Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, we investigated the mechanism of S100B neurotoxicity and the effect of cannabinoids, in C6 cells treated with 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine (MPTP) and co-cultured with differentiated PC12 cells. MPTP concentration- and time-dependently increased S100B density in C6 cells. This effect was followed by increased C6 cell proliferation and decreased cell viability of co-cultured PC12 cells. An antibody against S100B, given to PC12 cells before co-culture, led to their survival. Treatment with arachidonyl-2-chloroethylamide, a CB1 agonist, significantly inhibited MPTP-induced S100B density in C6 cells and protected co-cultured PC12 cells from cell death. Because MPTP selectively increased the levels of anandamide in C6 cells, the involvement of the endocannabinoid system was investigated by using selective inhibitors of endocannabinoid inactivation (cellular re-uptake or enzymatic hydrolysis) and selective cannabinoid CB1 and CB2 receptor antagonists and by silencing the CB1 receptor. Our data suggest that selective activation of CB1 receptors by either exogenous or endogenous cannabinoids might afford neuroprotection in MPTP-induced neurotoxicity also by controlling S100B up-regulation in activated glial cells.
J Mol Med (Berl) 2007 Dec
PMID:Cannabinoid CB1 receptor stimulation affords neuroprotection in MPTP-induced neurotoxicity by attenuating S100B up-regulation in vitro. 1763 88

The best-known endocannabinoid ligands, anandamide and 2-AG, signal at least seven receptors and involve ten metabolic enzymes. Genes for the receptors and enzymes were examined for heterogeneities in tempo (relative rate of evolution, RRE) and mode (selection pressure, Ka/Ks) in six organisms with sequenced genomes. BLAST identified orthologs as reciprocal best hits, and nucleotide alignments were performed with ClustalX and MacClade. Two bioinformatics platforms, LiKaKs (a distance-based LWL85 model) and SNAP (a parsimony-based NG86 model) made pairwise comparisons of orthologs in murids (rat and mouse) and primates (human and macaque). Mean RRE of the 18 endocannabinoid genes was significantly greater in murids than primates, whereas mean Ka/Ks did not differ significantly. Next we used FUGE (tree-based maximum-likelihood model) to compute human lineage-specific Ka/Ks calculations for 18 genes, which ranged from 1.11 to 0.00, in rank order from highest to lowest: PTPN22, NAAA, TRPV1, TRPA1, NAPE-PLD, MAGL, PPARgamma, FAAH1, COX2, FAAH2, ABDH4, CB2, GPR55, DAGLbeta, PPARalpha, TRPV4, CB1, DAGLalpha; differences were significant (p < 0.0001). Rat and mouse presented different rank orders (e.g., GPR55 generated the greatest Ka/Ks ratio). The 18 genes were then tested for recent positive selection (within 10,000 yr) using an extended haplotype homozygosity analysis of SNP data from the HapMap database. Significant evidence (p < 0.05) of a positive "selective sweep" was exhibited by PTPN22, TRPV1, NAPE-PLD, and DAGLalpha. In conclusion, the endocannabinoid system is collectively under strong purifying selection, although some genes show evidence of adaptive evolution.
J Mol Evol 2007 Sep
PMID:Tempo and mode in the endocannaboinoid system. 1767 65

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

The endocannabinoid system has emerged as a versatile neuromodulatory system, implicated in a plethora of physiological and pathophysiological processes. Cannabinoid receptor type 1 (CB1 receptor) and endocannabinoids are widely distributed in the brain. Their roles in learning and memory have been well documented, using rodents in various memory tests. Depending on the test, the endocannabinoid system is required in the acquisition and/or extinction of memory. In particular, the activation of CB1 receptor-mediated signaling is centrally involved in the facilitation of behavioral adaptation after the acquisition of aversive memories. As several human psychiatric disorders, such as phobia, generalized anxiety disorders, and posttraumatic stress disorder (PTSD) appear to involve aberrant memory processing and impaired adaptation to changed environmental conditions, the hope has been fuelled that the endocannabinoid system might be a valuable therapeutic target for the treatment of these disorders. This review summarizes the current data on the role of the endocannabinoid system in the modulation of extinction learning.
Mol Neurobiol 2007 Aug
PMID:The endocannabinoid system and extinction learning. 1795 54

The majority of effects of cannabinoids are mediated by the two receptors CB1 and CB2. In addition to neuronal cells, CB1 receptors are expressed in T lymphocytes, in which they are involved in cannabinoid-induced T helper cell biasing. Although basally expressed only weakly in T cells, CB1 receptors are up-regulated in these cells by stimuli such as cannabinoids themselves. This effect is mediated by interleukin-4. In this study, we investigated basal and interleukin-4-inducible expression of the CB1 gene in T lymphocytes. In a promoter analysis, two regions [nucleotides (nts) -3086 to -2490 and nts -1950 to -1653] were identified, which suppress basal transcription of the gene in Jurkat T cells, whereas the region between nts -648 and -559 enhanced basal CB1 transcription. Interleukin-4 markedly induced transcription of CB1 in Jurkat cells and primary human T cells. Experiments using transcription factor decoy oligonucleotides demonstrated that STAT6 mediates regulation of the gene by interleukin-4. Using reporter gene assays and the transcription factor decoy oligonucleotide approach, a binding site for STAT6 was identified at nt -2769 on the human CB1 gene promoter. Interleukin-4 also caused up-regulation of functional CB1 receptor proteins. In interleukin-4 pretreated, but not in naive Jurkat cells, the CB1 agonist R(+)-methanandamide caused a significant inhibition of forskolin-induced cAMP formation. This effect was blocked by the CB1-selective antagonists N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) and 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-mo rpholinyl-1H-pyrazole-3-carboxamide (AM281). Taken together, these data show that CB1 receptors are expressed and up-regulated by interleukin-4 in T lymphocytes, which enables CB1-mediated communication to cells of other systems, such as neuronal cells.
Mol Pharmacol 2008 Mar
PMID:Analysis of promoter regions regulating basal and interleukin-4-inducible expression of the human CB1 receptor gene in T lymphocytes. 1815 15

In this study we evaluated the effects of the CB1/CB2 cannabinoid receptor agonist CP55, 940 (CP) on antigen-induced asthma-like reaction in sensitized guinea pigs and we tested the ability of the specific CB2 receptor antagonist SR144528 (SR) and CB1 receptor antagonist AM251 (AM) to interfere with the effects of CP. Ovalbumin-sensitized guinea pigs placed in a respiratory chamber were challenged with the antigen given by aerosol. CP (0.4 mg/kg b.wt.) was given i.p. 3 hrs before ovalbumin challenge. Sixty minutes before CP administration, some animals were treated i.p. with either AM, or SR, or both (0.1 mg/kg b.wt.). Respiratory parameters were recorded and quantified. Lung tissue specimens were then taken for histopathological and morphometric analyses and for eosinophilic major basic protein immunohistochemistry. Moreover, myeloperoxidase activity, 8-hydroxy-2-deoxyguanosine, cyclic adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP) levels, and CB1 and CB2 receptor protein expression by Western blotting were evaluated in lung tissue extracts. In the bronchoalveolar lavage fluid, the levels of prostaglandin D2 and tumour necrosis factor-alpha TNF-alpha were measured. Ovalbumin challenge caused marked abnormalities in the respiratory, morphological and biochemical parameters assayed. Treatment with CP significantly reduced these abnormalities. Pre-treatment with SR, AM or both reverted the protective effects of CP, indicating that both CB1 and CB2 receptors are involved in lung protection. The noted treatments did not change the expression of cannabinoid receptor proteins, as shown by Western blotting. These findings suggest that targeting cannabinoid receptors could be a novel preventative therapeutic strategy in asthmatic patients.
J Cell Mol Med 2008 Dec
PMID:Activation of cannabinoid receptors prevents antigen-induced asthma-like reaction in guinea pigs. 1826 75

Gastric emptying regulates food intake. Oleoylethanolamide (OEA), an endogenous acylethanolamide chemically related to the endocannabinoid anandamide, inhibits food intake, but its effect on gastric emptying is unknown. Here, we investigated the effect and the role of OEA on gastric emptying in mice fed either a standard (STD) or a high-fat diet (HFD) for 14 weeks. Gastric emptying was reduced by OEA, but not by its saturated analog, palmitoylethanolamide. The effect of OEA was unaffected by rimonabant (cannabinoid CB1 receptor antagonist), SR144528 (cannabinoid CB2 receptor antagonist), 5'-iodoresiniferatoxin (transient receptor potential vanilloid type 1 antagonist), or MK886 (peroxisome proliferator-activated receptor-alpha) antagonist. Compared to STD mice, HFD mice showed delayed gastric emptying and higher levels of gastric OEA. HFD-induced increase in OEA levels was accompanied by increased expression of the OEA-synthesizing enzyme N-acyl-phosphatidylethanolamine-selective phospholipase D and decreased expression of the OEA-degrading enzyme fatty acid amide hydrolase. These results might suggest that elevation of gastric OEA could possibly contribute to the delayed gastric emptying observed in HFD-fed animals. HFD regulates OEA levels in the stomach through an increase of its biosynthesis and a decrease of its enzymatic degradation. The inhibitory effect of OEA on gastric emptying here observed might underlie part of the anorexic effects of this compound previously reported.
J Mol Med (Berl) 2008 Apr
PMID:Inhibitory effect of the anorexic compound oleoylethanolamide on gastric emptying in control and overweight mice. 1827 75

Physiological roles of endocannabinoids, a group of endogenously produced cannabinoid-like lipid molecules that activate G protein-coupled cannabinoid receptors, are being increasingly appreciated in female reproduction. Adverse effects of cannabinoids on female fertility have been suspected for decades; however, underlying molecular and genetic bases by which they exert these effects were not clearly understood. The discovery of cannabinoid receptors (CB1 and CB2), endocannabinoid ligands (anandamide and 2-acylglycerol) as well as their key synthetic and hydrolytic pathways has helped to better understand the roles of cannabinoid/endocannabinoid signaling in preimplantation embryo development, oviductal embryo transport, embryo implantation and postimplantation embryonic growth. This review focuses on various aspects of the endocannabinoid system in female fertility based on studies that used knockout mouse models. The information generated from studies in mice is likely to shed deeper insight into fertility regulation in women.
Mol Cell Endocrinol 2008 Apr 16
PMID:Aspects of endocannabinoid signaling in periimplantation biology. 1829 62

It has been shown that the endocannabinoids inhibit luteinizing hormone (LH) and prolactin (PRL) secretion. When the effects of the two well-known endocannabinoids arachidonoylethanolamide (AEA, anandamide) and 2-arachidonoyl-glycerol (2AG) have been compared it became evident that AEA caused inhibition was higher than that one of 2AG. AEA also diminished the two investigated hormonal levels in CB1 receptor inactivated mice. AEA, being an endogenous ligand of vanilloid type 1 (TPRV1) receptor, while activating TPRV1 receptor has an effect on both LH and PRL levels decrease because these later were abolished when capsazepin, antagonist of TPRV1 receptor was previously administered to the CB1 KO animals. We postulate that the difference between the effects of AEA and 2AG on the serum levels of LH and PRL is due to the difference in receptor activation of these two compounds, namely AEA can activate both CB1 and TRPV1 receptor but 2AG acts only on CB1 receptor.
Mol Cell Endocrinol 2008 Apr 16
PMID:The role of endocannabinoids in the regulation of luteinizing hormone and prolactin release. Differences between the effects of AEA and 2AG. 1830 64

Endocannabinoids, via cannabinoid receptors (CB1 and CB2), affect reproductive functions at both local and central level. Due to the high complexity of the endocannabinoid system, to the widespread distribution outside the nervous system and to the high degree of evolutionary conservation, a deep CB1 molecular characterization among species may be useful to elucidate the activity of endocannabinoids at multiple levels. In this review we report CB1 characterization in non-mammalian animal models and, in particular, in the anuran amphibian, the frog, Rana esculenta; we also describe its expression during the annual sexual cycle. Moreover, since reproductive functions are under control of gonadotropin releasing hormone (GnRH), cb1 mRNA and protein expression profile in the forebrain has been compared to those of GnRH-I, the mammalian form primarily involved in gonadotropin release.
Mol Cell Endocrinol 2008 Apr 16
PMID:Non-mammalian vertebrate models and the endocannabinoid system: relationships with gonadotropin-releasing hormone. 1832 58


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>