about the contribution of these residues and especially of those in the fourth transmembrane domain in the function of the CB(2) cannabinoid receptor. Replacing W158 (very highly conserved in GPCRs) and W172 (conserved in CB(1) and CB(2) cannabinoid receptors but not in many other GPCRs) of the human CB(2) receptor with A or L or with F or Y produced different results. We found that the conservative change of W172 to F or Y retained cannabinoid binding and downstream signaling (inhibition of adenylyl cyclase), whereas removal of the aromatic side chain by mutating W172 to A or L eliminated agonist binding. W158 was even more sensitive to being mutated. We found that the conservative W158F mutation retained wild-type binding and signaling activities. However, W158Y and W158A mutants completely lost ligand binding capacity. Thus, the Trp side chains at positions 158 and 172 seem to have a critical, but different, role in cannabinoid binding to the human CB(2) receptor.
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PMID:Functional role of tryptophan residues in the fourth transmembrane domain of the CB(2) cannabinoid receptor. 1108 Feb 1

The acute effects of cannabinoid drugs on the synthesis of noradrenaline, dopamine, and serotonin (5-HT) were assessed, simultaneously, using the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. Treatment (1 h, i.p.) with Delta(9)-tetrahydrocannabinol (THC, 5, 10, and 20 mg/kg) and the cannabinoid receptor agonist WIN 55,212-2 (WIN, 2 and 4 mg/kg) increased dopa/noradrenaline synthesis (40-70%) in various brain regions enriched in this neurotransmitter (e.g., cerebral cortex, hippocampus, hypothalamus). In most brain regions, the content of noradrenaline was reduced by cannabinoid drugs (27-66%). For the effects of WIN (2 and 4 mg/kg), an inverse correlation ( r=-0.61, P=0.036) was obtained between the accumulation of dopa and the content of noradrenaline in the hypothalamus. The stimulatory effect on dopa accumulation induced by THC was antagonized by the selective CB(1) receptor antagonists SR141716A and AM 281 (10 mg/kg). In contrast, THC and WIN decreased the synthesis of dopa/dopamine in the corpus striatum (16-37%) and that of 5-HTP/5-HT (20-35%) in brain regions enriched in 5-HT (e.g., cerebral cortex and hippocampus). These inhibitory effects of THC and WIN were also antagonized by AM 281 and/or SR141716A. THC did not alter the content of 5-HT or dopamine in the brain. The effects may be related to the activation of presynaptic inhibitory cannabinoid CB(1) receptors located on the neurones themselves (serotonin) and on facilitatory (dopamine) and inhibitory interneurones (noradrenaline).
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PMID:Differential effects of acute cannabinoid drug treatment, mediated by CB1 receptors, on the in vivo activity of tyrosine and tryptophan hydroxylase in the rat brain. 1506 21

Nanomolar concentrations of Delta9-tetrahydrocannabinol or cannabidiol are demonstrated to enhance mitogen-induced degradation of tryptophan in human peripheral blood mononuclear cells in dependence of CB1- or CB2-receptor activation. In contrast, suppression of this pathway by cannabinoids in the micromolar concentration range was achieved independent of cannabinoid receptor activation. Both cannabinoids also suppressed tryptophan degradation in myelomonocytic THP-1 cells stimulated with lipopolysaccharide. We conclude, that suppression of tryptophan degradation by cannabinoids via indoleamine-2,3-dioxygenase, which is independent of cannabinoid receptor activation, might enhance the availability of tryptophan for serotonin biosynthesis and consequently can be important in the action of cannabinoids to improve mood disturbances.
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PMID:Delta9-tetrahydrocannabinol and cannabidiol modulate mitogen-induced tryptophan degradation and neopterin formation in peripheral blood mononuclear cells in vitro. 1916 98

We developed a bacterial fermentation protocol for production of a stable isotope-labeled cannabinoid receptor CB2 for subsequent structural studies of this protein by nuclear magnetic resonance spectroscopy. The human peripheral cannabinoid receptor was expressed in Escherichia coli as a fusion with maltose binding protein and two affinity tags. The fermentation was performed in defined media comprised of mineral salts, glucose and (15)N(2)-L-tryptophan to afford incorporation of the labeled amino acid into the protein. Medium, growth and expression conditions were optimized so that the fermentation process produced about 2mg of purified, labeled CB2/L of culture medium. By performing a mass spectroscopic characterization of the purified CB2, we determined that one of the two (15)N atoms in tryptophan was incorporated into the recombinant protein. NMR analysis of (15)N chemical shifts strongly suggests that the (15)N atoms are located in Trp-indole rings. Importantly, analysis of the peptides derived from the CNBr cleavage of the purified protein confirmed a minimum of 95% incorporation of the labeled tryptophan into the CB2 sequence. The labeled CB2, purified and reconstituted into liposomes at a protein-to-lipid molar ratio of 1:500, was functional as confirmed by activation of cognate G proteins in an in vitro coupled assay. To our knowledge, this is the first reported production of a biologically active, stable isotope-labeled G protein-coupled receptor by bacterial fermentation.
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PMID:Preparation of stable isotope-labeled peripheral cannabinoid receptor CB2 by bacterial fermentation. 2004 6