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)

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.
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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.
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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.
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PMID:Effects of cannabinoids on synaptic transmission in the frog neuromuscular junction. 1726 83

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.
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PMID:2-Arachidonoylglycerol enhances the phagocytosis of opsonized zymosan by HL-60 cells differentiated into macrophage-like cells. 1760 53

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.
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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

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.
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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.
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PMID:Endogenous cannabinoid anandamide inhibits nicotinic acetylcholine receptor function in mouse thalamic synaptosomes. 1819 36

Endocannabinoids are involved in synaptic signaling and neuronal protection; however, our understanding of the mechanisms by which endocannabinoids protect neurons from harmful insults remains elusive. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid and a full agonist for cannabinoid receptors (CB1 and CB2), is a substrate for cyclooxygenase-2 (COX-2) and can be metabolized by COX-2. Here we show, however, that 2-AG is also capable of suppressing elevation of hippocampal COX-2 expression in response to proinflammatory and excitotoxic stimuli. 2-AG prevents neurodegeneration from toxic assaults that elevate COX-2 expression and inhibits the COX-2 elevation-enhanced excitatory glutamatergic synaptic transmission. The action of 2-AG on suppression of COX-2 appeared to be mediated via the pertussis toxin-sensitive G protein-coupled CB1 receptor and MAPK/NF-kappaB signaling pathways. Our results reveal that 2-AG functions as an endogenous COX-2 inhibitor protecting neurons from harmful insults by preventing excessive expression of COX-2, which provides a mechanistic basis for opening up new therapeutic approaches for protecting neurons from inflammation- and excitotoxicity-induced neurodegeneration.
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PMID:Endocannabinoid 2-arachidonoylglycerol protects neurons by limiting COX-2 elevation. 1853 82

We have shown that the major active agent of Cannabis sativa, Delta(9)-tetrahydrocannabinol, activates peroxisome proliferator-activated receptor gamma [PPARgamma, O'Sullivan, S.E., Tarling, E.J., Bennett, A.J., Kendall, D.A., Randall, M.D., 2005c. Novel time-dependent vascular actions of delta9-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma. Biochem. Biophys. Res. Commun. 337, 824-831]. The aim of the present study was to investigate whether another pharmacologically active phytocannabinoid, cannabidiol, similarly activates PPARgamma. Functional vascular studies were carried out in rat aortae in vitro by myography. PPARgamma activation was investigated using reporter gene assays, a PPARgamma competition-binding assay and an adipogenesis assay. Cannabidiol caused time-dependent (over 2 h) vasorelaxation of pre-constricted aortae, sensitive to PPARgamma antagonism (GW9662, 1 microM) and super oxide dismutase inhibition. The vascular effects of cannabidiol were not affected by endothelial denudation, nitric oxide synthase inhibition, pertussis toxin, cannabinoid CB1 or cannabinoid CB2 receptor antagonism, or capsaicin pre-treatment. When aortae were contracted with U46619 in a Ca2+-free buffer, vasorelaxation to cannabidiol was substantially reduced. Furthermore, cannabidiol (1-30 microM) inhibited the contractile response to the re-introduction of Ca2+. In a reporter gene assay, cannabidiol increased the transcriptional activity of PPARgamma. Cannabidiol was also found to bind to PPARgamma and stimulate the differentiation of 3T3-L1 fibroblasts into adipocytes, a PPARgamma-mediated response. These results show that cannabidiol binds to and activates PPARgamma, which partially underlies the time-dependent vascular effects of cannabidiol. However, cannabidiol-induced vasorelaxation in the rat isolated aorta appears to be largely due to calcium channel inhibition.
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PMID:Time-dependent vascular actions of cannabidiol in the rat aorta. 1928 60

CB2 is a Gi protein-coupled receptor activated by endo- and phytocannabinoids, thus inhibiting stimulated adenylyl cyclase activity. CB2 is expressed in bone cells and Cb2 null mice show a marked age-related bone loss. CB2-specific agonists both attenuate and rescue ovariectomy-induced bone loss. Activation of CB2 stimulates osteoblast proliferation and bone marrow derived colony-forming units osteoblastic. Here we show that selective and nonselective CB2 agonists are mitogenic in MC3T3 E1 and newborn mouse calvarial osteoblastic cultures. The CB2 mitogenic signaling depends critically on the stimulation of Erk1/2 phosphorylation and de novo synthesis of MAP kinase-activated protein kinase 2 (Mapkapk2) mRNA and protein. Further downstream, CB2 activation enhances CREB transcriptional activity and cyclin D1 mRNA expression. The CB2-induced stimulation of CREB and cyclin D1 is inhibitable by pertussis toxin, the MEK-Erk1/2 inhibitors PD098059 and U0126, and Mapkapk2 siRNA. These data demonstrate that in osteoblasts CB2 targets a Gi protein-cyclin D1 mitogenic axis. Erk1/2 phosphorylation and Mapkapk2 protein synthesis are critical intermediates in this axis.
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PMID:CB2 cannabinoid receptor targets mitogenic Gi protein-cyclin D1 axis in osteoblasts. 2080 55


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