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)

The cellular cGMP content increased in response to a variety of receptor agonists, which activate [e.g., prostaglandin (PG) E1, E2, and F2 alpha] or inhibit (e.g., alpha-adrenergic, muscarinic, and opiate agonists) adenylate cyclase in neuroblastoma X glioma hybrid NG108-15 cells. The responses were additive when PGF2 alpha and enkephalin were mixed. The inhibitory guanine nucleotide regulatory protein (Ni) is involved in adenylate cyclase inhibition; this function of Ni is lost when it is ADP-ribosylated by islet-activating protein (IAP), pertussis toxin [H. Kurose, T. Katada, T. Amano, and M. Ui (1983) J. Biol. Chem. 258, 4870-4875]. The cGMP rise induced by stimulation of the receptors linked to adenylate cyclase inhibition was also diminished by IAP; the time course and dose response for the IAP-induced diminution were the same between adenylate cyclase inhibition and cGMP generation. Ni thus appears to mediate guanylate cyclase activation as well as adenylate cyclase inhibition initiated via the same receptors. Melittin also increased cGMP. No additivity was shown when enkephalin and melittin were combined, suggesting that phospholipase A2 might play a role in Ni-mediated guanylate cyclase activation. On the other hand, the PGF2 alpha-induced cGMP rise was associated with increased incorporation of 32Pi into phosphatidylinositol; was not affected by cholera toxin, IAP or forskolin; and showed no additivity when combined with A23187, which increased cGMP by itself. PGs would occupy receptors linked to phosphatidylinositol breakdown, thereby increasing the availability of intracellular Ca2+, which is responsible for guanylate cyclase activation. Thus, dual pathways are proposed for a receptor-mediated cGMP rise in NG108-15 cells.
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PMID:Dual pathways of receptor-mediated cyclic GMP generation in NG108-15 cells as differentiated by susceptibility to islet-activating protein, pertussis toxin. 298 51

Some enteric strains of Escherichia coli release a heat-stable enterotoxin which, in contrast to cholera and heat-labile E. coli enterotoxins, stimulates guanylate cyclase (GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2). We have examined the tissue spcificity of its action and the relation of its action to those of the 8-bromo analogues of cyclic GMP and cyclic AMP. Heat-stable enterotoxin stimulated guanylate cyclase activity and increased cyclic GMP concentration throughout the small and large intestine. It increased transepithelial electric potential difference and short-circuit current in the jejunum, ileum and caecum but not in the duodenum or distal colon. This pattern of electrical responses was mimicked by 8-bromo-cyclic GMP. However, 8-bromo-cyclic AMP produced an electrical response in all intestinal segments. The enterotoxin failed to stimulate guanylate cyclase inliver, lung, pancreas or gastric antral mucosa. In the intestines, it stimulated only the particulate and not the soluble form of the enzyme. Preincubation of the toxin with intestinal membranes did not render it capable of stimulating pancreatic guanylate cyclase. Cytosol factors did not enhance the toxin's stimulation of intestinal guanylate cyclase. This study supports the role of cyclic GMP as intracellular mediator for heat-stable enterotoxin and suggests that the toxin affects a membrane-mediated mechanism for guanylate cyclase activation that is unique to the intestines.
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PMID:Mode of action of heat-stable Escherichia coli enterotoxin. Tissue and subcellular specificities and role of cyclic GMP. 610 8

Subcutaneously administered chlorpromazine reduced intestinal fluid accumulation induced by Escherichia coli heat-stable enterotoxin in infant mice. The antisecretory effect of chlorpromazine, although dose related, was, even with high doses, less than that observed with respect to cholera toxin. Whereas 100 micrograms chlorpromazine abolished cholera toxin-induced intestinal secretion almost completely, 500 microgram chlorpromazine (equivalent to 200 microgram/g body wt) lowered secretion induced by heat-stable enterotoxin by only 41%. The effect of chlorpromazine on intestinal secretion was quantitatively similar regardless of whether heat-stable enterotoxin or the cyclic GMP analogue, 8-Br-cyclic GMP, was the secretagogue. This finding, which suggested that the inhibitory effect of chlorpromazine on heat-stable enterotoxin was independent of guanylate cyclase, was confirmed by assaying this enzyme in intestinal homogenates from mice that had been inoculated with chlorpromazine, and also in experiments in which chlorpromazine was added to guanylate cyclase assay mixtures in vitro. Caution is advised before chlorpromazine is routinely adopted for the treatment of all syndromes of watery diarrhea.
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PMID:Effect of chlorpromazine on intestinal secretion mediated by Escherichia coli heat-stable enterotoxin and 8-Br-cyclic GMP in infant mice. 610 96

Recent studies have added important new information to our understanding of the pathogenesis and ethiology of diarrheal disease. Vibrio cholerae produces a heat-labile enterotoxin, affecting cyclic AMP. A very similar heat-labile enterotoxin is produced also by certain strains of Escherichia coli, as well as by Citrobacter, Klebsiella, and Aeromonas. E. coli may also produce a heat-stable enterotoxin, stimulating guanylate cyclase activity. In order to produce the pathologic effects, E. coli first attaches to epithelial cells of the intestinal tract by means of pili or surface antigens. Enterotoxin can be demonstrated by both in vivo and in vitro tests, but none are yet suitable for routine diagnostic laboratories. A third mechanism whereby E. coli causes diarrheal disease consists of enteroinvasiveness. Campylobacter, Yersinia, and Clostridium difficile have been added to the list of enteric pathogens of man.
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PMID:Enteropathogenicity: recent developments. 612 11

A simple assay for the heat-stable enterotoxin (ST) of Escherichia coli was developed on the basis of ST activation of guanylate cyclase in membranes from the intestinal mucosa of mice. ST activated guanylate cyclase in mucosal membranes in a linear fashion over a 50-fold range of toxin concentrations with Mg++-guanosine 5'-triphosphate as substrate. Activation of guanylate cyclase was detectable at concentrations of ST that were five- to 10-fold lower than those resulting in increases in the ratio of gut weight to carcass weight of mice. This assay was used to quantify ST in crude and purified samples from culture filtrates of wild-type strains and recombinant strains of E coli containing the gene for ST. Activation of guanylate cyclase was specific for ST; purified cholera toxin and E coli heat-labile enterotoxin did not activate guanylate cyclase. Thus, this assay for ST is sensitive, specific, and will facilitate rapid analysis of samples for quantification of ST.
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PMID:A simple, sensitive, and specific assay for the heat-stable enterotoxin of Escherichia coli. 614 Dec 7

Escherichia coli heat-stable enterotoxin is a low-molecular-weight substance that has been shown to induce the active secretion of fluid and electrolytes in the small intestine. In this study, we have characterized the effects of purified E. coli heat-stable toxin (ST, strain 18D, serotype 042:K86:H37) on the motility of rabbit small intestine by using myoelectric recording techniques. Substances, such as cholera toxin, that activate the adenylate cyclase-cAMP system induced predominantly migrating action-potential complex activity. E. coli ST, a toxin that activates the guanylate cyclase-cGMP system, was infused into isolated in vivo ileal loops of New Zealand White rabbits. Inactivated toxin was also studied by exposing the ST to 1 mM dithiothreitol for 90 min. Active E. coli ST induced only repetitive bursts of action potentials. When the toxin was inactivated with dithiothreitol, no alteration in myoelectric activity was observed. We speculate that repetitive bursts of action-potential activity may represent a virulent factor of the bacterium, altering motor activity to slow transit and allowing for bacterial proliferation and invasion.
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PMID:Escherichia coli heat-stable toxin: its effect on motility of the small intestine. 627 61

Recent experimental results from our laboratories revealed the following facts: Addition of GMP to homogenates or cytosol prepared from endometrial tissue or cultured endometrial adenocarcinoma cells during the assay for specific estrogen binders markedly increases specific binding levels. The effect is completed in about 15 min at 4 C (Fleming et al, 1983). Cyclic AMP has the opposite effect and in many cases lowers the number of binding sites to undetectable levels. ATP, a nucleotide that stimulates a particulate form of guanylate cyclase, Na2MoO4, a compound that can elevate cGMP levels (Fleming and Blumenthal, unpublished) and GTP, a metabolic precursor of cGMP, increase specific estradiol binding in the presence of plasma membranes and soluble factors. Cyclic AMP reduces the levels of estrogen binding when added to cell homogenates or to cytosol and counteracts the effects of cGMP, MoO4, ATP and GTP. ATP is required for the expression of cGMP and cAMP effects on estradiol binding. It is therefore likely that phosphorylations are involved in the generation and inactivation of estrogen binding sites. Divalent cation requirements for these effects also suggest participation of protein kinases in these processes. The reported effects of nucleotides and molybdate have been observed in specimens of histologically normal endometrium, in specimens of endometrial carcinoma, in two endometrial adenocarcinoma cell lines, HEC-1 and HEC-50 (Suzuki et al, 1980), and in two breast cancer cell lines, CG-5, a variant of MCF-7 obtained in Iacobelli's laboratory (Natoli et al, 1983), and in T47D) (Fleming et al, in press) Rapid changes in the levels of estrogen binding capacity observed in endometrial cells in culture can be associated with changes in cGMP/cAMP ratios shown, to vary during the cell cycle. Although it has not yet been demonstrated that cGMP-induced increases in specific estrogen binding can enhance responses to available estrogens, such possibility is of potential importance. Reduction of estrogen receptor levels in patients with cancers of estrogen sensitive tissues may inhibit tumor growth promoted by endogenous estrogen. Cho-Chung et al have recently reported that cholera toxin causes a reduction in estrogen receptor levels and arrests hormone dependent growth of DMBA-induced mammary carcinoma in rats (Cho-Chung et al, 1983). They postulated that the effect of cholera toxin is mediated by a cAMP effect on the estrogen receptor, an hypothesis supported by the observation that only tumors containing receptor responded to treatment. Conversely, cGMP-induced increases in specific estrogen binders may be useful in promoting a response of tumors to estr
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PMID:Regulation of estrogen receptor levels in endometrial cancer cells. 670 55

We assessed the role of cyclic nucleotides in modulating lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) generation in human peripheral blood monocytes. Exposure of monocytes to LPS (3 ng/ml) evoked a delayed, time-dependent generation of TNF-alpha that reached a maximum level 5-6 hr after LPS challenge and remained constant for up to 24 hr. This effect was concentration dependent and resulted in a 20-40-fold increase in the release of TNF-alpha that was sensitive to actinomycin D and cycloheximide. Treatment of monocytes with agents reputed to activate the cAMP/cAMP-dependent protein kinase (PKA) cascade in general inhibited LPS-induced TNF-alpha generation. Thus, the beta 2-adrenoceptor agonists albuterol and procaterol partially (approximately 40%) suppressed TNF-alpha generation in a propranolol-sensitive manner. Furthermore, 8-bromo-cAMP, cholera toxin, prostaglandin E2, and a number of drugs (i.e., rolipram (ZK 62711), denbufylline (BRL 30892), Ro 20-1724, benafentrine (AH 21-132), that inhibit the phosphodiesterase (PDE) 4 isoenzyme family abolished cytokine generation. In contrast, forskolin, inhibitors of PDE3 and PDE5, and activators of soluble and particulate guanylyl cyclase were essentially inactive. Interestingly, rolipram failed to potentiate the inhibitory effect of albuterol on LPS-induced TNF-alpha biosynthesis but, paradoxically, synergized with albuterol in the generation of cAMP and in the activation of PKA. When PGE2 was used to activate adenylyl cyclase, however, rolipram potentiated cAMP accumulation, PKA activation, and inhibition of TNF-alpha generation. In contrast, forskolin did not increase the cAMP content of monocytes in the absence or presence of rolipram. Collectively, these data suggest that LPS-induced TNF-alpha generation by human peripheral blood monocytes is due to increased transcription and subsequent translation of the TNF-alpha gene and that these effects are suppressed by a range of agents that activate the cAMP/PKA cascade. However, the failure of rolipram to potentiate the inhibitory effect of albuterol and procaterol on TNF-alpha generation suggests that beta 2-adrenoceptor agonists may affect gene expression and/or post-transcriptional regulatory processes by, at least in part, a cAMP-independent mechanism(s).
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PMID:Suppression of lipopolysaccharide-induced tumor necrosis factor-alpha generation from human peripheral blood monocytes by inhibitors of phosphodiesterase 4: interaction with stimulants of adenylyl cyclase. 747 3

Cyclic GMP accumulation in pinealocytes is elevated > 100-fold by norepinephrine (NE) through a mechanism involving conjoint activation of alpha 1- and beta 1-adrenergic receptors. Little or no stimulation occurs if either alpha 1- or beta 1-adrenergic receptors alone are activated. It appears that alpha 1-adrenergic effects are mediated by Ca2+ acting in part through nitric oxide (NO), and beta 1-adrenergic effects are mediated by Gs. In the study presented here we investigated effects of adrenergic agonists or related postreceptor-active agents on stimulation of pineal cyclic GMP accumulation by the NO generator sodium nitroprusside (NP). The cyclic GMP response to NP (1 mM) was potentiated by NE and isoproterenol (ISO) but not by phenylephrine, indicating that activation of beta 1-adrenergic receptors potentiates the effects of NP. Similarly, vasoactive intestinal peptide (VIP), cholera toxin (CTX), and forskolin, all of which are known to mimic the effects of ISO in this system, also potentiated the effects of NP. In contrast, neither dibutyryl cyclic AMP nor agents that elevate intracellular Ca2+ levels caused marked potentiation of the effects of NP on pineal cyclic GMP. Depletion (90%) of Gs alpha by 21-h treatment with CTX reduced beta-adrenergic potentiation of NP. These findings indicate that beta-adrenergic agonists and VIP potentiate the effects of NP through a mechanism involving Gs. The molecular basis of this action may be an increase in guanylyl cyclase responsiveness to NO.
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PMID:Stimulation of cyclic GMP accumulation by sodium nitroprusside is potentiated via a Gs mechanism in intact pinealocytes. 783 64

The action of highly purified Clostridium difficile toxin A was studied in the jejunum of rats in vivo. C. difficile toxin A reversed dose-dependently net fluid absorption into net fluid secretion, accompanied by an increase in prostaglandin E2 but not 5-hydroxytryptamine output into the gut lumen. Accordingly, indomethacin but not the 5-hydroxytryptamine receptor antagonists ketanserin plus tropisetron were able to inhibit toxin A-induced fluid secretion. Atropine and hexamethonium were without effect on the action of toxin A, such excluding a nervous mechanism. The cyclic nucleotides cyclic AMP and cyclic GMP appear not to be involved in the mediation of the secretory response. The reduced cyclic GMP levels are most likely the result of a complete destruction of the villus membranes, where the guanylate cyclase is located. Histological studies revealed massive damage to intestinal villi, whereas the majority of the crypts seem to be unaffected. In conclusion, toxin A-induced intestinal fluid secretion appears to be caused mainly by severe mucosal damage. PGE2-release may be the consequence of the inflammation accompanying this damage. The mechanism seems to be completely different to those of cholera toxin or Escherichia coli heat stable enterotoxin.
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PMID:Effects of purified Clostridium difficile toxin A in the small intestine of the rat in vivo. 790 88


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