Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of cannabinoids on phosphoinositide metabolism stimulated by activation of muscarinic receptors, alpha 1-adrenoceptors or glutamate receptors was examined in rat hippocampal cultures. Carbachol stimulated phosphoinositide turnover by 5.5-fold over basal level, whereas glutamate and norepinephrine stimulated phosphoinositide turnover by 2-fold. Addition of cannabinoids, such as delta 8-tetrahydrocannabinol, delta 9-tetrahydrocannabinol or the psychoinactive cannabidiol inhibited formation of inositol phosphates evoked by carbachol, glutamate or norepinephrine by 55-90%. The cannabinoids alone only slightly inhibited the basal unstimulated formation of inositol phosphates. The inhibitory effect of the cannabinoids was dose-dependent and was achieved within the range of pharmacologically relevant concentrations. IC50 values for delta 8-tetrahydrocannabinol, delta 9-tetrahydrocannabinol and cannabidiol were 9.6 +/- 1.0, 9.7 +/- 0.3 and 7.9 +/- 0.4 microM, respectively. Pretreatment with pertussis toxin (100 ng/ml, 18 h) did not affect the carbachol-induced stimulation of phosphoinositide turnover or its inhibition by the cannabinoids. This suggests that the inhibition by the cannabinoids of the stimulated formation of inositol phosphates is not mediated through a pertussis toxin-sensitive GTP-binding protein nor through the known effect of the cannabinoids on adenylate cyclase inhibition.
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PMID:Cannabinoids inhibit agonist-stimulated formation of inositol phosphates in rat hippocampal cultures. 810 6

Delta-9-tetrahydrocannabinol (THC) is the major psychoactive component of marijuana. Suppression of mitogen-stimulated blastogenesis of human lymphocytes in vitro by THC was previously demonstrated. This effect was shown to be concentration dependent with the non-toxic concentrations 5, 7.5, and 10 micrograms THC/ml showing the greatest suppression. However, the mechanism(s) by which THC induces suppression are still unclear. The current study examines the effect of THC on the adenosine 3':5'-cyclic monophosphate (cAMP) pathway second messenger system, which is involved in activation of human peripheral blood lymphocytes. Lymphocyte cAMP levels were stimulated using three hormone receptor stimulators, isoproterenol, histamine, or 5'-N-ethylcarboxamide adenosine (NECA), each of which utilizes a different receptor to enhance cAMP production. THC suppressed cAMP levels independently of the hormone and receptor utilized. Levels of cAMP in non-mitogen-stimulated peripheral blood mononuclear cells and plastic non-adherent lymphocytes, as well as cells stimulated with phytohemmagglutinin, were suppressed by THC. Suppression of cAMP production by THC was further examined to determine whether inhibition involved a GTP-binding protein (Gi), which is known to down-regulate cAMP production. Cells were pre-treated with pertussis toxin to inhibit Gi activity; this blocked the THC-induced suppression of cAMP production. These results suggest that THC can exert its effects on second messenger systems at the lymphocyte membrane level, and that a pertussis toxin-sensitive Gi protein may be involved. Thus, second messenger regulated pathways may be involved in THC-induced immune suppression. However, the relationship between alteration of cAMP production and suppression of lymphocyte function due to the presence of THC in the medium remains to be established.
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PMID:Suppression of lymphocyte adenosine 3':5'-cyclic monophosphate (cAMP) by delta-9-tetrahydrocannabinol. 839 73

The present investigation was undertaken to characterize cannabinoid receptor binding in the absence of the membrane environment, inasmuch as cannabinoid drugs have been noted to influence the behavior of integral membrane proteins. The zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) was able to solubilize the cannabinoid receptor from rat brain membranes, with the greatest yield and specific activity being obtained at a detergent/protein ratio of 0.5:1. [3H]CP-55940 bound to a single class of binding sites in the CHAPS extract, which exhibited a Kd of 0.94 nM as determined by nonlinear regression analysis of equilibrium binding data. The order of potency for cannabinoid agonists in heterologous equilibrium binding studies was CP-55244 > or = desacetyllevonantradol > delta 9-tetrahydrocannabinol > cannabinol >> cannabidiol, consistent with the relative affinities for these agonists in brain membrane preparations. CP-55243, the biologically inactive enantiomer of CP-55244, competed for binding of [3H]CP-55940 by < 50% at 1 microM, similar to its poor affinity for the receptor in membranes. The CHAPS-solubilized cannabinoid receptor exhibited functional interactions with guanine nucleotide-binding proteins (G proteins). GTP and nonhydrolyzable analogs decreased [3H]CP-55940 binding by 75%. The concentration-effect curves for guanine nucleotides exhibited a potency order similar to that observed for other G protein-linked receptors. Kinetic analyses indicated that GTP analogs increased the rate of agonist dissociation, decreasing the t1/2 from 60 min at 0-4 degrees to a multiphasic dissociation that exhibited a component having a t1/2 of < 1 min. The cannabinoid agonist desacetyllevonantradol was able to reduce pertussis toxin-catalyzed ADP-ribosylation of G proteins by 50%, demonstrating a receptor effect on G protein functions. These studies demonstrate that the membrane environment is not necessary for agonist binding to the cannabinoid receptor. Furthermore, the cannabinoid receptor maintains its functional interactions with pertussis toxin-sensitive G proteins in detergent solution.
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PMID:Solubilization of the cannabinoid receptor from rat brain and its functional interaction with guanine nucleotide-binding proteins. 842 66

The G-protein-coupled central cannabinoid receptor (CB1) has been shown to be functionally associated with several biological responses including inhibition of adenylate cyclase, modulation of ion channels and induction of the immediate-early gene Krox-24. Using stably transfected Chinese Hamster Ovary cells expressing human CB1 we show here that cannabinoid treatment induces both phosphorylation and activation of mitogen-activated protein (MAP) kinases, and that these effects are inhibited by SR 141716A, a selective CB1 antagonist. The two p42 and p44 kDa MAP kinases are activated in a time- and dose-dependent manner. The rank order of potency for the activation of MAP kinases with various cannabinoid agonists is CP-55940 > delta 9-tetrahydrocannabinol > WIN 55212.2, in agreement with the pharmacological profile of CB1. The activation of MAP kinases is blocked by pertussis toxin but not by treatment with hydrolysis-resistant cyclic AMP analogues. This suggests that the signal transduction pathway between CB1 and MAP kinases involves a pertussis-toxin-sensitive GTP-binding protein and is independent of cyclic AMP metabolism. This coupling of CB1 subtype and mitogenic signal pathway, also observed in the human astrocytoma cell line U373 MG, may explain the mechanism of action underlying cannabinoid-induced Krox-24 induction.
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PMID:Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. 852 80

The purpose of this study was to elucidate brain areas that mediate cannabinoid-induced antinociception as assessed in the tail-flick test. Intracerebroventricular administration of the prototypical cannabinoid, delta 9-tetrahydrocannabinol, and the potent bicyclic analog, CP-55,940, produced antinociception at ED50 values of 373 and 64 nmol/rat, respectively. Hypothermic and cataleptic effects also were observed after i.c.v. administration of CP-55,940, but not delta 9-tetrahydrocannabinol. In contrast, the endogenous cannabinoid, anandamide, failed to elicit any apparent pharmacological effects. Administration of CP-55,940 into the caudate putamen produced catalepsy, but failed to produce either antinociception or hypothermia. Micro-injection of CP-55,940 into the ventrolateral aspect of the periaqueductal gray (PAG), in the region of the dorsal raphe, produced antinociception (ED50 dose = 28 nmol/rat), catalepsy and hypothermia. CP-56,667, the inactive stereoisomer of CP-55,940, failed to produce any effects when injected into the same site. Additional studies demonstrated that pertussis toxin completely prevented the pharmacological effects of CP-55,940 when both agents were administered into the posterior ventrolateral PAG. In contrast, dibutyryl-cAMP failed to attenuate cannabinoid-induced antinociception. Finally, CP-55,940 administered into either the posterior dorsolateral or the anterior ventrolateral areas of the PAG was without effect. These results indicate that the antinociceptive and cataleptic effects of cannabinoids in the PAG are dose-related, exhibit regional specificity and are enantioselective. Moreover, the complete prevention of these pharmacological effects by pertussis toxin pretreatment in the PAG is consistent with the involvement of G proteins. These findings suggest that the posterior ventrolateral PAG may be an important brain area for the antinociceptive and cataleptic effects of the cannabinoids.
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PMID:Investigation of brain sites mediating cannabinoid-induced antinociception in rats: evidence supporting periaqueductal gray involvement. 863 25

Anandamide has been identified in porcine brain as an endogenous cannabinoid receptor ligand and is believed to be a counterpart to the psychoactive component of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC). Here we report that anandamide directly inhibits (IC50, 2.7 muM) Shaker-related Kv1.2 K+ channels that are found ubiquitously in the mammalian brain. Delta 9-THC also inhibited Kv1.2 channels with comparable potency (IC50, 2.4 muM), as did several N-acyl-ethanolamides with cannabinoid receptor binding activity. Potassium current inhibition occurred through a pertussis toxin-insensitive mechanism and was not prevented by the cannabinoid receptor antagonist SR141716A. Utilizing excised patches of Kv1.2 channel-rich membrane as a rapid and sensitive bioassay, we found that phospholipase D stimulated the release of an endogenous anandamide-like K+ channel blocker from rat brain slices. Structure-activity studies were consistent with the possibility that the released blocker was either anandamide or another N-acyl-ethanolamide.
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PMID:Anandamide, an endogenous cannabinoid, inhibits Shaker-related voltage-gated K+ channels. 893 28

Delta-9-tetrahydrocannabinol (THC) injection suppresses serum interleukin-12 (IL-12) levels in Legionella pneumophila-infected mice. Dendritic cells are a major producer of IL-12 and mouse, bone marrow-derived dendritic cell cultures produced high levels of the IL-12p40 following L. pneumophila infection. Treatment with THC suppressed this cytokine response in a concentration-dependent manner and the endocannabinoid, 2-arachidonoyolglycerol, less potently suppressed cytokine production. Dendritic cells expressed mRNA for cannabinoid receptor 1 (CB(1)), cannabinoid CB(2) receptor, and vanilloid receptor 1 (TRPV1) and the addition of the G(i) inhibitor, pertussis toxin, completely attenuated suppression induced by 3 and 6 muM THC but not by 10 muM THC. Furthermore, THC suppression was partially attenuated in dendritic cells from cannabinoid CB(1) receptor and CB(2) receptor knockout mice and in dendritic cells co-treated with THC and cannabinoid receptor antagonists. Cytokine suppression was not attenuated by pretreatment with the TRPV1 antagonist, capsazepine. These results suggest that THC-induced suppression of serum IL-12 is partly due to a suppression of IL-12 production by dendritic cells and that G(i) signaling and cannabinoid receptors, but not TRPV1, are involved in this suppressive effect.
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PMID:Role of cannabinoid receptors in Delta-9-tetrahydrocannabinol suppression of IL-12p40 in mouse bone marrow-derived dendritic cells infected with Legionella pneumophila. 1644 17

In the present study, we evaluated the effects of the synthetic cannabinoid receptor agonist (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN55,212-2) and the active component of Cannabis delta-9-tetrahydrocannabinol (triangle up(9)-THC) on Na(+),K(+)-ATPase activity in synaptosomal mice brain preparation. Additionally, the potential exogenous cannabinoids and endogenous opioid peptides interaction as well as the role of G(i/o) proteins in mediating Na(+),K(+)-ATPase activation were also explored. The ouabain-sensitive Na(+),K(+)-ATPase activity was measured in whole-brain pure intact synaptosomes (obtained by Percoll gradient method) of female CF-1 mice and was calculated as the difference between the total and the ouabain (1 mM)-insensitive Na(+),K(+)-ATPase activities. Incubation in vitro of the synaptosomes with WIN55,212-2 (0.1 pM-10 microM) or triangle up(9)-THC (0.1 pM-0.1 microM), in a concentration-dependent manner, stimulated ouabain-sensitive Na(+),K(+)-ATPase activity. WIN55,212-2 was less potent but more efficacious than triangle up(9)-THC. N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM-251) (10 nM), a CB(1) cannabinoid receptor selective antagonist, had not effect per se but antagonized the enhancement of Na(+),K(+)-ATPase activity induced by both, WIN55,212-2 and triangle up(9)-THC. AM-251 produced a significant reduction in the E(max) of cannabinoid-induced increase in Na(+),K(+)-ATPase activity, but did not significantly modify their EC(50). On the other hand, co-incubation with naloxone (1 microM), an opioid receptor antagonist, did not significantly modify the effect of WIN55,212-2 and completely failed to modify the effect of triangle up(9)-THC on synaptosomal Na(+),K(+)-ATPase. Finally, pre-incubation with 0.5 microg of pertussis toxin (G(i/o) protein blocker) completely abolished the enhancement of ouabain-sensitive Na(+),K(+)-ATPase activity induced by WIN55,212-2. A lower dose, 0.25 microg, decreased the E(max) of WIN55,212-2 by 70% but did not significantly affect its EC(50). These results suggest that WIN55212-2 and triangle up(9)-THC indirectly enhance Na(+),K(+)-ATPase activity in the brain by activating cannabinoid CB(1) receptors in a naloxone-insensitive manner. In addition, the effect of WIN55,212-2 on neuronal Na(+),K(+)-ATPase is apparently due to activation of G(i/o) proteins.
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PMID:Role of cannabinoid CB1 receptors and Gi/o protein activation in the modulation of synaptosomal Na+,K+-ATPase activity by WIN55,212-2 and delta(9)-THC. 1764 88


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