Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cultured ARL15 cells respond to abnormally low extracellular K+ concentrations by increasing the abundance of Na,K-ATPase (the Na/K pump). This response is preceded by significant increases in the mRNAs of the alpha 1 and beta 1 subunits of this enzyme, implying transcriptional or post-transcriptional regulation in the response. The present study concerned the possible participation of serum factors in low K+ induction of Na,K-ATPase. In normal K+ (4.5 mM) or low K+ (0.68 mM) the presence of 10% calf serum had no effect on Na,K-ATPase activity. The serum independence of the response to low K+ raised the possibility that low K+ may itself elicit a "growth" response. Accordingly, the effect of low K+ on mRNA abundances of four proto-oncogenes (c-fos, c-myc, c-jun and c-ski) was evaluated in the early phase of the response by quantitative Northern blot analysis. The mRNA for c-fos was transiently elevated by low K+, with a peak at 30 min. In contrast, low K+ had no measurable effect on the abundances of c-myc, c-jun and c-ski, for up to 2 hr of exposure. The early elevation of c-fos mRNA makes it a candidate mediator in this signal-transduction pathway. Induction of c-fos mRNA by the phorbol ester, PMA, or by dioctanoyl glycerol, however, had no effect on Na,K-ATPase activity. These results indicate that an increase in c-fos mRNA alone is not sufficient to induce Na,K-ATPase. Whether induction of c-fos is necessary for the response to low K+ remains to be determined in future studies.
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PMID:Serum independence of low K+ induction of Na,K-ATPase: possible role of c-fos. 131 15

Intracellular acidic compartments serve several functions, including uptake of nutrients, processing and sorting of secreted and membrane-bound proteins, and even entry of viruses into cells. In this study, we examined the distribution of acidic compartments in normal human keratinocytes cultured in serum-free medium. Acridine orange was used to stain acidic organelles (red fluorescence), and adherent cells were evaluated by fluorescence microscopy and by interactive laser cytometry (ILC). Keratinocytes cultured in low [Ca++] (0.15 mM) exhibited morphologic characteristics associated with basal cells; red acidic vesicles in these cells were aggregated around the nucleus, sparing the peripheral cytoplasm. After 24 h of culture in high [Ca++] (1.5 mM) keratinocytes showed morphologic changes associated with differentiated cells, including increased number and dispersal of red vesicles to the periphery of the cytoplasm. Keratinocytes cultured in 0.15 mM [Ca++], but treated with phorbol 12-myristate 13-acetate (PMA, 5-100 ng/ml) to induce terminal differentiation, developed similar features. Incubation in media with either high [Ca++] or PMA also induced radial extension of the microtubule network, suggesting that the distribution of acidic organelles occurs along this network. Finally, crude keratinocyte membranes were evaluated by radioactive assay for the presence of three ion-translocating ATPase activities, plasma membrane Na/K ATPase, mitochondrial ATPase, and vacuolar H+ pump ATPase, the latter being the activity responsible for acidification of intracellular compartments. Both basaloid and differentiated keratinocytes exhibited similar vacuolar H+ pump ATPase activity, as measured by its sensitivity to bafilomycin.
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PMID:Increased number and microtubule-associated dispersal of acidic intracellular compartments accompany differentiation of cultured human keratinocytes. 153 43

Colony stimulating factor-1 (CSF-1) stimulates DNA synthesis in quiescent murine bone marrow-derived macrophages (BMM). CSF-1 action has been shown to involve activation of the CSF-1 receptor kinase. The protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate (PMA), is itself weakly mitogenic and synergises with CSF-1 for stimulation of BMM DNA synthesis suggesting a possible role for protein kinase C in the stimulation of BMM DNA synthesis. In this report we show that several agents which raise intracellular cAMP (8-bromoadenosine 3':5'-cyclic monophosphate, 3-isobutyl-1-methylxanthine, cholera toxin, and prostaglandin E2) reversibly inhibit DNA synthesis in BMM induced by CSF-1, granulocyte macrophage-colony stimulating factor, interleukin-3, and PMA. The suppressive action of cAMP elevation on the proliferative response to CSF-1 can be manifested even late in the G1 phase of the cell cycle. Several CSF-1-stimulated earlier responses, viz. protein synthesis, Na+/H+ exchange, Na+,K(+)-ATPase and c-myc-mRNA expression, were not inhibited thus showing a striking difference from some other cellular systems involving growth factor-mediated responses. c-fos-mRNA levels were raised and stabilized by the cAMP-elevating agents, and this modulation was not altered by CSF-1. Thus, the signaling pathways in the macrophages involving tyrosine kinase and protein kinase C activation are associated with increased proliferation while those involving elevation of cAMP (and presumably activation of cAMP-dependent protein kinases) appear to have an inhibitory effect.
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PMID:Inhibition of the signaling pathways for macrophage proliferation by cyclic AMP. Lack of effect on early responses to colony stimulating factor-1. 168 93

One of the targets of free radicals and neutrophil-derived oxidants that is known to be generated during ischemic-reperfusion injury of the myocardium is the sarcolemma. We therefore examined the susceptibility of sarcolemmal Na(+)-K(+)-ATPase and ouabain binding sites to O2-., H2O2,.OH, HOCl, NH2Cl, and stimulated neutrophils. O2-. generated from xanthine oxidase action on xanthine had no significant effect on Na(+)-K(+)-ATPase activity. The inhibition of Na(+)-K(+)-ATPase activity and ouabain binding by H2O2 was dependent on concentration and the time of incubation. H2O2 (10 mM) inhibited 80% of Na(+)-K(+)-ATPase activity at 90 min..OH generated by Fenton's reagent (200 microM Fe2+ + 5 mM H2O2) significantly decreased maximum binding of ouabain (43.06 +/- 1.45 to 31.96 +/- 2.37 pmol/mg) and was significantly protected by 5 mM mannitol (P less than 0.05). The dissociation constant of ouabain binding was unaffected by Fenton's reagent or H2O2. In contrast, lower concentrations of HOCl, NH2Cl, or PMA-stimulated human neutrophils (4 X 10(6) cells/ml) had significant inhibitory effects on Na(+)-K(+)-ATPase activity. We conclude that O-2. per se is not damaging to sarcolemmal Na(+)-K(+)-ATPase activity. The formation of H2O2 and the more destructive .OH or HOCl and NH2Cl disrupt sarcolemmal function by inhibiting Na(+)-K(+)-ATPase activity and destroying ouabain binding sites.
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PMID:Sarcolemmal Na(+)-K(+)-ATPase: inactivation by neutrophil-derived free radicals and oxidants. 217 23

Treatment of T lymphoblasts with stimuli that mobilize [Ca2+]i, such as ionophores (ionomycin and A23187) and endoplasmic reticulum Ca(2+)-ATPase inhibitors (thapsigargin, 2,5-di-(tert.-butyl)-hydroquinone and cyclopiazonic acid), activated T cell binding to extracellular matrix (ECM) proteins. T lymphoblast adhesion to ECM proteins stimulated by ionomycin, thapsigargin, or PMA was inhibited by an anti-beta 1 integrin mAb (4B4), confirming the role of beta 1 integrins in regulated T cell-ECM interactions. Study of the alpha integrin subunit specificity of activated lymphoblast-fibronectin interactions demonstrated that alpha 5 beta 1 was the major integrin receptor regulating binding to fibronectin. These results indicate that intracellular Ca2+ mobilization plays a major contributory role in the activation of T cell beta 1 integrins.
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PMID:Beta 1 integrin-mediated T cell adhesion is regulated by calcium ionophores and endoplasmic reticulum Ca(2+)-ATPase inhibitors. 750 67

Rabbit lenses were bathed within a bicameral Ussing-type chamber under short-circuit conditions. In this situation the short-circuit current (Isc) reflects, across the anterior aspect, the presence of anteriorly facing K+ conductance(s) plus the Na(+)-K+ pump current. Across the posterior surface the Isc is primarily carried by the movement of Na+ from the posterior bathing solution to the lens. Addition of acetylcholine (ACh) to the posterior hemichamber did not affect the translens electrical parameters; but, its introduction to the anterior bath at 1 microM immediately reduced the Isc from 8.91 +/- 1.47 to 5.84 +/- 1.28 microA cm-2 and increased the translens resistance from 1.50 +/- 0.08 to 1.59 +/- 0.09 K omega cm2 (+/- S.E.S; P < 0.05 as paired values, n = 25 lenses). The suppressed Isc gradually recovered and reached 75% of the control value 5 min after the introduction of the neurotransmitter. In six cases the recovery was nearly complete (> or = 95% of control) within this time. The preaddition of 0.1 microM atropine prevented an effect by 1 microM ACh. When atropine was added within 1 min of ACh, the suppressed Isc immediately recovered. The ACh-elicited Isc suppression was averted in lenses pre-exposed to either K+ channel blockers (quinidine or barium) or to the endoplasmic reticular Ca(2+)-ATPase inhibitor thapsigargin (Tg: 0.1 microM), which in itself produced Isc inhibitions similar to those seen with ACh under control conditions. Similarly comparable were the ACh-evoked Isc inhibitions garnered upon introduction of the agonist to lenses bathed in the absence of extracellular Ca2+. In these cases, however, the Isc recovered fully within 2-3 min. This condition also revealed that the anterior removal of medium Ca2+ increased the Isc by about 50%, a completely reversible phenomenon; Ca2+ restoration in the presence of the Ca2+ channel blocker, nifedipine (10 microM), blunted markedly the reversal to the control Isc. Overall, these results suggest that ACh receptor activation induces the release of intracellularly stored Ca2+, which in turn leads to the temporary deactivation of a K+ conductance(s); in addition, secondary Ca2+ inflow may further extend the observed inhibition. During this study, the Isc of about 30% of the lenses used spontaneously oscillated (common duration of 30 min, with a mean peak frequency of 0.76 +/- 0.32 cycle min-1 and mean amplitude of 4.07 +/- 2.65 microA cm-2; +/- S.D.S, n = 24). Experiments attempted to determine the sensitivity of the oscillatory activity to ACh. Tg, nifedipine, and the phorbol ester PMA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Acetylcholine modulation of the short-circuit current across the rabbit lens. 755 76

Various cellular and physiological functions of plants depend on the functioning of the plasma-membrane H(+)-ATPase. The primary structure of the enzyme has recently been deduced from pma (plasma membrane H(+)-ATPase) cDNAs isolated from various higher plants. It is encoded by a multigene family including at least two major subfamilies. The pma genes are expressed in a tissue-specific manner. In addition, at least some of them are regulated at the transcriptional level. Strategies involving gene overexpression and antisense RNA have been used to obtain transgenic plants with modified PMA level. Whether individual isoforms play specific roles is discussed in the light of different experimental approaches.
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PMID:The multigene family of the H(+)-ATPase of plant plasma membranes. 759 36

The present work was designed to study the mechanism of inhibitory action of flufenamic and tolfenamic acids on the degranulation response of human polymorphonuclear leukocytes (PMNs). We have recently shown that fenamates inhibit PMN degranulation as well as other PMN functions at micromolar drug concentrations. However, the mechanism of their action remains unknown. To clarify this mechanism, the degranulation response was induced by agents known to activate different steps in the activation cascade in PMNs: the receptor-mediated activator fMLP (N-formyl-L-methionyl-L-leucyl-L-phenylalanine); a calcium ionophore (A23187); an inhibitor of calcium-ATPase (thapsigargin); and an activator of protein kinase C (phorbol myristate acetate, PMA). For comparison, SK&F 96365 (an inhibitor of receptor-mediated calcium entry), Ro 31-8220 (an inhibitor of protein kinase C) and ketoprofen (another cyclooxygenase inhibitor) were used. Flufenamic and tolfenamic acids inhibited A23187- and fMLP-induced degranulation in a dose-dependent manner. The thapsigargin-triggered response was reduced only slightly and that induced by PMA remained unaltered. The pattern of the inhibitory action of fenamates differed from those of Ro 31-8220 and ketoprofen. The action of fenamates resembled that of the inhibitor of receptor-mediated calcium entry, SK&F 96365, especially when A23187, fMLP or PMA were used to stimulate the cells. This prompted us to measure the effects of flufenamic and tolfenamic acids on receptor-mediated calcium entry. The two fenamates inhibited the fMLP-induced increase in intracellular free calcium in fura-2 loaded PMNs in the presence but not in the absence of extracellular calcium. The results suggest that the suppressive actions of fenamates on PMN degranulation are neither related to the activity of cyclooxygenase nor PMA-activated protein kinase C. In contrast, fenamates resemble the antagonist of receptor-mediated calcium entry, SK&F 96365, in their antagonistic action on PMN degranulation.
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PMID:Pharmacological control of human polymorphonuclear leukocyte degranulation by fenamates and inhibitors of receptor-mediated calcium entry and protein kinase C. 763 63

Inhibition of Na+,K(+)-ATPase activity by hyperglycemia could be an important etiological factor of chronic complications in diabetic patients. The biochemical mechanism underlying hyperglycemia's inhibitory effects has been thought to involve the alteration of the protein kinase C (PKC) pathway since agonists of PKC can normalize hyperglycemia-induced inhibition of Na+,K(+)-ATPase activity. Paradoxically, elevated glucose levels and diabetes have been shown to increase PKC activities in vascular cells. The present study tested the hypothesis that the inhibition of Na+,K(+)-ATPase activity is mediated by the sequential activation of PKC and cytosolic phospholipase A2 (cPLA2). In cultured rat vascular smooth muscle cells (VSMC), increasing glucose levels in the medium from 5.5 to 22 mM elevated cPLA2 activity and increased [3H]arachidonic acid release and PGE2 production by 2.3-, 1.7- and 2-fold, respectively. Similar increases in cPLA2 activity were also induced by elevated glucose levels in human VSMC and rat capillary endothelial cells. The activation of cPLA2 was mediated by PKC since the increases in cPLA2 phosphorylation and enzymatic activity were inhibited by the PKC inhibitor GFX. In contrast, elevation of glucose levels decreased Na+,K(+)-ATPase activity as measured by ouabain-sensitive 86Rb uptake by twofold in rat VSMC. Surprisingly, both PMA, a PKC agonist, and GFX, a PKC inhibitor, were able to prevent glucose-induced decreases in 86Rb uptake. Further, the PLA2 inhibitor AACOCF3 abolished both glucose-induced activation of cPLA2 and the decrease in 86Rb uptake. These data indicated that hyperglycemia is inhibiting Na+,K(+)-ATPase activity by the sequential activation of PKC and cPLA2, resulting in the liberation of arachidonic acid and increased the production of PGE2, which are known inhibitors of Na+,K(+)-ATPase.
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PMID:Identification of the mechanism for the inhibition of Na+,K(+)-adenosine triphosphatase by hyperglycemia involving activation of protein kinase C and cytosolic phospholipase A2. 763 66

Influenza A virus (IAV)-induced polymorphonuclear leukocyte (pMNL) dysfunction is important in causing secondary bacterial infections that lead to most influenza-related deaths. We previously showed that PMNLs exposed to IAV followed by a variety of stimuli (e.g., FMLP, PMA) demonstrate inhibition of various activation steps and endstage functions, suggesting IAV alters an early step in cell signalling. The present study examined IAV's effect on trimeric and monomeric G-proteins, since alterations of these proteins could explain IAV-induced PMNL dysfunction to various stimuli. PMNLs exposed to IAV for 30 min had decreased membrane-associated basal and high affinity guanosine triphosphatase (GTPase) activity compared with control cells. immunoblotting studies, using trimeric G-protein alpha and beta subunit-specific Abs, showed IAV decreased plasma membrane association of the trimeric G-proteins alpha subunits Gi2 and Gq by 33% +/- 5 and 46% +/- 8, respectively; binding of Gi3 and Gs was not altered. Similar studies involving monomeric G-proteins demonstrated that IAV decreased the membrane binding of rap1A (35% +/- 4), but not rac G-proteins. Corresponding increases in these IAV-altered G-proteins were detected in intracellular compartments. These data suggest the mechanism of IAV-induced PMNL dysfunction involves alterations in the binding of trimeric and monomeric G-proteins to plasma membranes.
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PMID:Decreased binding of specific monomeric and trimeric G-proteins with the plasma membrane of polymorphonuclear leukocytes exposed to influenza A virus. 765 Mar 87


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