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

R(+)WIN 55,212-2 is a synthetic cannabinoid that controls disease progression in models of multiple sclerosis. This is associated with its ability to reduce migration of leukocytes into the central nervous system. Because leukocyte migration is dependent on induction of adhesion molecules and chemokines by pro-inflammatory cytokines, we examined the effects of R(+)WIN 55,212-2 on their expression. Using 1321N1 astrocytoma and A-172 glioblastoma as cell models we show that R(+)WIN 55,212-2, but not its inactive chiral form S(-)WIN 55,212-2, strongly inhibits the interleukin-1 (IL-1) induction of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and the chemokine IL-8. This inhibition is not mediated via the CB1 or CB2 cannabinoid receptors, because their selective antagonists and pertussis toxin failed to affect the inhibitory effects of R(+)WIN 55,212-2. Furthermore reverse transcription-PCR analysis did not detect the expression of either receptor in 1321N1 cells. R(+)WIN 55,212-2 was shown to inhibit adhesion molecule and chemokine expression at the level of transcription, because it strongly inhibited the IL-1 induction of ICAM-1, VCAM-1, and IL-8 mRNAs and blocked the IL-1 activation of their promoters. The NFkappaB pathway was then assessed as a lead target for R(+)WIN 55,212-2. NFkappaB was measured by expression of a transfected NFkappaB-regulated reporter gene. Using this assay, R(+)WIN 55,212-2 strongly inhibited IL-1 activation of NFkappaB. Furthermore R(+)WIN 55,212-2 inhibited the ability of overexpressed Myd88, Tak-1, and IKK-2 to induce the reporter gene suggesting that R(+)WIN 55,212-2 acts at or downstream of IKK-2 in the IL-1 pathway. However R(+)WIN 55,212-2 failed to inhibit IL-1-induced degradation of IkappaBalpha, excluding IKK-2 as a direct target. In addition electrophoretic mobility shift and chromatin immunoprecipitation assays showed that R(+)WIN 55,212-2 does not regulate the IL-1-induced nuclear translocation of NFkappaB or the ability of the latter to bind to promoters regulating expression of ICAM-1 and IL-8. These data suggest that R(+)WIN 55,212-2 blocks IL-1 signaling by inhibiting the transactivation potential of NFkappaB.
 ...
PMID:The synthetic cannabinoid R(+)WIN 55,212-2 inhibits the interleukin-1 signaling pathway in human astrocytes in a cannabinoid receptor-independent manner. 1610 34

We have examined the effects of the cannabinoid anandamide (AEA) and its stable analog, methanandamide (methAEA), on large-conductance, Ca2+-activated K+ (BK) channels using human embryonic kidney (HEK)-293 cells, in which the alpha-subunit of the BK channel (BK-alpha), both alpha- and beta1-subunits (BK-alphabeta1), or both alpha- and beta4-subunits (BK-alphabeta4) were heterologously expressed. In a whole cell voltage-clamp configuration, each cannabinoid activated BK-alphabeta1 within a similar concentration range. Because methAEA could potentiate BK-alpha, BK-alphabeta1, and BK-alphabeta4 with similar efficacy, the beta-subunits may not be involved at the site of action for cannabinoids. Under cell-attached patch-clamp conditions, application of methAEA to the bathing solution increased BK channel activity; however, methAEA did not alter channel activity in the excised inside-out patch mode even when ATP was present on the cytoplasmic side of the membrane. Application of methAEA to HEK-BK-alpha and HEK-BK-alphabeta1 did not change intracellular Ca2+ concentration. Moreover, methAEA-induced potentiation of BK channel currents was not affected by pretreatment with a CB1 antagonist (AM251), modulators of G proteins (cholera and pertussis toxins) or by application of a selective CB2 agonist (JWH133). Inhibitors of CaM, PKG, and MAPKs (W7, KT5823, and PD-98059) did not affect the potentiation. Application of methAEA to mouse aortic myocytes significantly increased BK channel currents. This study provides the first direct evidence that unknown factors in the cytoplasm mediate the ability of endogenous cannabinoids to activate BK channel currents. Cannabinoids may be hyperpolarizing factors in cells, such as arterial myocytes, in which BK channels are highly expressed.
 ...
PMID:Activation of large-conductance, Ca2+-activated K+ channels by cannabinoids. 1610 1

Oleamide (cis-9-octadecenoamide) exhibits some cannabimimetic responses despite its low affinities at the currently known cannabinoid receptors. Here we have investigated whether or not it is a vasorelaxant in rat small mesenteric arteries. Oleamide elicited vasorelaxation (EC50=1.2+/-0.2 microM, Rmax=99.1+/-3.9%, n=8) which was reduced by endothelial removal. Nitric oxide synthase inhibition reduced the response (EC50=5.3+/-1.6 microM, Rmax=59.2+/-7.7%, n=7; P<0.01) as did blockade of Ca2+-sensitive K+ channels (KCa) with apamin plus charybdotoxin (both 50 nM) (EC50=2.1+/-0.2 microM, Rmax=58.4+/-1.9%, n=5; P<0.05). Desensitisation of vanilloid receptors with capsaicin (10 microM for 30 min) shifted the oleamide concentration-response curve approximately 30-fold to the right (n=7; P<0.01). Pertussis toxin (400 ng ml-1 for 2 h) caused a two-fold shift in the response curve (EC50=2.2+/-0.4 microM, Rmax=66.8+/-4.5%, n=6; P<0.01). Rimonabant (CB1 cannabinoid receptor antagonist; SR141716A; 3 microM) significantly inhibited relaxation induced by oleamide (EC50=3.5+/-0.3 microM, Rmax=75.1+/-1.9%; n=8; P<0.05). In contrast, neither the more selective CB1 receptor antagonist, AM251 (1 microM), nor the CB2 antagonist, SR144528 (1 microM), had significant effects. O-1918 (10 microM), a putative antagonist at a novel endothelial cannabinoid receptor (abnormal-cannabidiol site), markedly reduced the relaxation to oleamide (n=7; P<0.01). It is concluded that oleamide responses in the rat isolated small mesenteric artery are partly dependent on the presence of the endothelium, activation of Ca2+-sensitive K+ channels (KC)) and involve capsaicin-sensitive sensory nerves. Oleamide may share a receptor (sensitive to rimonabant and O-1918, and coupled to KC) and Gi/o) with anandamide in this vessel. This might be distinct from both of the known cannabinoid receptors and the novel abnormal-cannabidiol site.
 ...
PMID:Vasorelaxant effects of oleamide in rat small mesenteric artery indicate action at a novel cannabinoid receptor. 1641 7

This study aimed to investigate the function of the cannabinoid receptor in the neuromuscular junction of the frog (Rana pipiens). Miniature end-plate potentials were recorded using the intracellular electrode recording technique in the cutaneous pectoris muscle in the presence of the cannabinoid agonists WIN55212-2 (WIN; R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)]-pyrolol[1,2,3de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone) and arachidonylcyclopropylamide [ACPA; N-(2-cyclopropyl)-5Z,8Z,11Z,147-eicosatetraenamide] and the cannabinoid antagonists 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide (AM281) and 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone (AM630). Adding WIN to the external medium decreased the frequency and amplitude of the miniature end-plate potentials (MEPPs); the WIN EC50 value was 5.8+/-1.0 microM. Application of ACPA, a selective agonist of cannabinoid receptor CB1, also decreased the frequency of the MEPPs; the ACPA EC50 value was 115.5+/-6.5 nM. The CB2 antagonist AM630 did not inhibit the effects of WIN, indicating that its action is not mediated through the CB2 receptor. However, the CB1 antagonist AM281 inhibited the effects of WIN and ACPA, suggesting that their actions are mediated through the CB1 receptor. Pretreatment with the pertussis toxin inhibited the effects of WIN and ACPA, suggesting that their effects are mediated through Gi/o protein activation. The N-type Ca2+ channel blocker omega-conotoxin GVIA (omega-CgTX) diminished the frequency of the MEPPs, with an omega-CgTX EC50 value of 2.5+/-0.40 microM. Blocking the N-type Ca2+ channels with 5 microM omega-CgTX before addition of ACPA to the bath had no additional inhibitory effect on the MEPPs, whereas in the presence of 1 microM omega-CgTX, ACPA had an additional inhibition effect. These results suggest that cannabinoids modulate transmitter release in the end-plate of the frog neuromuscular junction by activating CB1 cannabinoid receptors in the nerve ending.
 ...
PMID:Effects of cannabinoids on synaptic transmission in the frog neuromuscular junction. 1726 83

The receptor(s) used by cannabinoids to relax vascular smooth muscle is unknown. Here, we investigated the effects of 2-arachidonylglyceryl ether (2-AG ether), a metabolically stable endocannabinoid, and abnormal cannabidiol (abn-CBD) on relaxation of permeabilized pulmonary arterial strips monitored with force, and on extracellular signal-regulated mitogen-activated protein kinases (ERK1/2) phosphorylation in permeabilized vascular smooth muscle cells using immunoblotting. We found that 2-AG ether and abn-CBD caused relaxation and increased phosphorylation of ERK1/2. 2-AG ether effects were completely abolished by N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251), and N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A), and partially blocked by (-)-1.3-dimethoxy-2-(3-3,4-trans-p-menthadien-(1,8)-yl)-orcinol (O-1918). In contrast, abn-CBD effects were completely abolished by O-1918, and only partially blocked by AM251, and SR141716A. Both 2-AG ether and abn-CBD effects were partially blocked by pertussis toxin, an inhibitor of Gi/o proteins. PD98059, an inhibitor of mitogen activated protein kinase kinase (MEK), completely abolished the relaxation, but only partially blocked the increased phosphorylation of ERK1/2 by 2-AG ether. In contrast, abn-CBD-induced relaxation was partially blocked and the increased phosphorylation of ERK1/2 was abolished by PD98059. These findings suggest that 2-AG ether and abn-CBD-induced vascular smooth muscle relaxation are mediated by the cannabinoid CB1 receptor, and the abn-CBD receptor, respectively, and are modulated by cross-talk between the receptors. These responses occur mainly by coupling to pertussis toxin sensitive G proteins, but also, in part independent of these G proteins, which have been classically thought to initiate MEK/ERK1/2 signaling to relax vascular smooth muscle.
 ...
PMID:2-Arachidonylglyceryl ether and abnormal cannabidiol-induced vascular smooth muscle relaxation in rabbit pulmonary arteries via receptor-pertussis toxin sensitive G proteins-ERK1/2 signaling. 1729 52

The phytocannabinoid cannabidiol (CBD) possesses no psychotropic activity amid potentially beneficial therapeutic applications. We here characterized interactions between CBD (1 microM) and the endocannabinoid system in cultured rat hippocampal cells. The CBD-induced Ca2+ rise observed in neurons and glia was markedly reduced in the presence of the endogenous cannabinoid anandamide in neurons, with no alteration seen in glia. Neuronal CBD responses were even more reduced in the presence of the more abundant endocannabinoid 2-arachidonyl glycerol, this action was maintained in the presence of the CB1 receptor antagonist AM281 (100 nM). Neuronal CBD responses were also reduced by pre-exposure to glutamate, expected to increase endocannabinoid levels by increasing in [Ca2+]i. Application of AM281 at 1 microM elevated CBD-induced Ca2+ responses in both cell types, further confirming our finding that endocannabinoid-mediated signalling is negatively coupled to the action of CBD. However, upregulation of endogenous levels of endocannabinoids via inhibition of endocannabinoid hydrolysis (with URB597 and MAFP) could not be achieved under resting conditions. Because delta9-tetrahydrocannabinol did not mimic the endocannabinoid actions, and pertussis toxin treatment had no effect on CBD responses, we propose that the effects of AM281 were mediated via a constitutively active signalling pathway independent of CB1 signalling. Instead, signalling via G(q/11) and phospholipase C appears to be negatively coupled to CBD-induced Ca2+ responses, as the inhibitor U73122 enhanced CBD responses. Our data highlight the interaction between exogenous and endogenous cannabinoid signalling, and provide evidence for the presence of an additional pharmacological target, sensitive to endocannabinoids and to AM281.
 ...
PMID:Interactions of cannabidiol with endocannabinoid signalling in hippocampal tissue. 1741 58

2-Arachidonoylglycerol is an endogenous ligand for the cannabinoid receptors (CB1 and CB2). While evidence is accumulating that the CB1 receptor plays important regulatory roles in various nervous tissues and cells, the physiological roles of the CB2 receptor, which is abundantly expressed in the immune system, are yet to be determined. In this study, we examined in detail the effect of 2-arachidonoylglycerol on the phagocytosis of opsonized zymosan by HL-60 cells that had differentiated into macrophage-like cells. We found that the addition of 2-arachidonoylglycerol augmented the phagocytosis of opsonized zymosan by the differentiated HL-60 cells. The effect was observed from 1 nM and increased with increasing concentrations of 2-arachidonoylglycerol. Treatment of the cells with SR144528 or pertussis toxin abolished the effect of 2-arachidonoylglycerol, indicating that the CB2 receptor and Gi/o are involved in the augmented phagocytosis. Phosphatidylinositol 3-kinase and extracellular signal-regulated kinase were also suggested to be involved; treatment of the cells with wortmannin or PD98059 abrogated the 2-arachidonoylglycerol-augmented phagocytosis. These results strongly suggest that 2-arachidonoylglycerol, derived from stimulated inflammatory cells, has an important role in augmenting the phagocytosis of invading microorganisms by macrophages/monocytes thereby stimulating inflammatory reactions and immune responses.
 ...
PMID:2-Arachidonoylglycerol enhances the phagocytosis of opsonized zymosan by HL-60 cells differentiated into macrophage-like cells. 1760 53

CB1 and CB2 receptors mediate most responses to cannabinoids but not some of the cardiovascular actions of endocannabinoids such as anandamide and virodhamine, or those of some synthetic agents, like abnormal cannabidiol (abn-cbd). These agents induce vasorelaxation which is antagonised by rimonabant but only at high concentrations relative to those required to block CB1 receptors. Vasorelaxation to anandamide is sensitive to Pertussis toxin (though that to abn-cbd is not), and so is thought to be mediated by a G protein-coupled receptor through Gi/o. An orphan receptor, GPR55, apparently a cannabinoid receptor, is activated by abn-cbd, but is not the receptor mediating vasorelaxation to this agent, as the response persists in vessels from GPR55 knockout mice. However, the activity of anandamide in GPR55 knockout mice is not yet reported and so the role of GPR55 as a cannabinoid receptor mediating vascular responses has yet to be finalised.
 ...
PMID:GPR55 and the vascular receptors for cannabinoids. 1770 27

The effects of the endogenous cannabinoid anandamide [arachidonylethanolamide (AEA)] on the function of nicotinic acetylcholine receptor (nAChR) were investigated using the 86Rb+ efflux assay in thalamic synaptosomes. AEA reversibly inhibited 86Rb+ efflux induced by 300 microM ACh with an IC50 value of 0.9 +/- 2 microM. Pre-treatment with the cannabinoid (CB1) receptor antagonist SR141716A (1 microM), the CB2 receptor antagonist SR144528 (1 microM), or pertussis toxin (0.2 mg/mL) did not alter the inhibitory effects of AEA, suggesting that known CB receptors are not involved in AEA inhibition of nAChRs. AEA inhibition of 86Rb+ efflux was not reversed by increasing acetylcholine (ACh) concentrations. In radioligand binding studies, the specific binding of [3H]-nicotine was not altered in the presence of AEA, indicating that AEA inhibits the function of nAChR in a non-competitive manner. Neither the amidohydrolase inhibitor phenylmethylsulfonyl fluoride (0.2 mM) nor the cyclooxygenase inhibitor, indomethacin, (5 microM) affected AEA inhibition of nAChRs, suggesting that the effect of AEA is not mediated by its metabolic products. Importantly, the extent of AEA inhibition of 86Rb+ efflux was significantly attenuated by the absence of 1% fatty acid free bovine serum albumin pre-treatment, supporting previous findings that fatty acid-like compounds modulate the activity of nAChRs. Collectively, the results indicate that AEA inhibits the function of nAChRs in thalamic synaptosomes via a CB-independent mechanism and that the background activity of these receptors is affected by fatty acids and AEA.
 ...
PMID:Endogenous cannabinoid anandamide inhibits nicotinic acetylcholine receptor function in mouse thalamic synaptosomes. 1819 36

We recently reported that Delta(9)-tetrahydrocannabinol (Delta(9)-THC) has the ability to stimulate the proliferation of human breast carcinoma MCF-7 cells. However, the mechanism of action remains to be clarified. The present study focused on the relationship between receptor expression and the effects of Delta(9)-THC on cell proliferation. RT-PCR analysis demonstrated that there was no detectable expression of CB receptors in MCF-7 cells. In accordance with this, no effects of cannabinoid 1/2 (CB1/2) receptor antagonists and pertussis toxin on cell proliferation were observed. Although MCF-7 cell proliferation is suggested to be suppressed by Delta(9)-THC in the presence of CB receptors, it was revealed that Delta(9)-THC could exert upregulation of living cells in the absence of the receptors. Interestingly, Delta(9)-THC upregulated human epithelial growth factor receptor type 2 (HER2) expression, which is known to be a predictive factor of human breast cancer and is able to stimulate cancer cells as well as MCF-7 cells. Actinomycin D-treatment interfered with the upregulation of HER2 and cell proliferation by cannabinoid. Taken together, these studies suggest that, in the absence of CB receptors, Delta(9)-THC can stimulate the proliferation of MCF-7 cells by modulating, at least in part, HER2 transcription.
 ...
PMID:Delta(9)-Tetrahydrocannabinol enhances MCF-7 cell proliferation via cannabinoid receptor-independent signaling. 1824 80


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