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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hormone serotonin (5-hydroxytryptamine) has been implicated as the cause of the diarrhea seen in many patients with the carcinoid syndrome. To determine whether serotonin is an intestinal secretagogue, the effect of serotonin on intestinal water and electrolyte transport was evaluated in the rabbit. Two weeks of daily subcutaneous injection of serotonin suspended in oil resulted in a blood serotonin level elevated to twice that of controls. Intestinal transport was studied in vivo by a perfusion technique. Serotonin treatment resulted in ileal secretion and decreased mid-jejunal absorption of water and electrolytes but did not effect water absorption in the proximal jejunum or colon. Intestinal absorption of D-glucose and the amino acid L-tryptophan and glucose-dependent water and electrolyte absorption were normal in serotonin-treated animals. Serotonin-induced ileal secretion was reversed by methysergide, a peripheral antagonist of serotonin action. No alterations in intestinal histology or permeability occurred in serotonin-treated animals. Serotonin-induced intestinal secretion was not associated with alterations in the activities of intestinal mucosal adenylate cyclase, cyclic nucleotide phosphodiesterase, or Na-K-ATPase.
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PMID:Effect of serotonin treatment on intestinal transport in the rabbit. 83 7

In cholera, bacteria proliferation in the lumen of the small bowel results in an increase in adenylate cyclase activity and concentration of adenosine 3',5'-cyclic monophosphate (cAMP). Clinical manifestations of cholera can be attributed to the change in cAMP synthesis. Accumulation of cAMP in intestinal epithelial cells lead to the development of 2 separate alterations of active ion transport, both of which contribute to the overall rate of secretion of salt and water. Inhibition of sodium chloride absorption occurs in villus cells, while stimulation of active secretion of anion (chloride and bicarbonate) occurs in secretory cells. Glucose is useful in reinstituting salt and H2O absorption as it does not interfere with the specific effects of cAMP on active ion transport but independently stimulates salt and H2O absorption. If enough of sodium-glucose solution is given, fecal losses can be fully replaced and fluid balance maintained. However, an oral glucose electrolyte therapy does not decrease diarrhea, and it is important to design an oral solution that could stimulate extra fluid absorption. Oral sugar-electrolyte solutions are used world wide to treat diarrhea of diverse and often undetermined causes; theoretically, they should be useful for replacing fluid losses in any form of diarrhea, infectious or noninfectious, as long as the intestine can absorb the ingested glucose. Palmer proposed an interesting variation on the glucose theme by using sucrose. Although oral sugar-electrolyte therapy has proved to be successful, innovations are still needed.
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PMID:New strategies for treating watery diarrhea. 90 68

Infants and young children are particularly susceptible to a recently identified viral enteritis which is highly contagious and seems both common and universal. In this disease, virus invades the upper intestinal epithelium, causing acute diarrhoea with early fever and vomiting. We studied a similar disease in pigs, infecting three-week-old animals with transmissible gastroenteritis virus (TGE), which also invades the upper intestinal epithelium. In this model, diarrhoea is massive 16-40 hours after infection, when stools contain increased electrolytes but no excess of sugar. In the jejunum of intact pigs at the 40-hour stage we found altered Na+ and water flux, decreased mucosal activities of disaccharidases and Na+, K+-ATPase, but normal adenylate cyclase activity. At the same stage the response of Na+ flux to glucose was blunted in jejunal epithelium studied in Ussing short-circuit chambers and in suspensions of villous cells; Cl- flux responded normally to theophylline, and thymidine kinase and sucrase activities of cells isolated from jejunal villi were similar to those found in crypt cells. Probably by 40 hours after infection most virus has been shed from the mucosa. Viral diarrhoea clearly differs from enterotoxigenic diarrhoea. Consideration of its pathogenesis must take into account the dynamic nature of the mucosal epithelium and the factors governing differentiation of enterocytes as they migrate from crypt to villus. Sufficient information is available now to characterize one specific and apparently prevalent viral enteritis in man and to identify additional viral enteritides. There is hope that preventative therapy can be developed. Our understanding of the mechanisms of viral diarrhoea is limited, but the availability of an animal model and the promise of others makes us optimistic that these deficiencies can be remedied. Greater understanding of the pathogenesis of viral diarrhoea should better the active therapy of affected infants and children.
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PMID:Viral gastroenteritis: recent progress, remaining problems. 104 55

1. Some kinetic properties of adenylate cyclase in separately isolated upper villous and crypt cells from rat and guinea pig small intestine were compared. An apparent Km of 0.4 mM was found for both enzymes in the rat. The slight difference between the V-values measured in the fluoride-stimulated state (132 and 165 pmoles cyclic AMP formed per min per mg protein respectively) indicated an approximately equal enzyme content of both cell populations and argues strongly against a preferential localization in the brushborder region of the epithelial cell. 2. Prolonged contact of the small intestine with luminally administered choleragen led to an irreversible activation of adenylate cyclase in both villous and crypt compartments. The maximal stimulation of the upper villous enzyme (4-7 times) exceeded the maximal effect on the crypt enzyme by two-fold. 3. A lag phase of at least 30 min was found between the first luminal contact with the purified choleragen and a significant activation of the adenylate cyclase associated with isolated intestinal brushborders from the upper villous region. 4. By using a short exposure time (2 min) of the luminal surface to high amounts of choleragen, adenylate cyclase activity in the upper villus could be optimally stimulated in the absence of any alteration of crypt cell activity. 5. By comparing, in vivo, the effects of short and prolonged contact with choleratoxin on the unidirectional and net flux of ions and water in ileal and jejunal segments, it was concluded that both villous and crypt regions contribute to the secretion of water and electrolytes (sodium, chloride and bicarbonate ions) during cholera. The serosal to mucosal flux of sodium and chloride ions increased without a significant alteration of the opposite flux. These results imply that absorptive and secretory processes occur within the same epithelial compartment. 6. The view that the crypt epithelium fulfills a specific role during the choleragen-induced secretion of ions and water is incompatible with the results of the present study.
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PMID:The response of small intestinal villous and crypt epithelium to choleratoxin in rat and guinea pig. Evidence against a specific role of the crypt cells in choleragen-induced secretion. 111 79

1. The role of adenylate cyclase in rat pancreas is further investigated by means of cholera toxin, which is known to activate the enzyme in several tissues. 2. Cholera toxin activates rat pancreatic adenylate cyclase in vitro upon preincubation of tissue slices with the toxin for more than 30 min, but not when it is merely present during the enzyme assay. The maximal effect is reached after 90 min pre-incubation. The half-maximally activating concentration is 3.5 mu-g/ml upon pre-incubation for 90 min. 3. After pre-treatment of pancreatic tissue slices with 2 mu-g/ml cholera toxin, further stimulation of adenylate cyclase activity can be obtained by adding pancreozymin-C-octapeptide, secretin, or fluoride to the assay medium, but the final activity with maximally effective concentrations of the hormones is not higher, and with fluoride even less, than that without the toxin pre-treatment. 4. The in vivo effects of the two hormones and of cholera toxin have been studied after cannulation of the pancreas. Pancreozymin-C-octapeptide (intravenously) markedly stimulates both flow rate and rate of protein secretion. Synthetic secretin (intravenously), in addition to its expected effect on flow rate, slightly stimulates protein secretion, which is not due to a wash-out effect. Cholera toxin, topically applied to the cannulated rat pancreas, causes a steady increase of the flow rate after a delay of 20--30 min. The rate of protein secretion is not affected or slightly decreased by the toxin. Pancreozymin-C-octapeptide, given intravenously 1 h after cholera toxin application, causes the same increase in flow rate and rate of protein secretion as would be expected without cholera toxin treatment. 5. The sodium and potassium levels in the pancreatic fluid after administration of secretin or cholera toxin do not change, while the chloride level decreases in both cases. 6. These observations indicate that the rat pancreas adenylate cyclase activity is a rate-limiting factor in the regulation of water and electrolyte secretion. A possible auxiliary role in the regulation of enzyme secretion cannot yet be excluded.
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PMID:Rat pancreas adenylate cyclase. III. Its role in pancreatic secretion assessed by means of choleara toxin. 113 64

The size distribution of adenylate cyclase from the rat renal medulla solubilized with the nonionic detergents Triton X-100 and Lubrol PX was determined by gel filtration and by centrifugation in sucrose density gradients made up in H2O or D2O. The physical parameters of the predominant form in Triton X-100 are s20,w, 5.9S; Strokes radius, 62 A; partial specific volume (v), 0.74 ml/g; mass, 159,000 daltons; f/f0, 1.6; axial ratio (prolate ellipsoid), 11. For the minor form the values are: s20w, 3.0; Stokes radius, 28 A; mass, 38,000 daltons; f/f0, 1.2. The corresponding values determined in Lubrol PX are similar. The value for V for the enzyme indicates that it binds less than 0.2 mg detergent/mg protein. Since interactions with detergents probably substitute for interactions with lipids and hydrophobic amino acid side chains, these findings suggest that no more than 5% of the surface of adenylate cyclase is involved in hydrophobic interactions with other membrane components. Thus, most of the mass of the enzyme is not deeply embedded in the lipid bilayer of the plasma membrane. Similar studies have been performed on the soluble guanylate cyclase of the rat renal medulla. In the absence of detergent, the molecular properties of this enzyme are: s20w, 6.3S; Stokes radius, 54 A, V, 0.75 ml/g; mass, 154,000 daltons f/f0, 1.4; Axial ratio, 7. The addition of 0.1% Lubrol PX to this soluble enzyme increases it activity two- to fourfold and changes the physical properties to: s20,w, 5.5S; Stokes radius, 62 A; V, 0.74 ml/g; mass, 148,000 daltons, f/f0, 1.6; axial ratio, 11. These results show that Lubrol PX activates the enzyme by causing a conformational change with unfolding on the polypeptide chain. Guanylate cyclase from the particulate cell fraction can be solubilized with Lubrol PX but has properties quite different from those of the enzyme in the soluble cell fraction. It is a heterogeneous aggregate with s20,w, 10S; Stokes radius, 65 A; mass about 300,000 daltons. The conditions which solubilize guanylate cyclase also solubilize adenylate cyclase and the two activities can be separated on the same sucrose gradient.
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PMID:The size of adenylate cyclase and guanylate cyclase from the rat renal medulla. 125 62

In experiments on frog urinary bladder the mechanisms behind the gradual development of a hydroosmotic reaction to antidiuretic hormone (ADH) were investigated. It was suggested that the velocity of hydroosmotic reaction may be limited by (a) formation and insertion of particle aggregates into the apical membrane or (b) by velocity of cAMP formation. The urinary bladders were exposed to 23 nM ADH for different times (from 1 to 20 min) and water flow was measured over a period of 40 min. It was found that the value of the full hydroosmotic response increased progressively with the time of exposure to the hormone; however, the enhancement of water flow was equal during each time interval before reaching the reaction maximum. A direct correlation between the value of ADH-stimulated water flow, cAMP content in bladder tissue and frequency of particle aggregates in the granular cell apical membrane was observed. The content of cAMP in ADH-treated bladders was higher by 80% in the absence than in the presence of an osmotic gradient. Pretreatment of urinary bladders with 50 microM cyclic nucleotide phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, significantly accelerated the development of the hydroosmotic reaction and increased the magnitude of water flow in comparison with the effect of ADH only. No changes in cyclic AMP phosphodiesterase activity were found in the urinary bladder homogenates under the action of ADH, so it seems likely that accumulation of cAMP depends only on the increase of adenylate cyclase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Does the gradual hydroosmotic response to antidiuretic hormone depend on intracellular cAMP accumulation or on the formation of intramembrane particle aggregates? 127 17

This investigation was performed in order to establish a new histochemical method for the identification of lymphatic capillaries. The microvasculature in specimens from human foreskin was examined for adenylate cyclase and alkaline phosphatase activity by light and electron microscopy. Lymphatic capillaries showed positive adenylate cyclase reactivity and negative alkaline phosphatase reactivity whereas the blood capillaries showed a positive reaction for alkaline phosphatase and a negative one for adenylate cyclase. The presence of adenylate cyclase activity in the endothelium of the lymphatic capillary may relate to microvascular function including the transcapillary exchange of water and solutes.
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PMID:Enzyme-histochemical identification of the human lymphatic capillary by adenylate cyclase. 129 34

The effect of the domestic Forskolin on lowering the intraocular pressure (IOP) of rabbits was studied. The results showed that the Forskolin significantly lowered the normal IOP of rabbits and blocked the ocular hypertension induced by water load in rabbits (p < 0.01). The maximum decrease value of 2%, 1% and 0.5% of the Forskolin was 0.59. 0.36 and 0.19 kPa (1 kPa = 7.5 mmHg), which showed the noticeable dose-effect relationship. Topical ocular application of Forskolin lowered IOP in 1/2 hour, reached to a peak in 2-3 hours and remained significantly for 10 hours. The pupillary diameter did not change when IOP were reduced. Furthermore, the Forskolin had potent stimulative properties to adenylate cyclase (AC). The greater the ability of the Forskolin to stimulate AC, the stronger the effect of IOP lowering.
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PMID:[The experimental studies of the effect of Forskolin on the lowering of intraocular pressure]. 130 93

The massive secretion of salt and water in cholera-induced diarrhea involves binding of cholera toxin (CT) to ganglioside GM1 in the apical membrane of intestinal epithelial cells, translocation of the enzymatically active A1-peptide across the membrane, and subsequent activation of adenylate cyclase located on the cytoplasmic surface of the basolateral membrane. Studies on nonpolarized cells show that CT is internalized by receptor-mediated endocytosis, and that the A1-subunit may remain membrane associated. To test the hypothesis that toxin action in polarized cells may involve intracellular movement of toxin-containing membranes, monolayers of the polarized intestinal epithelial cell line T84 were mounted in modified Ussing chambers and the response to CT was examined. Apical CT at 37 degrees C elicited a short circuit current (Isc: 48 +/- 2.1 microA/cm2; half-maximal effective dose, ED50 integral of 0.5 nM) after a lag of 33 +/- 2 min which bidirectional 22Na+ and 36Cl- flux studies showed to be due to electrogenic Cl- secretion. The time course of the CT-induced Isc response paralleled the time course of cAMP generation. The dose response to basolateral toxin at 37 degrees C was identical to that of apical CT but lag times (24 +/- 2 min) and initial rates were significantly less. At 20 degrees C, the Isc response to apical CT was more strongly inhibited (30-50%) than the response to basolateral CT, even though translocation occurred in both cases as evidenced by the formation of A1-peptide. A functional rhodamine-labeled CT-analogue applied apically or basolaterally at 20 degrees C was visualized only within endocytic vesicles close to apical or basolateral membranes, whereas movement into deeper apical structures was detected at 37 degrees C. At 15 degrees C, in contrast, reduction to the A1-peptide was completely inhibited and both apical and basolateral CT failed to stimulate Isc although Isc responses to 1 nM vasoactive intestinal peptide, 10 microM forskolin, and 3 mM 8Br-cAMP were intact. Re-warming above 32 degrees C restored CT-induced Isc. Preincubating monolayers for 30 min at 37 degrees C before cooling to 15 degrees C overcame the temperature block of basolateral CT but the response to apical toxin remained completely inhibited. These results identify a temperature-sensitive step essential to apical toxin action on polarized epithelial cells. We suggest that this event involves vesicular transport of toxin-containing membranes beyond the apical endosomal compartment.
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PMID:Mechanism of cholera toxin action on a polarized human intestinal epithelial cell line: role of vesicular traffic. 131 83


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