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:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mg2+-dependent activity of intestinal brush border guanylate cyclase was stimulated 4-5-fold by 50-100 microM hemin. Higher concentrations were inhibitory. In the presence of 25% dimethyl sulfoxide, which stimulated activity 9-times, 50 microM hemin further increased activity 1.7-fold. However, when activity was stimulated 32-fold by the Escherichia coli heat-stable enterotoxin, or 26-fold by Lubrol PX, hemin produced only concentration-dependent inhibition. The first type of activation was more sensitive to hemin than the second. Reduction of hemin by dithiothreitol eliminated stimulation of basal activity, while inhibition of Lubrol PX-stimulated activity remained. Protoporphyrin IX also had no effect on basal activity, however, it inhibited enterotoxin- and Lubrol PX-stimulated activities similarly, but only to half the extent of hemin. Substitution of Mn2+ for Mg2+ elevated basal activity 15-fold, and this Mn2+-dependent activity was inhibited by hemin. Mn2+-dependent activity was stimulated (43%) by enterotoxin, however, the stimulated activity was more sensitive to hemin inhibition than the basal Mn2+-dependent activity and both inhibition curves were congruent above 50 microM hemin. Hemin inhibition of Lubrol PX-stimulated activity was much less with Mn2+ than with Mg2+. These results were interpreted as suggesting two sites of hemin inhibition; on an inhibitory regulator and on the enzyme. We also found that the secretory effect of enterotoxin in the suckling mouse bioassay was reduced 56% by the oral administration of hemin.
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PMID:Regulation of intestinal mucosa guanylate cyclase by hemin, heme and protoporphyrin IX. 288 83

Challenge of guinea pig mast cells with antigen under aerobic conditions induced the expected release of histamine and led to a significant increase in intracellular calcium ([Ca2+]i) and cyclic adenosine monophosphate (cAMP) levels. Prior exposure to CO decreased the immunological histamine release. This effect was accompanied by a decrease in the levels of [Ca2+]i and by an increase in the cyclic guanosine monophosphate (cGMP) levels. The exposure of mast cells to nitrogen (N2) did not modify the release of histamine. The CO-mediated inhibition of the immunological release of histamine was reversed by the soluble guanylate cyclase inhibitor (1 H-[1.2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ) and by oxyhaemoglobin (HbO2). Incubation of mast cells for 4 h with hemin, a heme oxygenase (HO) inducer, resulted in an increase in HO activity, measured as bilirubin production. Hemin abated the immunological release of histamine, in similar fashion to exogenous CO, and increased the cGMP levels. These effects were reversed by ODQ and HbO2. It is proposed that CO from an exogenous or endogenous source stimulates guanylyl cyclase and causes cGMP formation which then induces calcium to be sequestrated so that the [Ca2+]i concentration falls and histamine release is inhibited.
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PMID:Modulation of the immunological response of guinea pig mast cells by carbon monoxide. 1043 58

Within the central nervous system, acetylcholine (ACh) functions as a state-dependent modulator at a range of sites, but its signaling mechanisms are yet unclear. Cholinergic projections from the brain stem and basal forebrain innervate the suprachiasmatic nucleus (SCN), the master circadian clock in mammals, and cholinergic stimuli adjust clock timing. Cholinergic effects on clock state require muscarinic receptor-mediated activation of guanylyl cyclase and cGMP synthesis, although the effect is indirect. Here we evaluate the roles of carbon monoxide (CO) and nitric oxide (NO), major activators of cGMP synthesis. Both heme oxygenase 2 (HO-2) and neuronal nitric oxide synthase (nNOS), enzymes that synthesize CO and NO, respectively, are expressed in rat SCN, with HO-2 localized to the central core of the SCN, whereas nNOS is a punctate plexus. Hemin, an activator of HO-2, but not the NO donor, SNAP, mimicked cholinergic effects on circadian timing. Selective inhibitors of HO fully blocked cholinergic clock resetting, whereas NOS inhibition partially attenuated this effect. Hemoglobin, an extracellular scavenger of both NO and CO, blocked cholinergic stimulation of cGMP synthesis, whereas l-NAME, a specific inhibitor of NOS, had no effect on cholinergic stimulation of cGMP, but decreased the cGMP basal level. We conclude that basal NO production generates cGMP tone that primes the clock for cholinergic signaling, whereas HO/CO transmit muscarinic receptor activation to the cGMP-signaling pathway that modulates clock state. In light of the recently reported inhibitory interaction between HO-2/CO and amyloid-beta, a marker of Alzheimer's disease (AD), we speculate that HO-2/CO signaling may be a defective component of cholinergic neurotransmission in the pathophysiology of AD, whose manifestations include disintegration of circadian timing.
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PMID:Carbon monoxide and nitric oxide: interacting messengers in muscarinic signaling to the brain's circadian clock. 1157 81

Reactive oxygen species (ROS) increase the contractile response of airway smooth muscle (ASM). Heme oxygenase (HO) catabolizes heme to the powerful antioxidant bilirubin. Because HO is expressed in the airways, we investigated its effects on ASM contractility and ROS production in guinea pig trachea. HO expression was higher in the epithelium than in tracheal smooth muscle. Incubation of tracheal rings (TR) with the HO inhibitor tin protoporphyrin (SnPP IX) or the HO substrate hemin increased and decreased, respectively, ASM contractile response to carbamylcholine. The effect of hemin was reversed by SnPP and mimicked by the antioxidants superoxide dismutase (SOD) and catalase. Hemin significantly reduced the effect of carbamylcholine in rings treated with the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), compared with ODQ-treated rings without hemin incubation, suggesting that the CO-guanosine 3',5'-cyclic monophosphate pathway was not involved in the control of tracheal reactivity. SnPP and hemin increased and decreased ROS production by TR by 18 and 38%, respectively. Bilirubin (100 pM) significantly decreased TR contractility and ROS production. Hemin, bilirubin, and SOD/catalase decreased phosphorylation of the contractile protein myosin light chain, whereas SnPP significantly augmented it. These data suggest that modulation of the redox status by HO and, moreover, by bilirubin modulates ASM contractility by modulating levels of phosphorylated myosin light chain.
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PMID:Heme oxygenase modulates oxidant-signaled airway smooth muscle contractility: role of bilirubin. 1216 79

The aim of the present study was to determine whether cobalt poisoning induces haem oxidase isoenzyme-1 (HO-1) in coronary artery smooth muscle, or accounts for any changes in coronary smooth muscle cell (SMCs) membrane ionic currents that could result from this type of heavy metal poisoning. In SMCs isolated from cobalt-treated guinea-pig coronaries, K+ channel currents (IK) were much smaller than those in cells isolated from non-treated animals. Haemin (HO substrate) increased IK concentration dependently. This effect was mimicked by 1% CO and was abolished by pretreatment of cells with a competitive HO inhibitor, by inhibitors of guanylyl cyclase, protein kinase G or phospholipase C, as well as by blocking inositol trisphosphate-dependent Ca release, or sarcoplasmic reticulum Ca-ATPase, or by bathing cells in Ca-free external solution. Expression of the Na/Ca exchanger-1 (NCX-1) protein was reduced substantially in SMCs from coronary arteries of cobalt-treated animals. No expression of HO-1 was detected. It is concluded that acute cobalt poisoning in vivo depresses Ca-sensitive K currents via CO-dependent modulation of intracellular calcium availability, most probably by suppressing the expression of NCX-1 protein.
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PMID:Calcium-dependent changes in potassium currents in guinea-pig coronary artery smooth muscle cells after acute cobalt loading in vivo. 1534 Aug 49

Hemin (10 microM) and carbon monoxide (CO) increased iberiotoxin-blockable IKCa in portal vein smooth muscle cells. CO-induced IKCa activation was abolished by 10 microM ODQ, 10 microM cyclopiazonic acid and 1 microM KT5823. The hemin-induced effect on IKCa was abolished by pretreatment with Sn-protoporphyrin IX, a heme oxygenase inhibitor and Fe2+ chelator but was insensitive to inhibitors of soluble guanylate cyclase (GC) and cGMP-dependent protein kinase (PKG). There was no effect of hemin on IKCa in the presence of 3 microM dithiotreitol into the bath or 3 mM glutathione into the pipette solution. Superoxide dismutase (1000 U/ml) or catalase (3000 U/ml) added into the pipette solution also abolished the effect of hemin on IKCa in this tissue. Additionally, 10 microM hemin could not influence IKCa in Ca2+-free external solution or in the presence of 30 microM SKF 95356. It was concluded that CO increases IKCa via its "conventional" signaling pathway, which involves soluble GC and PKG activation and subsequent stimulation of sarcoplasmic reticulum Ca2+ pump activity resulting in Ca2+-dependent activation of IKCa due to the accumulation of Ca2+ into the space near the plasma membrane. On the other hand, internally produced CO could not yield the same IKCa increase, while Fe2+ derived from heme oxygenase 2-dependent degradation of hemin in portal vein smooth muscle cells gives rise to reactive oxygen species namely hydroxyl and superoxide radicals. Both radicals are responsible for the SKF 95356-sensitive non-selective cation channel activation, the Ca2+ influx and the subsequent increase of Ca2+ concentration near the plasma membrane that augments the KCa channel activity.
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PMID:Heme oxygenase-2 products activate IKCa: role of CO and iron in guinea pig portal vein smooth muscle cells. 1554 71

Enterocytes maintain fluid-electrolyte homeostasis by keeping a tight barrier and regulating ion channels. Carbon monoxide (CO), a product of heme degradation, modulates electrolyte transport in kidney and lung epithelium, but its role in regulating intestinal fluid-electrolyte homeostasis has not been studied. The major source of endogenous CO formation comes from the degradation of heme via heme oxygenase. We hypothesized that heme activates electrolyte transport in intestinal epithelial cells. Basolateral hemin treatment increased baseline Caco-2 cell short-circuit currents (I(sc)) twofold (control = 1.96 +/- 0.14 microA/cm(2) vs. hemin = 4.07 +/- 0.16 microA/cm(2), P < 0.01); apical hemin had no effect. Hemin-induced I(sc) was caused by Cl- secretion because it was inhibited in Cl- -free medium, with ouabain, 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), or DIDS. Apical electrogenic Na+ channel inhibitor benzamil had no effect on hemin-induced I(sc). Hemin did not alter the ability of Caco-2 cells to respond maximally to forskolin, but a soluble guanylate cyclase inhibitor, [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) inhibited the effects of hemin. A CO-releasing molecule, tricarbonyldichlororuthenium II, induced active Cl- secretion that was also inhibited with ODQ. We conclude that hemin induces active Cl- secretion in Caco-2 cells via a cGMP-dependent pathway. These effects are probably the consequence of CO formation. Heme and CO may be important regulators of intestinal fluid-electrolyte homeostasis.
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PMID:Hemin induces active chloride secretion in Caco-2 cells. 1580

It has been proposed that the inducible isoform of heme oxygenase (HO) protects cells against oxidant-mediated injury. Although components of Agastache rugosa showed antioxidant effect, it is unclear this effect is related with HO-1 activity. Thus, we investigated the effects of Agastache rugosa leaf extract (ALE) on HO-1 protein expression and enzyme activity, and its protective effect against H(2)O(2)-induced oxidative damage was also investigated using RAW264.7 macrophage cells. Results showed that ALE concentration dependently increased HO-1 protein and enzyme activity, and protected cells from H(2)O(2)-induced cytotoxicity, with an IC(50) of 0.526 mg/ml. Hemin, a HO-1 inducer, also showed similar effect to ALE. Furthermore, the protective effect of both ALE and hemin was inhibited by a HO inhibitor, zinc protoporphyrin IX. The expression of HO-1 protein by ALE was reduced by pretreatment with LY83583 and ODQ, specific inhibitors of guanylate cyclase, but not by PKA inhibitors, H89 and KT5720, indicating that PKG signaling pathway regulates HO-1 induction by ALE. Taken together, it is concluded that PKG-dependent HO-1 induction is one of the important antioxidant mechanisms by which ALE protects RAW264.7 cells from H(2)O(2). Thus, ALE along with other actions may be beneficial for the treatment of oxidant-induced cellular injuries.
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PMID:Protein kinase G-dependent heme oxygenase-1 induction by Agastache rugosa leaf extract protects RAW264.7 cells from hydrogen peroxide-induced injury. 1618 32

We have studied the influence of nitric oxide (NO) and carbon monoxide (CO), putative messenger molecules in the brain as well as in the islets of Langerhans, on glucose-stimulated insulin secretion and on the activities of the acid alpha-glucoside hydrolases, enzymes which we previously have shown to be implicated in the insulin release process. We have shown here that exogenous NO gas inhibits, while CO gas amplifies glucose-stimulated insulin secretion in intact mouse islets concomitant with a marked inhibition (NO) and a marked activation (CO) of the activities of the lysosomal/vacuolar enzymes acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase (acid alpha-glucoside hydrolases). Furthermore, CO dose-dependently potentiated glucose-stimulated insulin secretion in the range 0.1-1000 microM. In intact islets, the heme oxygenase substrate hemin markedly amplified glucose-stimulated insulin release, an effect which was accompanied by an increased activity of the acid alpha-glucoside hydrolases. These effects were partially suppressed by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one. Hemin also inhibited inducible NO synthase (iNOS)-derived NO production probably through a direct effect of CO on the NOS enzyme. Further, exogenous CO raised the content of both cGMP and cAMP in parallel with a marked amplification of glucose-stimulated insulin release, while exogenous NO suppressed insulin release and cAMP, leaving cGMP unaffected. Emiglitate, a selective inhibitor of alpha-glucoside hydrolase activities, was able to markedly inhibit the stimulatory effect of exogenous CO on both glucose-stimulated insulin secretion and the activityof acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase, while no appreciable effect on the activities of other lysosomal enzyme activities measured was found. We propose that CO and NO, both produced in significant quantities in the islets of Langerhans, have interacting regulatory roles on glucose-stimulated insulin secretion. This regulation is, at least in part, transduced through the activity of cGMP and the lysosomal/vacuolar system and the associated acid alpha-glucoside hydrolases, but probably also through a direct effect on the cAMP system.
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PMID:Nitric oxide inhibits, and carbon monoxide activates, islet acid alpha-glucoside hydrolase activities in parallel with glucose-stimulated insulin secretion. 1700 69

Hemin, a heme oxygenase-1 (HO-1) inducer, was shown to exert numerous beneficial physiological functions in animals. Our previous study suggests that HO-1/carbon monoxide (CO) acts as a novel downstream signal system in the auxin-induced adventitious rooting. The objective of this study was to test whether nitric oxide (NO) is involved in hemin-induced cucumber adventitious rooting. Applications of hemin or CO aqueous solution to auxin-depleted cucumber explant induced up-regulation of cucumber HO-1 transcripts (CsHO1), NO production, and thereafter adventitious root formation, and some above responses were blocked by the combination treatment with two nitric oxide synthase (NOS)-like enzyme inhibitors N(G)-nitro-L-arginine methylester hydrochloride and N(G)-nitro-L-arginine, a HO-1 specific inhibitor zinc protoporphyrin IX, and a specific NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide potassium salt. However, these blocking responses were not observed using tungstate, an inhibitor of nitrate reductase, another NO producing enzyme in plants. Furthermore, the guanylate cyclase inhibitors 1H-(1,2,4)-oxadiazole[4,3-a]quinoxalin-1-one and 6-anilino-5,8-quinolinedione reduced root development induced by hemin, whereas the cell-permeable cyclic guanosine monophosphate (cGMP) derivative 8-Br-cGMP reversed this effect. Together, our results indicated that at least in our experimental conditions, NO might operate downstream of hemin promoting adventitious root formation probably in a cGMP-dependent manner.
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PMID:Nitric oxide is involved in hemin-induced cucumber adventitious rooting process. 2257 58


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