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 cellular mechanisms by which pepsinogen (PNG) secretion is controlled are not understood. The aim of this study was to explore whether modulation of PNG secretion is mediated by cAMP or calcium-calmodulin (C-C). PNG secretion in isolated rabbit gastric fundic glands (IGG) was tested, using agents believed to act via cAMP or C-C. IGG were stimulated for 30 minutes with histamine (H) 10(-5) M, isoproterenol (I) 10(-5) M, carbachol (C) 10(-5) M, cholecystokinin-octapeptide (CCK-8) 10(-7) M, forskolin (F) 10(-5) M, 8 bromo-cAMP (8B) 10(-3) M, and A23187 (A) 10(-6) M. PNG levels were determined by spectrophotometric assay of hemoglobin digestion products. PNG amounts secreted were (mean per cent above basal levels of total IGG PNG units +/- SEM): H, -0.02 +/- 0.30%; I, 3.5 +/- 0.9%; C, 5.1 +/- 2.2%; CCK-8, 5.3 +/- 1.5%; F, 10.6 +/- 3.8%; 8B, 13.8 +/- 4.5%; A, 2.1 +/- 1.1%. All secretagogues except H stimulated PNG release significantly above basal levels (p less than 0.05). A primary histaminergic mechanism for pepsinogen secretion is unlikely. Since two other adenylate cyclase activators, isoproterenol and forskolin and the 3':5'-cyclic adenosine monophosphate analog 8-bromo cAMP stimulated pepsinogen secretion, cAMP-dependence is probable. Since carbachol, CCK-8, and A23187, which are believed to act via calcium-calmodulin, also stimulated pepsinogen secretion, this system, too, presumably plays a substantial role. Thus the data support a dual 3':5'-cyclic adenosine monophosphate/calcium-calmodulin modulation of pepsinogen secretion.
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PMID:Evidence for dual modulation of pepsinogen secretion using isoproterenol, carbachol, CCK-8, forskolin, 8 bromo-cAMP, and A23187 probes. 309 67

To determine the role of the adenylate cyclase system in potentiation of enzyme secretion, we used cholera toxin to activate adenylate cyclase before examining the effects of agents on chief cell cAMP and pepsinogen secretion. Dispersed chief cells were obtained from guinea pig stomach by fractionation of mucosal cells on a Percoll gradient. Incubation of cells with 100 nM cholera toxin for 90 min and subsequent incubation with carbachol or cholecystokinin resulted in augmentation of cellular cAMP and potentiation of pepsinogen secretion. The rate of increase in cAMP with carbachol or cholecystokinin was similar to that for the potentiated secretory response. To determine the role of changes in cell calcium on these effects, we examined the actions of the ionophore A23187. In cells preincubated with cholera toxin, A23187 augmented cAMP and caused potentiation of pepsinogen secretion. The effects of A23187, carbachol, and cholecystokinin on cells preincubated with cholera toxin were abolished by removing extracellular calcium or by adding the calmodulin inhibitor trifluoperazine. These data indicate that in chief cells preincubated with cholera toxin, secretagogue-induced increases in cell calcium concentration activate calmodulin thereby augmenting levels of cAMP and causing potentiation of pepsinogen secretion. Modulation of adenylate cyclase by changes in chief cell calcium concentration appears to be one mechanism whereby secretagogue interaction can result in potentiation of pepsinogen secretion.
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PMID:Interaction between the calcium and adenylate cyclase messenger systems in dispersed chief cells from guinea pig stomach. Possible cellular mechanism for potentiation of pepsinogen secretion. 310 47

Gastrotropin (GT), a protein previously isolated from porcine ileal mucosa, with a molecular mass of 14,054 daltons, was extracted from canine ileum and purified to homogeneity. The canine and porcine peptides had similar relative molecular mass, charge, hydrophobicity, and amino acid compositions. Direct Edman degradation yielded no free amino acids, indicating a blocked NH2-terminus, and a partial sequence determination of the CNBr fragments demonstrated a high degree of homology with porcine GT. Previous studies have indicated that GT is a potent enterooxyntin, and to further characterize these observations we have investigated the actions of both porcine and canine GT on isolated enriched preparations of guinea pig and dog parietal and chief cells. The results of these studies demonstrate that GT is present in more than one species and that the cellular response to porcine and canine GT is identical. The efficacies of canine and porcine GT preparations in stimulating pepsinogen secretion and [14C]aminopyrine uptake were identical and equal to those of cholecystokinin octapeptide (CCK8) and pentagastrin. GT was 100-fold more potent than either of these two major secretagogues. Maximal [14C]aminopyrine accumulation was observed with 10(-8) M GT, with an ED50 of 2 x 10(-9) M compared to pentagastrin, which caused maximal accumulation at 10(-6) M and had an ED50 of 5 x 10(-8) M. Maximal pepsinogen secretion was observed with 10(-7) M GT, with an ED50 of 10(-10) M, compared to 10(-6) M for CCK8, with an ED50 of 10(-8) M. The maximal chief cell response to GT was unaffected by the addition of CCK8 or carbachol, but responded additively with forskolin, indicating that GT uses the same transduction mechanism as CCK8 and carbachol and does not involve the activation of adenylate cyclase. The ED50 values observed with both parietal and chief cells in these studies were close to the basal circulating levels of GT (3.5 x 10(-9) M) in adult pigs. These results clearly demonstrate that GT is a potent component of the enterooxyntin factor identified in studies of the role of the small bowel in the regulation of gastric secretion.
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PMID:Isolation and partial characterization of gastrotropin from canine ileum: further studies of the parietal and chief cell response. 316 34

1. The biogenic amines 5-hydroxytryptamine (5-HT) and histamine, and the peptides bombesin, gastrin-releasing peptide (GRP), vasoactive intestinal peptide (VIP), cholecystokinin (CCK), substance P and calcitonin gene-related peptide (CGRP) each mimicked slow synaptic excitation (slow e.p.s.p.) when applied to myenteric neurones of the guinea-pig small intestine. 2. Stimulation of the catalytic activity of adenylate cyclase by forskolin and intraneuronal elevation of cyclic 3',5'-adenosine monophosphate (cyclic AMP) also mimicked the slow e.p.s.p. and the actions of the aminergic and peptidergic messengers. 3. Adenosine prevented stimulation of adenylate cyclase by forskolin and abolished the slow e.p.s.p.-like actions of forskolin. 4. Exposure of the neurones to adenosine prior to or during application of bombesin, GRP, VIP, CCK or histamine blocked the actions of these substances. 5. Pre-treatment with adenosine did not suppress the slow e.p.s.p.-like actions of substance P, CGRP or 5-HT. 6. The results suggest that signal transduction for bombesin, GRP, VIP, CCK and histamine involves stimulation of adenylate cyclase and second messenger function of cyclic AMP. Transduction mechanisms for 5-HT, substance P and CGRP appear not to involve second messenger function of cyclic AMP.
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PMID:Transduction of aminergic and peptidergic signals in enteric neurones of the guinea-pig. 365 77

Adenylate cyclase from the guinea-pig pancreas was activated in a dose-dependent manner by both secretin and cholecystokinin-pancreozymin, but in contrast with results in other species the hormones were approximately equipotent. All other hormones and transmitter substances tested were without any effect on adenylate cyclase activity. Guanylate cyclase activity was shown to have both particulate and supernatant components in the guinea-pig pancreas. The particulate enzyme, but not the supernatant enzyme, was markedly activated by Triton X-100, and most of the induced activity was released into the supernatant. The supernatant enzyme was specifically Mn2+-dependent, but, even though Mn2+ was maximally effective at a concentration of 3 mM, activity could be raised further by increasing Ca2+ concentration. The particulate enzyme, by contrast, was relatively Mn2+-independent. Activity of the particulate guanylate cyclase was enhanced by phosphatidylserine. The supernatant enzyme displayed classical Michaelis-Menten kinetics, but the particulate enzyme deviated markedly from such kinetics. Under none of the conditions used was any significant activation of guanylate cyclase observed with any of the secretogen hormones or transmitter substances.
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PMID:The metabolism of cyclic nucleotides in the guinea-pig pancreas. Adenylate cyclase and guanylate cyclase. 610

Radioligand binding studies of neurotransmitter receptors have provided discrimination at the molecular level, permitting the differentiation of multiple receptor subtypes for several biogenic amines. Using this paradigm we have labeled two distinct receptors each for cholecystokinin (CCK) and for adenosine. Adenosine receptors were labeled in brain with [3H]N6-cyclohexyladenosine (3H-CHA) and [3H]1,3-diethyl-8-phenylxanthine (3H-DP). The adenosine receptor labeled by 3H-CHA appears to be an A1 site, associated with reduction of adenylate cyclase activity, while 3H-DP sites resemble A2 receptors linked to adenylate cyclase enhancement. Cholecystokinin-33 labeled by the Bolton-Hunter procedure with 125I(125I-BH-CCK) labels different receptors in brain and pancreas. The pancreatic receptor does not react with CCK derivatives of fewer than eight amino acids, while the brain receptor does recognize pentagastrin, the carboxyl-terminal five amino acids of CCK. The "brain type" CCK receptor may normally interact with CCK-4, the carboxyl-terminal tetrapeptide of CCK, recently identified as a unique neuropeptide highly concentrated in the brain. CCK-8, the other major molecular form of CCK, may be the endogenous ligand for the "pancreatic type" receptor.
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PMID:Multiple neurotransmitter receptors in the brain: amines, adenosine, and cholecystokinin. 610 42

The specificity of guanine nucleotide regulatory site(s) of rat pancreatic plasma membranes involved in adenylate cyclase activation, basal and cholecystokinin (CCK)-stimulated specific GTPase activity, and [125I]-CCK-33 binding was documented. The Km (for GTP) and Ki (for other nucleotides) of basal and CCK-8-dependent GTPase showed similar specificity, decreasing in the order GTP gamma S approximately GTP approximately Gpp[NH]p greater than ITP greater than GDP beta S greater than UTP, suggesting the identity of basal and CCK-stimulated GTPase activities. The same potency order for these nucleotides was obtained when tested as activator (Ka) or inhibitor (Ki for GDP beta S) of adenylate cyclase, in the presence of CCK-8. The IC 50 of these nucleotides on the binding of [125I]-CCK-33 indicated a similar specificity for nucleotide binding sites interacting with CCK receptors (GTP gamma S approximately Gpp[NH]p approximately GTP greater than ITP approximately GDP beta S greater than UTP). In membranes preactivated with 0.3 micron CCK-8 and 30 micron Gpp[NH]p or GTP gamma S, then washed free of hormone and unbound nucleotide, persistent effects of the nonhydrolyzable nucleotides were observed on the three activities tested. The present data indicate that the guanine nucleotide regulatory units involved in adenylate cyclase activation, GTPase activity and CCK binding have similar properties in rat pancreatic plasma membranes.
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PMID:Similar characteristics of guanine nucleotide regulatory sites involved in adenylate cyclase activation, specific GTPase activity, and cholecystokinin binding in rat pancreatic plasma membranes. 612 33

The effects of vasoactive intestinal peptide (VIP) and several other peptides have been examined on cyclic AMP accumulation in intact pieces and isolated horizontal cells of the teleost (carp) retina. VIP was the most effective peptide examined, inducing a dose-related response, and an approximately fivefold increase in cyclic AMP production when used at a concentration of 10 microM. Porcine histidine isoleucine-containing peptide and secretin, peptides structurally related to VIP, also stimulated cyclic AMP accumulation, but at concentrations of 10 microM induced responses which were only approximately 40% and 10%, respectively, of the response observed with 10 microM VIP. In contrast, several other peptides, including glucagon, neurotensin, somatostatin, luteinizing hormone-releasing hormone, alpha-melanocyte-stimulating hormone, cholecystokinin octapeptide26-33, gastrin-releasing peptide, thyrotropin-releasing hormone, and VIP10-28 were totally inactive. The response to 10 microM VIP was not antagonized by several dopamine antagonists, indicating the presence of a population of specific VIP receptors coupled to adenylate cyclase, distinct from the population of dopamine receptors coupled to adenylate cyclase also known to be present in this tissue. Finally, experiments involving the use of fractions of isolated horizontal cells indicate that these neurons possess a population of VIP receptors coupled to cyclic AMP production which would appear to share a common pool of adenylate cyclase with a population of similarly coupled dopamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of vasoactive intestinal peptide and other peptides on cyclic AMP accumulation in intact pieces and isolated horizontal cells of the teleost retina. 619 61

The cellular and molecular effects of forskolin, a direct, nonhormonal activator of adenylate cyclase, were assessed on the enzyme secretory process in dispersed rat pancreatic acinar cells. Forskolin stimulated adenylate cyclase activity in the absence of guanyl nucleotide. It promoted a rapid and marked increase in cellular accumulation of cyclic AMP alone or in combination with vasoactive intestinal peptide (VIP) but was itself a weak pancreatic agonist and did not increase the secretory response to VIP or other cyclic AMP dependent agonists. Somatostatin was a partial antagonist of forskolin stimulated cyclic AMP synthesis and forskolin plus cholecystokinin-octapeptide (CCK-OP) induced amylase release. Forskolin potentiated amylase secretion in response to calcium-dependent agonists such as CCK-OP, carbachol and A-23187, but did not affect the ability of CCK-OP and (or) carbachol to mobilize 45Ca from isotope preloaded cells; forskolin alone did not stimulate 45Ca release. In calcium-poor media, the secretory response to forskolin and CCK-OP was reduced in a both absolute and relative manner. The data suggests that calcium plays the primary role as intracellular mediator of enzyme secretion and that the role of cyclic AMP may be to modulate the efficiency of calcium utilization.
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PMID:Forskolin potentiates calcium-dependent amylase secretion from rat pancreatic acinar cells. 619 99

Rabbit isolated gastric glands were used to investigate the dependence of pepsinogen and acid secretions on extraglandular pH. Changing pH from 8.0 to 6.7 caused small increases in pepsinogen secretory responses to isoproterenol, carbachol, cholecystokinin octapeptide, Boots' secretin, and hyperosmolarity but caused large increases in responses to 8-bromoadenosine 3',5'-cyclic monophosphate (8BrcAMP), 8-bromoinosine 3',5'-cyclic monophosphate (8BrcIMP), and forskolin. The similar effect of pH on responses to 8BrcAMP, 8BrcIMP, and forskolin was suggested to reflect a commonality in their proposed mechanisms of action. It was concluded that reducing extraglandular pH indirectly caused an increase in activity of cAMP-dependent protein kinase or of a subsequent step in cAMP-dependent regulation of pepsinogen secretion. 8BrcAMP-stimulated acid secretion also increased as pH was changed from 8.0 to 6.7, and a similar explanation of the effect was suggested. However, histamine-stimulated acid secretion and adenyl cyclase activity decreased markedly as pH was lowered over this range. It was suggested that cAMP was rate limiting for stimulation by histamine and that the effect of pH on histamine-stimulated acid secretion could be attributed to an effect of pH on adenyl cyclase activity.
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PMID:pH dependence of pepsinogen and acid secretion in isolated gastric glands. 619 90


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