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)

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

Isolated gastric glands were used to investigate the action of forskolin, a novel diterpene extracted from the Indian plant Coleus forskohlii. Forskolin was found to stimulate both acid formation and pepsinogen secretion. The stimulation was rapid, reversible and dose dependent with an ED50 of approx. 1 microM. The efficacy of forskolin was similar to that of more commonly used secretagogues, e.g. histamine, carbachol, cyclic AMP derivatives. The responses to forskolin were not inhibited by any of the receptor-specific antagonists tested. Forskolin activated adenyl cyclase in gland homogenates over a dose range similar to that required for stimulation of secretory activity. Forskolin was found to be more effective in activating adenyl cyclase than histamine, isoproterenol or NaF. Treatment of gastric glands with forskolin resulted in a 100-fold increase in tissue cAMP levels, supporting the idea that forskolin activates adenyl cyclase in the intact cell. The results are interpreted to show that forskolin stimulation of gastric secretions is due to activation of adenyl cyclase with a consequent increase in tissue cAMP.
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PMID:Forskolin stimulation of acid and pepsinogen secretion by gastric glands. 629 72

Forskolin, a specific diterpene activator of adenylate cyclase in intact cells and cellular homogenates, was used to examine the relationship among adenosine 3',5'-cyclic monophosphate (cAMP) metabolism, gastric acid, and pepsinogen secretion in isolated gastric glands. This agent was found to stimulate [14C]aminopyrine (AP) accumulation and respiration, both measurements of which are indexes of parietal cell acid secretory responsiveness and pepsinogen secretion, which is a measure of chief cell activity. Forskolin also increased cAMP content and activated cAMP-dependent protein kinase in the glands. The histamine H2-receptor antagonist, cimetidine, inhibited forskolin-stimulated increases in AP accumulation and respiration when submaximal concentrations of forskolin were used but had not effect on the other response parameters. Forskolin also potentiated the action of the muscarinic agonist, carbachol, in both the presence and absence of cimetidine. Since there was a close kinetic and temporal correlation between the secretory response parameters and cAMP-dependent protein kinase activation, it appears that cAMP plays an important role in the mediation of gastric acid and pepsinogen secretion. The inhibitory action of cimetidine on forskolin-stimulated AP accumulation and respiration suggest that forskolin potentiates the action of endogenous histamine present in the glands. Forskolin potentiation of carbachol in the presence of maximum inhibitory concentrations of cimetidine indicates that previously observed potentiating interactions between carbachol and histamine, secretagogues which appear to act via cAMP-independent and cAMP-dependent mechanisms, respectively, involve intracellular events that occur subsequent to the binding of these agents to their respective receptors and subsequent to an increase in intracellular cAMP content.
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PMID:Forskolin stimulation of acid and pepsinogen secretion in isolated gastric glands. 631 18

We examined the interaction among secretagogues that stimulate pepsinogen secretion through different pathways in vivo and in vitro. In in vitro study, a combined administration of secretin and carbachol or cholecystokinin octapeptide (CCK-8) to the culture medium of chief cells potentiated pepsinogen secretion. Moreover, the response induced by carbachol or CCK-8 with forskolin was greater than that with secretin. We examined the interaction among receptor-related second mediators, and found that carbachol- or CCK-8-induced intracellular Ca2+ concentration ([Ca2+]i) increase was not affected by secretin or forskolin. Both these substances, however, significantly reduced secretin-induced cAMP production. On the contrary, CCK-8 significantly increased forskolin-induced cAMP production, while carbachol increased it slightly. Calcium ionophore, A23187, or protein kinase C activator, phorbol 12-myristate 13-acetate (PMA), did not alter secretin- or forskolin-induced cellular cAMP production; and the reductive effect of carbachol or CCK-8 on secretin-induced cAMP production was restored by their competitive antagonists, atropine or lorglumide. EC50 of those antagonists was almost the same value as IC50 on pepsinogen secretion and [Ca2+]i increase. These results indicate that secretin-induced cAMP production is interfered with by receptor related agonists like CCK-8 and carbachol. It may be suggested that there is a kind of "cross-talk," between the adenylate cyclase system, that is, the secretin receptor, and carbachol or CCK-8 receptor. The interactions between secretin and other secretagogues (carbachol, CCK-8, tetragastrin and histamine) were examined using the perfused rat stomach.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction among secretagogues on pepsinogen secretion from rat gastric chief cells. 755 Jan 21

Inhibition both in vivo and in vitro of pepsinogen secretion by somatostatin (SS) and the histological demonstration that fundic D-cells contain long cytoplasmic processes extending to chief cells suggest a possible direct effect of SS on chief cell function. The aim of the present study was to determine whether SS interacts directly with receptors on isolated gastric chief cells and, if so, how SS alters cell function. Binding of 125I-[Tyr11]SS14 to chief cells was saturable, time and temperature dependent, and was inhibited by both SS14 (Ki 1.6 nM) and SS28 (Ki 5.2 nM). SMS-201-995 was 1,300-fold less potent than SS14. Calcium-mobilizing secretagogues reduced binding of 125I-[Tyr11]SS14 with efficacies of cholecystokinin octapeptide (CCK-8) > carbachol > gastrin. Adenosine 3',5'-cyclic monophosphate (cAMP)-activating secretagogues also inhibited binding with efficacies of secretin > vasoactive intestinal polypeptide (VIP). 12-O-tetradecanoylphorbol 13-acetate (TPA) or A-23187 also decreased binding. Analyses demonstrated that CCK-8 and TPA were decreasing the affinity of SS receptors for 125I-[Tyr11]SS14 without affecting their binding capacity. Both SS14 and SS28 at a maximally effective concentration inhibited cAMP production caused by VIP or secretin (20-30%) but did not alter cytosolic calcium ([Ca2+]i), inositol phosphates, or pepsinogen release. We conclude that chief cells possess SS receptors with a high affinity for both SS14 and SS28 but low affinity for SMS-201-995 and thus resemble the SSB receptors described in the rat cerebral cortex. Although occupation of these receptors by SS has no effect on pepsinogen release induced by secretagogues acting through either the calcium or the cAMP pathway, SS receptor occupation is regulated by agents activating phospholipase C, adenylate cyclase, protein kinase C, and [Ca2]i.
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PMID:Chief cells possess somatostatin receptors regulated by secretagogues acting through the calcium or cAMP pathway. 791 Dec 77

In order to determine whether tachykinins alter the function of chief cells and to characterize the receptors mediating the effect, we investigated the abilities of various substance P (SP)-related peptides to inhibit the binding of 125I-Bolton-Hunter labeled substance P (125I-BH-SP) and their abilities to alter cell function in dispersed chief cells from guinea pig stomach. Binding of 125I-BH-SP was saturable, reversible, time- and temperature-dependent and was inhibited by several SP-related peptides with relative potencies of SP = physalaemin (IC50:0.19 nM) > SP methyl ester (SP-ME) (IC50:3.3 nM) > eledoisin (IC50:6.1 nM) > neurokinin A (NKA) (IC50: 65 nM) > neurokinin B (NKB) (IC50:80 nM). Analyses of these binding data demonstrated that chief cells possess a high and low affinity class of binding sites. Neither 125I-NKA nor [phenylalanyl-3,4,5-3H]senktide demonstrated saturable binding to chief cells. Acid stripping experiments demonstrated rapid ligand internalization with 55% of the bound radioligand internalized by 10 min. Phospholipase C activating agents (carbachol, CCK-8), adenylate cyclase activating agents (secretin, VIP), TPA and the calcium ionophore, A23187, all inhibited the binding of 125I-BH-SP and it was due to inhibition of ligand internalization with no change in surface bound parameters. SP (0.1 microM) stimulated pepsinogen secretion but was 4-times less efficacious than CCK-8 (10 nM) or carbachol (1 mM). 10 nM SP stimulated a rapid increase in cytoplasmic free calcium concentration ([Ca2+]i) followed by a sustained elevation lasting 2 min. Single cell spectroscopy demonstrated SP (10 pM to 1 microM) did not cause calcium oscillations. The NK1 receptor antagonist, CP96,345 specifically inhibited the SP-stimulated changes in [Ca2+]i and pepsinogen secretion. The relative potencies of SP-related peptides to stimulate pepsinogen secretion and [Ca2+]i demonstrated a close agreement with their abilities to inhibit the binding of 125I-BH-SP, and comparison of the dose-response curves suggests occupation of the low affinity sites mediate changes in biologic activity. In conclusion, the present study demonstrates that chief cells possess a NK1 subtype of tachykinin receptor, occupation of the low affinity sites of this receptor cause calcium mobilization and pepsinogen secretion, and that binding to this receptor is regulated by agents that activate phospholipase C, adenylate cyclase, protein kinase C and calcium mobilization.
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PMID:Gastric chief cells possess NK1 receptors which mediate pepsinogen secretion and are regulated by agents that increase cAMP and phospholipase C. 867 32

Cell isolation may impair secretory chief cell functions. To evaluate whether a monolayer culture results in a recovery, we compared the effects of cholecystokinin (CCK) octapeptide (CCK-8) on pepsinogen release from freshly isolated and from cultured porcine chief cells. CCK-8 had no significant effect on freshly isolated porcine chief cells but stimulated pepsinogen release from 36- and 60-hour cultured cells with EC50 values of 180 and 130 nmol/l, respectively. Maximal stimulation, achieved at a concentration of 1 micromol/l, amounted to 289 +/- 63 (p <0.01) and 401 +/- 64% (p <0.01) of the respective control value. In addition, the CCK-8 concentration-response curve for 60-hour, but not for 36-hour cultured chief cells displayed a second stimulatory peak at a CCK-8 concentration of 100 pmol/l (266 +/- 55% of control value, p < 0.05) with an EC50 value of 16 pmol/l. The CCKA-receptor antagonist devazepide (10 nmol/l) prevented the stimulatory effect of 1 micromol/l CCK-8 on pepsinogen release of 60-hour cultured cells. The adenylate cyclase activator forskolin (10 micromol/l) potentiated the low concentration CCK-8 effect, shifting the peak stimulation to a CCK-8 concentration of 10 pmol/l, and inhibited the high concentration CCK-8 effect on 60-hour cultured cells. These results indicate a time-dependent recovery of the CCK response of porcine gastric chief cells in monolayer culture and suggest that this model has an advantage over freshly isolated chief cells with regard to the pharmacological characterization of CCK effects.
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PMID:Recovery of cholecystokinin response of porcine gastric chief cells during monolayer culture. 901 5

Human gastric mucosa contains aspartic proteinases that can be separated electrophoretically on the basis of their physical properties into two major groups: Pepsinogen I (PGA, PGI); and Pepsinogen II (PGC, PGII). Pepsinogens consist of a single polypeptide chain with molecular weight of approximately 42,000 Da. Pepsinogens are mainly synthesized and secreted by the gastric chief cells of the human stomach before being converted into the proteolytic enzyme pepsin, which is crucial for the digestive processes in the stomach. Pepsinogen synthesis and secretion are regulated by positive and negative feed-back mechanisms. In the resting state pepsinogens are stored in granules, which inhibit further synthesis. After appropriate physiological or external chemical stimuli, pepsinogens are secreted in the stomach lumen where hydrochloric acid, secreted by the parietal cells, converts them into the corresponding active enzyme pepsins. The stimulus-secreting coupling mechanisms of pepsinogens appear to include at least two major pathways: one involving cAMP as a mediator, the other involving modification of intracellular Ca(2+)concentration. Physiological or external chemical stimuli acting through the intracellular metabolic adenyl cyclase are more effective in inducing ' de novo ' pepsinogen synthesis than those acting through intracellular Ca(2+). The activation of protein kinase C (PK-C) would appear to be involved in regulatory processes. The measurement of pepsinogens A and C in the serum is considered to be one of the non-invasive biochemical markers for monitoring peptic secretion and obtaining information on the gastric mucosa status of healthy subjects. Recently, pepsinogen measurements have been used as an effective biochemical method for evaluating and monitoring patients with gastrointestinal diseases and for checking the effects of drug treatment. The level of PGA in the serum is always high in normal gastritis, while in atrophic gastritis it is always low. In both cases the PGC level in the serum is high. In most gastrointestinal pathologies the ratio between the PGA/PGC decreases. Various reports concerning hormone and/or enzyme modification as well as gastrointestinal distress in the case of long distance exercise have been reported. It has been suggested that the origin of the gastrointestinal distress experienced by long distance runners is a transient ischaemia of the gastric mucosa; it is also suggested that a hypobaric-hypoxic environment could contribute to induce gastric mucosa necrosis. Interrelation between gastrointestinal distress, hypobaric-hypoxic environment and modifications of PGA and PGC, gastrin and cortisol was evaluated in 13 athletes after a marathon performed at 4300 m. Gastrointestinal symptoms occurred in approximately 40% of the athletes. After the race the athletes showed a significant increase of gastrin and cortisol, while the ratio between PGA/PGC decreased. No relationship was observed between gastrointestinal symptoms and hormonal changes after the race. A control group of five subjects, who had been exposed to the same environmental conditions, showed no gastrointestinal or hormonal alteration. Conversely, control subjects presented a significant decrease of cortisol related to the circadian rhythm. The same incidence of gastrointestinal symptoms at high altitude and at sea level and the absence of pathological alteration of PGA and PGC in the serum of the athletes indicates that running a marathon and living for 6 days at 4300 m does not induce gastric mucosa necrosis. Cortisol and gastrin alteration observed in the athletes at this altitude would seem to be related to an activation of the mesopontine and forebrain structures involved in the behavioural and metabolic integration of the autonomic control and arousal and psychophysical-exercise stress. 2000 Academic Press@p$hr
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PMID:Pepsinogens: physiology, pharmacology pathophysiology and exercise. 1067 78

Infection with Helicobater pylori (H. pylori) is associated with various stomach diseases such as chronic gastritis, peptic ulcer, and gastric carcinoma. In order to investigate the mechanisms of enhanced production of pepsinogen by H. pylori in cultured rat gastric cells that have the potential to produce pepsinogen, secretion and synthesis of pepsinogen in the cells exposed to H. pylori extract were determined by measuring the hydrolysis of hemoglobin. Various drugs were used to study the mechanisms of effects of H. pylori on the cells. Exposure of the gastric cells to H. pylori extract caused a significant increase in pepsinogen secretion into the culture medium within 30-180 min in a dose-dependent manner, accompanied by a significant increase in pepsinogen synthesis in the gastric cells after 60 min of incubation. Heat treatment of the H. pylori sonicate at 100 degrees C for 10 min completely abolished the stimulatory effect of H. pylori on pepsinogen secretion. 2',3'-Dideoxyadenosine (50 microM), a specific adenylate cyclase inhibitor, abolished the effect of H. pylori-induced pepsinogen secretion. Puromycin (10 microg/ml), a protein synthesis inhibitor, and nicorandil (0.1 mM), a specific intracellular calcium antagonist, reduced the H. pylori-induced pepsinogen secretion by 37% (p<0.01) and 25% (p<0.05), respectively. On the other hand, actinomycin D (1 microg/ml), an RNA synthesis inhibitor, did not affect the H. pylori-induced pepsinogen secretion. Consequently, dibutyryl cAMP potentially stimulated the pepsinogen secretion from gastric epithelial cells in a dose-dependent manner. H. pylori induces pepsinogen secretion and synthesis by gastric epithelial cells through an increase in the intracellular cAMP and mobilization of the intracellular calcium. In addition, H. pylori affects pepsinogen synthesis at the translational level.
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PMID:Helicobacter pylori induces pepsinogen secretion by rat gastric cells in culture via a cAMP signal pathway. 1135 Dec 76


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