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 effects of hepoxilin A3 (HxA3), a 12-lipoxygenase metabolite of arachidonic acid, on cytosolic calcium ([Ca2+]i), intracellular pH (pHi), transmembrane potential and right-angle light scattering in human neutrophils were investigated. A rapid, transient elevation of [Ca2+]i was observed with HxA3 which was dependent on the concentration used. The effect of HxA3 on [Ca2+]i was blocked by pertussis toxin, suggesting involvement of receptors coupled to GTP-binding proteins. Experiments in Ca2(+)-free medium and using intracellular Ca2+ chelators indicated that HxA3 mobilized Ca2+ from intracellular stores. At similar concentrations, HxA3 altered pHi, producing an initial acidification followed by an alkalinization. The initial acidification was decreased in cells loaded with a Ca2+ chelator. In the presence of N-ethyl-N-(1-methylethyl)amino amiloride, an inhibitor of the Na+/H+ antiport, HxA3 induced a greater acidification but failed to elicit the recovery phase, suggesting that the latter is due to activation of the antiport. HxA3 also depolarized the membrane potential, although this effect was small. A decrease in right-angle light scattering, qualitatively similar to that observed with chemotactic peptides, was seen with HxA3, indicating that the 12-lipoxygenase metabolite can induce shape changes in neutrophils. At the concentrations used for the above effects, HxA3 was unable to generate a respiratory burst. These findings suggest that hepoxilins, which are formed by stimulated neutrophils, may have a role as messengers in neutrophil activation.
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PMID:Hepoxilin A3 induces changes in cytosolic calcium, intracellular pH and membrane potential in human neutrophils. 210 77

The neurotransmitters histamine, dopamine and the peptide Phe-Met-Arg-Phe-NH2 (FMRFa) cause presynaptic inhibition in the nervous system of the marine mollusk Aplysia Californica by combined down-modulation of a Ca++ conductance and up-modulation of a K+ conductance. The action of FMRFa on the S-type K+ channels of Aplysia sensory neurons is mediated by a metabolite of the 12-lipoxygenase pathway of arachidonic acid, possibly 12-HPETE. A Pertussis toxin-sensitive GTP binding protein couples FMRFa receptor to the activation of the arachidonic cascade. Once produced, 12-HPETE does not require ATP- or GTP-dependent processes to act on the K+ channels, but it may directly modulate the channel via an external membrane receptor. Based on this observation, a role for eicosanoids as possible intercellular messengers in the C.N.S. is discussed.
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PMID:Arachidonic acid metabolites as mediators of synaptic modulation. 256 69

The potential mechanisms of angiotensin II (ANG II)-induced mitogenesis were studied in a Chinese hamster ovary fibroblast cell line overexpressing the rat vascular type 1a ANG II receptor (CHO-AT1a). ANG II had potent mitogenic effects in these CHO-AT1a cells, leading to a sustained increase in cell number as well as a dose-dependent increase in DNA synthesis. ANG II treatment also induced a biphasic elevation of mitogen-activated protein (MAP) kinase activity of both p42MAPK and p44MAPK with a rapid early peak at 5 min (2- to 6-fold) followed by a second sustained increase that reached a peak at 3 h (1.5- to 3-fold). We have previously shown that the 12-lipoxygenase (12-LO) pathway of arachidonate metabolism plays a key role in ANG II-induced growth of vascular smooth muscle and adrenal cells. In the present study, ANG II (10(-7) M) increased the formation of the 12-LO product, 12-hydroxyeicosatetraenoic acid (12-HETE). ANG II-induced DNA synthesis was inhibited by a specific LO inhibitor, cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (CDC, 10 microM). In contrast, a cyclooxygenase blocker of arachidonate metabolism such as ibuprofen had no effect on ANG II-induced DNA synthesis. ANG II-induced DNA synthesis was also partially (32%) blocked by pertussis toxin (PTX). CDC and PTX also selectively blocked only the late (3 h) peak of ANG II-induced MAP kinase activity, suggesting that the late sustained peak of MAP kinase activity may be linked to the mitogenic effect of ANG II. Direct addition of 12-HETE (10(-7) M) led to a sustained increase in cell number similar to the effect of ANG II. 12-HETE also caused an increase in MAP kinase activity, and 12-HETE effects were blocked by PTX. These results suggest that ANG II-induced mitogenic response is associated with sustained MAP kinase activation and that LO activation may play a key role in this process.
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PMID:Mechanisms of ANG II-induced mitogenic responses: role of 12-lipoxygenase and biphasic MAP kinase. 889 27

The inhibition of adenylyl cyclase (AC) by a 12-lipoxygenase metabolite of arachidonic acid, 12(S)-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12-HETE), was investigated using three different kinds of cells: NRK-49F (normal rat kidney fibroblasts), AtT-20 (mouse pituitary tumor cell line) and HL-60 (human leukemia cells) cells. The inhibition was very obvious in NRK-49F and AtT-20 cells, but it was almost negligible in HL-60 cells. There was no difference in terms of the binding of 12-HETE to NRK-49F and HL-60 cells. Pretreatment of NRK-49F cells with pertussis toxin almost completely ADP-ribosylated Gi proteins, but it did not affect the inhibition of 12-HETE on AC in this cell. This result excludes the involvement of Gi proteins in 12-HETE-mediated inhibition of AC. It was revealed that the characteristics of ACs in these cells were quite different in response to agonists and forskolin, suggesting that these cells do have different isoform of AC. We conclude that 12-HETE inhibits the activity of AC depending upon the isoform.
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PMID:Inhibition of adenylyl cyclases by 12(S)-hydroxyeicosatetraenoic acid. 891 39

In earlier reports and reviews, it was suggested that unlike its methyl ester, the free acid form of the 12-lipoxygenase-derived eicosanoid hepoxilin A3 (HXA3) does not enter neutrophils and other cells. Therefore, in the past, most studies on the biological activities of HXA3 on human neutrophils were conducted with its methyl ester. Here, we present evidence that free HXA3 is biologically active towards human neutrophils at submicromolar concentrations, which may occur under certain circumstances in vivo. Thus, HXA3 caused chemotaxis at concentrations as low as 30-40 nM, an effect which was attenuated at higher concentrations of this eicosanoid. Its chemotactic potency proved to be comparable to that of leukotriene B4, but higher than that of the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (fMLP), and greatly exceeded that of the other 12-lipoxygenase metabolite, 12(S)-hydroxy-5,8,10,14-eicosatetraenoic acid, which was inactive at comparable concentrations. The chemotactic activity of HXA3 was not abolished by serum albumin, but it was suppressed by pertussis toxin. Unlike fMLP, at this concentration range HXA3 did not cause respiratory burst or aggregation of the neutrophils or activation of protein kinase C. These observations suggest a remarkably selective and specific receptor-mediated process. At concentrations higher than 1 microM, HXA3 gives rise to an instantaneous release of calcium from intracellular stores which causes, however, only a slight, if any, liberation of arachidonic acid. On the other hand, pretreatment of the neutrophils with submicromolar concentrations of HXA3 significantly blunts the liberation of arachidonic acid caused by fMLP.
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PMID:Biological actions of the free acid of hepoxilin A3 on human neutrophils. 1064 52