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)

From diarrheal diseases come profound lessons about health and population growth, microbial pathogenesis, and the molecular pharmacology of signal transduction. Epidemics such as cholera, hemorrhagic colitis, salmonellosis, and cryptosporidiosis remind us of how interdependent we are, sharing enteric microbial flora on a global scale. Diarrhea morbidity and mortality teach us that disease and poverty do not control but are associated with population overgrowth. Great advances are being made in understanding new bacterial, viral, and parasitic causes and treatment of diarrhea, especially persistent diarrhea. In addition, microbial toxins provide unique pharmacologic tools to probe cell signaling pathways. The mechanism of action of cholera toxin, once thought so clear, now appears to involve additional pathways such as platelet-activating factor and prostaglandin synthesis. Escherichia coli ST has opened a whole family of activators of guanylate cyclase, including new mammalian products that regulate sodium transport. Clostridium difficile toxin A provides a novel tool to dissect mediators involved in inflammatory diarrhea. These lessons have both basic implications for science and practical applications for medicine and society.
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PMID:Lessons from diarrheal diseases: demography to molecular pharmacology. 819 98

A mammalian plasma-membrane-bound guanylyl cyclase is inhibited by NaCl and this inhibition is dependent on GTP concentrations and independent of the chloride salt type. This chloride inhibition is reversed by GTP analogs such as GTP gamma S, suggesting the involvement of G proteins. When the ability of bacterial toxins to affect this chloride-sensitive guanylyl cyclase was examined, pertussis toxin decreased the basal activity and the chloride sensitivity was greatly reduced. Cholera toxin induced a slight activation of the basal activity, without significant changes in the NaCl inhibition. These data indicate that G proteins regulate the chloride sensitivity of this guanylyl cyclase activity. Another property described here is the ability of ATP and analogs to inhibit the basal activity. However, these nucleotides did not modify the chloride sensitivity of the membrane-bound guanylyl cyclase activity.
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PMID:G-protein-sensitive guanylyl cyclase activity associated with plasma membranes. 855 11

Vibrio cholerae produce a variety of extracellular products that have deleterious effects on eukaryotic cells. The massive diarrhoea produced by V. cholerae is caused by cholera toxin (CT). CT is composed of 1A and 5B units. CT causes a significant amount of fluid secretion and haemorrhage in the ligated rabbit ileal loops. Its action involves the role of various biochemical pathways. CT acts by activation of adenylate cyclase-cAMP system located at the basolateral membrane of intestinal epithelial cells. The increase in cyclic AMP levels is mainly responsible for the altered transport of Na+ and Cl-. Besides activating cAMP, CT is also known to act through release of prostaglandins and involvement of intramural nerves. Besides CT, other bacterial toxins like Escherichia coli LT, Salmonella toxin, Shigella toxin and Campylobacter toxin also possess A-B structure. The structure and function of E. coli LT resembles closely that of CT. Most of the bacterial toxins exert their effect through involvement of ADP-ribosylating proteins whereas other toxins involve guanylate cyclase system, calcium and protein kinases for their ultimate action.
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PMID:Mechanism of action of cholera toxin & other toxins. 878 5

The purpose of this work was to examine whether the level of cAMP accumulation and protein kinase A (PKA) activity influence atrial natriuretic factor (ANF)-dependent guanosine 3',5'-cyclic monophosphate (cGMP) production in two renal cell types: rabbit cortical vascular smooth muscle cells (RCSMC) and SV-40-transformed human glomerular visceral epithelial cells (HGVEC-SV1). N-[2-(p-bromocinnamylamino)ethyl]- 5-isoquinolinesulfonamide (H-89), a PKA inhibitor, decreased ANF-stimulated cGMP production in RCSMC in a time- and concentration-dependent manner. ANF-stimulated cGMP production was markedly inhibited after prolonged 9- and 18-h incubations with 25 microM H-89 (52 and 65%, respectively) but was not altered after exposure of cells to this agent for 1 h. 1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine and N-(2-[methylamino]ethyl)-5-isoquinolinesulfonamide, protein kinase inhibitors not selective for PKA, did not reproduce the effect of H-89, even at higher concentrations (50 and 100 microM). Cycloheximide (10 microM), a protein synthesis inhibitor, limited the inhibitory effect of H-89, although alone it did not modify the ANF-stimulated cGMP production. H-89 did not affect cGMP production when it was stimulated by SIN-1, a nitric oxide donor. Prolonged incubation (18 h) with 8-bromo cAMP or cholera toxin, an activator of Gs protein resulting in adenylate cyclase stimulation, enhanced ANF-dependent cGMP production by 225 and 176%, respectively. This stimulatory effect was blocked by 25 microM H-89. 125I-ANF binding to RCSMC at 4 degrees C was not affected by preincubation of the cells with H-89. There was a 44% decrease in the expression of ANF C receptors measured as the ANF-(4-23)-displaceable 125I-ANF binding at 37 degrees C, which could not, however, explain the inhibitory effect of H-89 on cGMP production. Modulation of ANF- and C-type natriuretic peptide-dependent cGMP production by H-89 and cholera toxin was also found in HGVEC-SV1 with the same characteristics as in RCSMC. Taken together, these results suggest that PKA activity controls the function of natriuretic peptide guanylate cyclase-coupled receptors in the two cell types studied. PKA-dependent inhibition of a negatively regulatory protein distinct from the receptor itself seems necessary for a full cGMP response.
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PMID:Protein kinase A activity modulates natriuretic peptide-dependent cGMP accumulation in renal cells. 903 14

Bacterial toxins are associated with disease in humans and animals. Toxins can either be preformed in food or produced by bacteria in the intestine. There are two types of toxins: heat-labile protein toxins and heat stabile toxins. Heat labile toxins are produced by Bacillus cereus, Clostridium perfringens, Escherichia coli, and Vibrio cholerae, and heat-stabile enterotoxins consisting of relatively few amino acids are produced by Escherichia coli and acts by activation of guanylate cyclase. Similarly, heat-stabile entero-toxins are also produced by Staphylococcus aureus, a common cause of food poisoning in the United States, and Yersenia enterocolitica. Protein toxins produced by enteric bacteria can intoxicate intestinal cells and can also be taken up from the gut and reach other cells in the body. For example the Shiga-like toxins (vero-toxins) can intoxicate endothelial cells in the kidney and cause kidney failure. Intracellular transport and processing of a few of the protein toxins produced by enteric bacteria, namely Clostridium difficile toxin A and B, cholera toxin and the related heat-labile toxin produced by Escherichia coli, and Shiga toxin and Shiga-like toxins are presented.
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PMID:Intracellular transport and processing of protein toxins produced by enteric bacteria. 919 18

Heat-stable enterotoxins (STa), which cause an acute secretory diarrhea, have been suggested to mediate their actions through the guanylyl cyclase-C (GC-C) receptor. The GC-C gene was disrupted by insertion of neo into exon 1 and subsequent homologous recombination. GC-C null mice contained no detectable GC-C protein. Intestine mucosal guanylyl cyclase activity was approximately 16-fold higher in wild-type mice than in the GC-C null mice, and STa-stimulable guanylyl cyclase activity was absent in the null animals. Thus, GC-C is the major cyclase activity present in the intestine, and also completely accounts for the STa-induced elevations of cGMP. Gavage with STa resulted in marked fluid accumulation within the intestine of wild-type and heterozygous suckling mice, but GC-C null animals were resistant. In addition, infection with enterotoxigenic bacteria that produce STa led to diarrhea and death in wild-type and heterozygous mice, while the null mice were protected. Cholera toxin, in contrast, continued to cause diarrhea in GC-C null mice, demonstrating that the cAMP signaling pathway remained intact. Markedly different diets (high carbohydrate, fat, or protein) or the inclusion of high salt (K+, Na+) in the drinking water or diet also did not severely affect the null animals. Given that GC-C is a major intestinal receptor in all mammals, the pressure to retain a functional GC-C in the face of diarrhea-inflicted mortality remains unexplained. Therefore, GC-C likely provides a protective effect against stressors not yet tested, possibly pathogens other than noninvasive enterotoxigenic bacteria.
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PMID:Disruption of the guanylyl cyclase-C gene leads to a paradoxical phenotype of viable but heat-stable enterotoxin-resistant mice. 929 28

Soluble guanylate cyclase (sGC) consisting of two different subunits (alpha: Mr = 74,000, beta: Mr = 69,000) was purified more than 12,000-fold in terms of specific activity from the supernatant of bovine lung homogenates and characterized. The heme content determined with the pyridine hemochromogen method and Bradford's protein assay was 0.8 heme per dimer. Cholera, pertussis, and botulinum C3 toxins modified exclusively the beta-subunit of sGC, yielding the ADP-ribose-bound compound with 1:1 stoichiometry, and Vmax for the cyclase reaction was increased 10 times by this modification. When the ADP-ribosylation of sGC was performed simultaneously with two or three bacterial toxins which have distinct amino acid specificities, the resultant enzyme had only one ADP-ribose, and the activity was the same as that of the enzyme modified with one toxin. When NO was incorporated into the reaction mixture containing the ADP-ribosylated sGC, the cyclase activity noticeably increased by approximately the same amount as that seen for the unmodified enzyme. Such effects were not seen with CO. When ADP-ribosylated sGC was incubated with Mn2+, the enzyme activity was synergistically increased. The heme-deleted sGC was also ADP-ribosylated by bacterial toxins and its activity was raised. These findings suggest that sGC has an ADP-ribosylation site near the GTP binding site, like other GTP-binding proteins, and that the beta-subunit regulates the activity.
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PMID:Purification of bovine soluble guanylate cyclase and ADP-ribosylation on its small subunit by bacterial toxins. 934 80

The cytosolic calcium level ([Ca2+]i) and the membrane-bound guanylyl cyclase activity in the isolated rat intestinal epithelial cells were investigated. Heat-stable enterotoxin of Vibrio cholerae non-01 (NAG-ST) was found to increase both the [Ca2+]i and the enzyme activity. These changes occur similarly until 5 min of incubation with NAG-ST, indicating that these changes might be involved in NAG-ST induced signal transduction in rat enterocytes.
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PMID:Rise of cytosolic Ca2+ and activation of membrane-bound guanylyl cyclase activity in rat enterocytes by heat-stable enterotoxin of Vibrio cholerae non-01. 949 23

We investigated the effects of adrenomedullin (ADM) on cGMP production in cultured SV-40 transformed cat iris sphincter smooth muscle (SV-CISM-2) cells. ADM increased cGMP accumulation in a time- and concentration- dependent manner. The peptide increased cGMP formation in the transformed cells by 405-fold as compared to 1. 6-fold in primary cultured CISM cells. The basal cGMP concentrations in both cell types were comparable. In addition, ADM increased cAMP accumulation in SV-CISM-2 cells and in primary cultured cells by 18. 9- and 5.8-fold, respectively. The ADM receptor antagonist, ADM(26-52), but not the atrial natriuretic peptide (ANP) receptor antagonist, anantin, inhibited ADM-induced cGMP formation. The phorbol ester, phorbol 12, 13-dibutyrate (PDBu), which inhibits particulate guanylate cyclases in smooth muscle, blocked ADM-stimulated cGMP accumulation. In contrast, inhibitors of the soluble guanylate cyclases, such as LY83583 and ODQ, and inhibitors of the nitric oxide cascade had little effect on ADM-stimulated cGMP production. The stimulatory effect of ADM on cGMP formation is due to activation of the guanylate cyclase system and not to a much reduced phosphodiesterase activity. ADM stimulated guanylate cyclase activity in membrane fractions isolated from SV-CISM-2 cells in a concentration-dependent manner with EC(50) value of 72 nM. Pertussis toxin, an activator of the G-protein, Gi, inhibited ADM-stimulated cGMP accumulation, whereas cholera toxin, a stimulator of the Gs G-protein and subsequently cAMP accumulation, had little effect. Pretreatment of the plasma membrane fraction with Gialpha antibody attenuated ADM-stimulated guanylate cyclase activity by 75%. We conclude that ADM increases intracellular cGMP levels in SV-CISM-2 cells through activation of the ADM receptor and subsequent stimulation of a Gi-mediated membrane-bound guanylate cyclase.
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PMID:Activation of particulate guanylate cyclase by adrenomedullin in cultured SV-40 transformed cat iris sphincter smooth muscle (SV-CISM-2) cells. 1098 85

Nitric-oxide synthase type I (NOS I) is expressed primarily in gonadotrophs and in folliculo-stellate cells of the anterior pituitary. In gonadotrophs, the expression and the activity of NOS I are stimulated by gonadotropin-releasing hormone (GnRH) under both experimental and physiological conditions. In the present study, we show that pituitary adenylate cyclase-activating polypeptide (PACAP) is twice as potent as GnRH at increasing NOS I levels in cultured rat anterior pituitary cells. The action of PACAP is detectable after 4-6 h and maximal at 24 h, this effect is mimicked by 8-bromo-cAMP and cholera toxin and suppressed by H89 suggesting a mediation through the cAMP pathway. Surprisingly, NADPH diaphorase staining revealed that these changes occurred in gonadotrophs exclusively although PACAP and cAMP, in contrast to GnRH, have the potential to target several types of pituitary cells including folliculo-stellate cells. There was no measurable alteration in NOS I mRNA levels after cAMP or PACAP induction. PACAP also stimulated cGMP synthesis, which was maximal within 15 min and independent of cAMP, however, only part resulted from NOS I/soluble guanylate cyclase activation implying that in contrast to GnRH, PACAP has a dual mechanism in cGMP production. Interestingly, induction of NOS I by PACAP markedly enhanced the capacity of gonadotrophs to produce cGMP in response to GnRH. The fact that PACAP may act on gonadotrophs to alter NOS I levels, generate cGMP, and potentiate the cGMP response to GnRH, suggests that cGMP could play important cellular functions.
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PMID:Pituitary adenylate cyclase-activating polypeptide stimulates nitric-oxide synthase type I expression and potentiates the cGMP response to gonadotropin-releasing hormone of rat pituitary gonadotrophs. 1224 42


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