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 molecular basis for the control of energy balance by the endocannabinoid anandamide (AEA) is still unclear. Here, we show that murine 3T3-L1 fibroblasts have the machinery to bind, synthesize and degrade AEA, and that their differentiation into adipocytes increases by approximately twofold the binding efficiency of cannabinoid receptors (CBR), and by approximately twofold and approximately threefold, respectively, the catalytic efficiency of the AEA transporter and AEA hydrolase. In contrast, the activity of the AEA synthetase and the binding efficiency of vanilloid receptor were not affected by the differentiation process. In addition, we demonstrate that AEA increases by approximately twofold insulin-stimulated glucose uptake in differentiated adipocytes, according to a CB1R-dependent mechanism that involves nitric oxide synthase, but not lipoxygenase or cyclooxygenase. We also show that AEA binding to peroxisome proliferator-activated receptor-gamma, known to induce differentiation of 3T3-L1 fibroblasts into adipocytes, is not involved in the stimulation of glucose uptake.
Cell Mol Life Sci 2007 Jan
PMID:Endocannabinoids in adipocytes during differentiation and their role in glucose uptake. 1718 72

The endocannabinoids, a recently discovered endogenous, lipid derived, signaling system regulating energy metabolism, have effects on central and peripheral energy metabolism predominantly via the cannabinoid receptor type 1 (CB1). CB1 is expressed centrally in the hypothalamus and nucleus accumbens and peripherally in adipocytes and skeletal muscle. This study determined the effect of endocannabinoids on the expression of genes regulating energy metabolism in human skeletal muscle. Primary cultures of myotubes (lean and obese; n=3/group) were treated with the cannabinoid receptor agonist, anandamide (AEA) (0.2 and 5microM) and the CB1 specific antagonist AM251 (0.2 and 5microM) separately and in combination for 24h. The expression of mRNA for AMP-activated protein kinase (AMPK) alpha 1 (alpha1) and alpha 2 (alpha2), pyruvate dehydrogenase kinase 4 (PDK4) and peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1alpha) were determined using 'Real Time' RT-PCR. AMPKalpha1 mRNA increased in lean and obese myotubes in response to AM251 (P<0.05). AEA inhibited the effect of AM251 on AMPKalpha1 mRNA levels in myotubes from lean and obese subjects (P<0.05); the dose-response curve was shifted to the left in the obese. In response to AM251, irrespective of the presence of AEA, PDK4 expression was decreased in lean and obese myotubes (P<0.05). Taken together these data suggest that endocannabinoids regulate pathways affecting skeletal muscle oxidation, effects particularly evident in myotubes from obese individuals.
Mol Cell Endocrinol 2007 Mar 15
PMID:Effects of cannabinoid receptors on skeletal muscle oxidative pathways. 1727 Mar 42

Studies in rodent models demonstrated that the central cannabinoid receptor (Cnr1) mediates the orexigenic effects of cannabinoids. To analyze whether genetic variation in the cannabinoid receptor gene (CNR1) is implicated in human obesity, we initially genotyped 8 single nucleotide polymorphisms (SNPs) located in the 5' region (rs9353527, rs754387, rs6454676), intron 2 (rs806379, rs1535255), exon 3 (rs2023239), intron 3 (rs806370) and the coding region (rs1049353) in up to 364 German obesity trios (extremely obese child or adolescent and both parents). The transmission disequilibrium test (TDT) was negative for these SNPs (p>0.05). However, there was a slight trend towards preferential transmission of the A-allele of rs1049353 (p=0.12). We therefore genotyped this SNP in 235 independent German obesity families (at least two obese sibs and both parents) and in parallel screened the CNR1 coding region for sequence variations in 120 German extremely obese children and adolescents who mainly contributed to the initial trend observed for rs1049353. The trend for preferential transmission of the A-allele could not be substantiated (pedigree disequilibrium test, PDT p=0.15; A-allele less frequently transmitted). In the mutation screen we detected two rare variations, one novel non-conservative mutation (c.1256C>A; A419E) and the known variant 1419+1G>C. In addition, we confirmed the presence of rs1049353. As these variants could not explain the initial TDT, we conclude that there is no evidence for an association of CNR1 alleles with obesity in our study groups.
Mol Genet Metab 2007 Apr
PMID:No evidence for an involvement of variants in the cannabinoid receptor gene (CNR1) in obesity in German children and adolescents. 1729 52

The advent of the highly selective cannabinoid receptor (CB1) antagonist, rimonabant (SR141716; Acomplia) can revolutionize the ability of the clinicians to manage obesity. Large-scale clinical trials have demonstrated that rimonabant therapy can reduce obesity. Although, the precise mechanisms of action of rimonabant have to be further dissected, it is emerging, from both preclinical and clinical research, that not only is rimonabant an antiobesity drug, but also its pleiotropic functions affect a broad range of diseases, from obesity-related comorbidities to drug dependence and cancer. Here we review recent data from the literature and discuss the full pharmacological potential of this drug.
Mol Pharmacol 2007 Jun
PMID:Rimonabant: just an antiobesity drug? Current evidence on its pleiotropic effects. 1732 63

Ligands of structurally diverse natures are able to bind at the CB(1) cannabinoid receptor, suggesting the existence of multiple binding sites on the receptor. Modeling studies have implicated Ser2.60(173) and Ser7.39(383) as possible interaction site(s) for CB(1) agonists. To test the importance of these residues for receptor recognition, recombinant human CB(1) receptors, stably expressed in human embryonic kidney 293 cells, were used to investigate the consequences of mutating Ser2.60 (to S2.60A) or Ser7.39 (to S7.39A) in radioligand binding and guanosine 5'-3-O-(thio)triphosphate functional assays. The S7.39A mutant resulted in a total ablation of [(3)H](-)-3-[2-hydroxyl-4-(1,1-dimethylheptyl)phenyl]-4-[3-hydroxylpropyl] cyclohexan-1-ol (CP55,940) high-affinity binding. However, [(3)H](R)-(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]-pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)methanone (WIN55,212-2) binding properties at S7.39A were comparable with those of the wild-type (WT) receptor. The binding affinity of (-)-11beta-hydroxy-3-(1',1'-dimethylheptyl)hexahydrocannabinol (AM4056) and (-)-11-hydroxydimethylheptyl-Delta(8)-tetrahydrocannabinol (HU210) were drastically reduced (50- to 100-fold) at the S7.39A mutant. Likewise, the EC(50) for HU210 and AM4056-mediated activation of the S7.39A receptor was increased by >200-fold. In contrast, the binding affinity and potency of WIN55,212-2, CP55,940, HU210, and AM4056 were unaltered at the S2.60A mutant compared with WT human CB(1) receptors. These results clearly suggest that Ser7.39, but not Ser2.60, plays a crucial role in mediating ligand specific interactions for CP55,940, HU210, and AM4056 at the human CB(1) receptor. Our modeling studies predict that Ser7.39 in a g-chi1 conformation may induce a helix bend in TMH7 that provides docking space for CP55,940 binding; the S7.39A mutation may alter this binding space, precluding CP55,940 binding.
Mol Pharmacol 2007 Jun
PMID:Mutation studies of Ser7.39 and Ser2.60 in the human CB1 cannabinoid receptor: evidence for a serine-induced bend in CB1 transmembrane helix 7. 1738 24

The endocannabinoid 2-arachidonoylglycerol (2-AG) enhances cell migration through the CB2 cannabinoid receptor. In this study, using an immunoprecipitation and mass spectrometry-based proteomic approach, we first identified the 90-kDa heat shock protein (Hsp90), a chaperone protein with novel signaling functions, as a CB2-interacting protein. The CB2/Hsp90 interaction was confirmed in human embryonic kidney 293 cells expressing transfected CB2 and in differentiated HL-60 cells expressing endogenous CB2, by coimmunoprecipitation and Western blot experiments, as well as by treatment with geldanamycin (GA), a specific Hsp90 inhibitor. Disruption of the CB2/Hsp90 interaction by treatment with GA or reducing Hsp90 levels with specific short interfering RNAs markedly inhibited 2-AG-induced cell migration, demonstrating that Hsp90 is crucial for 2-AG-induced cell migration. 2-AG treatment resulted in a CB2-mediated stimulation of Rac1 activity, and treatment with GA blocked 2AG-induced activation of Rac1. It is noteworthy that expression of the dominant-negative form of Rac1 reduced 2-AG-induced cell migration. These data demonstrate that 2-AG-induced activation of Rac1 is essential for 2-AG-induced cell migration, and the CB2/Hsp90 interaction is needed for 2-AG-induced activation of Rac1. Furthermore, 2-AG-induced Rac1 activation was sensitive to pertussis toxin treatment, hence involving G(i) proteins. In addition, treatment with GA significantly inhibited the CB2/Galpha(i2) interaction. As a whole, our data indicate that Hsp90 may serve as scaffold to keep the CB2 receptor and its signaling components, including Galpha(i2), in proximity, thus facilitating CB2-mediated signaling to cell migration through the G(i)-Rac1 pathway. By demonstrating that Hsp90 is essential for CB2-mediated signaling to cell migration, this study reveals a novel role of Hsp90 in the signaling events mediated by a G protein-coupled receptor.
Mol Pharmacol 2007 Nov
PMID:Involvement of the 90-kDa heat shock protein (Hsp-90) in CB2 cannabinoid receptor-mediated cell migration: a new role of Hsp-90 in migration signaling of a G protein-coupled receptor. 1769 52

Colorectal cancer is an increasingly important cause of death in Western countries. Endocannabinoids inhibit colorectal carcinoma cell proliferation in vitro. In this paper, we investigated the involvement of endocannabinoids on the formation of aberrant crypt foci (ACF, earliest preneoplastic lesions) in the colon mouse in vivo. ACF were induced by azoxymethane (AOM); fatty acid amide hydrolase (FAAH) and cannabinoid receptor messenger ribonucleic acid (mRNA) levels were analyzed by the quantitative reverse transcription polymerase chain reaction (RT-PCR); endocannabinoid levels were measured by liquid chromatography-mass spectrometry; caspase-3 and caspase-9 expressions were measured by Western blot analysis. Colonic ACF formation after AOM administration was associated with increased levels of 2-arachidonoylglycerol (with no changes in FAAH and cannabinoid receptor mRNA levels) and reduction in cleaved caspase-3 and caspase-9 expression. The FAAH inhibitor N-arachidonoylserotonin increased colon endocannabinoid levels, reduced ACF formation, and partially normalized cleaved caspase-3 (but not caspase-9) expression. Notably, N-arachidonoylserotonin completely prevented the formation of ACF with four or more crypts, which have been show to be best correlated with final tumor incidence. The effect of N-arachidonoylserotonin on ACF formation was mimicked by the cannabinoid receptor agonist HU-210. No differences in ACF formation were observed between CB(1) receptor-deficient and wild-type mice. It is concluded that pharmacological enhancement of endocannabinoid levels (through inhibition of endocannabinoid hydrolysis) reduces the development of precancerous lesions in the mouse colon. The protective effect appears to involve caspase-3 (but not caspase-9) activation.
J Mol Med (Berl) 2008 Jan
PMID:Increased endocannabinoid levels reduce the development of precancerous lesions in the mouse colon. 1782 81

The CB1 cannabinoid receptor is a G-protein coupled receptor that has important physiological roles in synaptic plasticity, analgesia, appetite, and neuroprotection. We report the discovery of two structurally related CB1 cannabinoid receptor interacting proteins (CRIP1a and CRIP1b) that bind to the distal C-terminal tail of CB1. CRIP1a and CRIP1b are generated by alternative splicing of a gene located on chromosome 2 in humans, and orthologs of CRIP1a occur throughout the vertebrates, whereas CRIP1b seems to be unique to primates. CRIP1a coimmunoprecipitates with CB1 receptors derived from rat brain homogenates, indicating that CRIP1a and CB1 interact in vivo. Furthermore, in superior cervical ganglion neurons coinjected with CB1 and CRIP1a or CRIP1b cDNA, CRIP1a, but not CRIP1b, suppresses CB1-mediated tonic inhibition of voltage-gated Ca2+ channels. Discovery of CRIP1a provides the basis for a new avenue of research on mechanisms of CB1 regulation in the nervous system and may lead to development of novel drugs to treat disorders where modulation of CB1 activity has therapeutic potential (e.g., chronic pain, obesity, and epilepsy).
Mol Pharmacol 2007 Dec
PMID:CB1 cannabinoid receptor activity is modulated by the cannabinoid receptor interacting protein CRIP 1a. 1789 7

Endocannabinoids are fatty acid derivatives that have a variety of biological actions, most notably via activation of the cannabinoid receptors. These receptors are also targets for drugs derived from Cannabis sativa. In the nervous system, endocannabinoids act as neuromodulators that depress neurotransmitter release at the presynaptic terminal. In most instances of neural endocannabinoid signaling, the compounds appear to be released from the postsynaptic neuron to act on the presynaptic terminal in a "retrograde" manner. Several common mechanisms involved in postsynaptic endocannabinoid production and presynaptic depression produced via activation of the CB1 cannabinoid receptor have been identified. However, significant problems remain in defining the mechanisms underlying endocannabinoid production, release, and movement across the membrane. These issues are discussed in the present review.
J Mol Neurosci 2007 Sep
PMID:Endocannabinoid liberation from neurons in transsynaptic signaling. 1790 51

About 40 years ago, cannabinoids were considered as the substances responsible for the psychoactive properties of marijuana and other derivatives of Cannabis sativa, whereas their medicinal use remained unexplored. However, with the discovery of the endocannabinoid system 20 years later, the compounds able to modify this system are being reconsidered for their therapeutic potential. Thus, the term "cannabinoid" includes now much more compounds than those present in C. sativa derivatives, for instance, numerous synthetic cannabinoids obtained by modifications from plant-derived cannabinoids or from the compounds that behave as endogenous ligands for the different cannabinoid receptor types. The term "cannabinoid" should also refer to some prototypes of selective antagonists for these receptors. The explanation for this exponential growth in cannabinoid pharmacology is the discovery and characterization of the endocannabinoid signaling system (receptors, ligands, and inactivation system) which plays a modulatory role mainly in the brain but also in the periphery. The objective of the present review article was to give an overview of the present state-of-the-art of biochemistry of the endocannabinoid system. Other authors in this volume will review their functions in the brain, their alterations in a variety of neurological and psychiatric pathologies, and the proposed therapeutic benefits in these diseases of new cannabinoid-related compounds that improve the pharmacological properties of classic cannabinoids.
Mol Neurobiol 2007 Aug
PMID:An overview on the biochemistry of the cannabinoid system. 1795 45


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