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 role of a pertussis toxin sensitive GTP-binding protein in mediating between cholecystokinin receptors and phosphatidylinositol 4,5-bisphosphate phosphodiesterase as well as in preventing cholecystokinin from increasing cellular cyclic AMP has been investigated using dispersed acini from rabbit pancreas. Pertussis toxin pretreatment (500 ng/ml, 2 h) did not affect cholecystokinin(octapeptide) (CCK-8)-induced increases in cytosolic free Ca2+ as judged from changes in fluorescence obtained from quin2-loaded acini. Although pretreatment with pertussis toxin was also without effect on resting acinar cell cyclic AMP levels, adenylate cyclase activity was increased, since inhibition of cyclic AMP phosphodiesterase activity by isobutylmethylxanthine (IBMX) resulted in an additional increase in cyclic AMP levels in toxin-treated acini, indicating that acinar cell adenylate cyclase activity is under some tonic inhibitory control by the pertussis toxin-sensitive inhibitory GTP-binding protein (Gi) of the adenylate cyclase system. CCK-8 gave an increase in cyclic AMP levels in both control (1.6-fold) and toxin-treated (2.3-fold) acini, leading to cyclic AMP levels in the toxin-treated acini 2-times as high as those in control acini. In the presence of IBMX, the cyclic AMP response to CCK-8 was again markedly enhanced in acini pretreated with the toxin (3.2- vs. 1.8-fold), resulting in cAMP levels in the toxin-treated acini 3.7-times those in the absence of IBMX, 2.5-times those in control acini in the presence of IBMX and 7.0-times those in control acini in the absence of IBMX. Neither the pretreatment with pertussis toxin, nor the presence of IBMX alone, nor the combination had an effect on basal amylase secretion. However, all three treatments potentiated the stimulatory effect of CCK-8 on amylase secretion and the amount of potentiation was proportional to the cyclic AMP levels reached. Our findings suggest that in the intact pancreatic acinar cell Gi inhibition of the catalytic subunit of the adenylate cyclase may largely be responsible for preventing cholecystokinin from increasing cellular cyclic AMP. They moreover show that cyclic AMP is a modulatory agent in rabbit pancreatic enzyme secretion, not able to stimulate secretion itself, but potentiating effects mediated by the phosphatidylinositol-calcium pathway.
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PMID:Pertussis toxin stimulates cholecystokinin-induced cyclic AMP formation but is without effect on secretagogue-induced calcium mobilization in exocrine pancreas. 243 69

In this study we examine the mechanism by which somatostatin (SRIF-14) inhibits cholecystokinin octapeptide- (CCK-8) but not substance P-mediated release of [3H]acetylcholine (ACh) from the guinea pig ileum. 2',5'-Dideoxyadenosine, an inhibitor of adenylate cyclase, antagonized the action of CCK-8 and forskolin but had no effect on substance-P-evoked release of [3H]ACh. Addition of theophylline enhanced the release of [3H]ACh stimulated by CCK-8 but not by substance P. These observations suggest that CCK-8, but not substance P, can stimulate cholinergic transmission via an adenosine 3',5'-cyclic monophosphate (cAMP)-dependent pathway. Somatostatin inhibited release of [3H]ACh evoked by CCK-8 and forskolin in a dose-related manner. CCK-8- and forskolin- but not substance P-evoked release of [3H]ACh were maximally inhibited in the presence of 10(-6) M somatostatin (49 +/- 5 and 48 +/- 7% of control, respectively). Pretreatment with pertussis toxin (inactivates inhibitory guanine nucleotide binding proteins) reversed the inhibitory effect of somatostatin on the release of [3H]ACh evoked by CCK-8. These observations suggest that CCK-8 but not substance P can stimulate [3H]ACh by a cAMP-dependent pathway. Somatostatin appears to inhibit the cAMP-dependent component of CCK-8-mediated cholinergic transmission via activation of a pertussis toxin-sensitive G protein.
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PMID:Differential action of somatostatin on peptide-induced release of acetylcholine. 247 31

Cellular mechanisms underlying the actions of antisecretory agents were studied with dispersed canine fundic cells; aminopyrine accumulation monitored parietal cell (PC) function. Canine PC have pharmacologically typical histamine (H) H2 and muscarinic (M) receptors. PC also have gastrin (G) receptors, which were selectively blocked by gastrin/CCK antagonists. Potentiating interactions occurred between secretagogues, one of the components of the interdependency between regulatory pathways. Prostaglandins (PG) E2 inhibited H-stimulated PC function. Treatment of PC with pertussis toxin (PT), which inactivates the inhibitory GTP-binding protein of adenylate cyclase (Gi), markedly reduced PG inhibition, indicating PG action via Gi. PC function can also be directly inhibited by H+/K+-ATPase inhibitors, such as omeprazole. When canine mucosal cells were studied, stimulatory G and inhibitory M receptors were present on fundic somatostatin (S) cells. Histamine was localized to canine fundic mast cells, which lacked G or M receptors, a conclusion that may not pertain to fundic histamine cells in other species. Nonparietal cell receptors may be important modulators of the regulation of acid secretion.
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PMID:Mechanisms of action of antisecretory drugs. Studies on isolated canine fundic mucosal cells. 288 44

Functional and specific receptors for vasoactive intestinal peptide (VIP) (determined by their capacity to bind 125I-VIP and activate adenylate cyclase) and cyclic AMP-dependent phosphodiesterase activities were characterized in enterocytes of human fetal small intestine between 18 and 23 weeks of gestation. Half-maximal stimulation of the cyclase and inhibition of 125I-VIP binding in membrane preparations were respectively observed at 1.4 and 5 X 10(-10) M VIP. The peptides structurally related to VIP activated the cyclic AMP generating system at pharmacological doses (10(-7) M and above) in the following order of potency: VIP greater than PHI greater than GRF greater than secretin. Other peptides or test substances, including GIP, pancreatic glucagon, somatostatin-14, gastrin, CCK, neurotensin, pancreatic polypeptide, PYY, substance P, histamine and isoproterenol are inactive in this system, while the ubiquitous adenylate cyclase activators NaF, forskolin and prostaglandins were effective. These results, combined with the appearance of intestinal VIP in nerve fibers at 8 weeks and with the morphological and enzymatic maturation at 9-12 weeks of the intestinal mucosa, indicate that this neuropeptide may regulate either the differentiation or function of enterocytes during the early development of human intestinal mucosa.
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PMID:Vasoactive intestinal peptide receptor activity in human fetal enterocytes. 298 18

Pepsinogen secretion (PS) is modulated at the intracellular level by both cAMP and calcium ion. Cholecystokinin octapeptide (CCK-8), a potent stimulus for PS, is believed to act through calcium. The most extensively studied pathway for calcium-mediated modulation involves the formation of calcium/calmodulin complexes, leading to activation of calmodulin. We have therefore examined the hypothesis that an inhibitor of calmodulin might inhibit PS stimulated by CCK-8. The phenothiazine derivative trifluoperazine (TFP) was chosen as a calmodulin antagonist. We measured in vitro secretion of pepsinogen by isolated gastric glands as a function of TFP concentration 10(-6) M-5 X 10(-4) M), in the presence and absence of a maximal concentration of CCK-8 (10(-7) M). Cellular viability was determined by measurement of release of the enzyme lactate dehydrogenase (LDH) into the medium. TFP did not significantly inhibit PS stimulation by CCK-8 at any concentration (P greater than 0.05). At 10(-4) M, TFP actually augmented PS stimulation by CCK-8 (P less than 0.05). TFP alone significantly stimulated PS (P less than 0.05) at 5 X 10(-5) M and above. TFP did not raise cAMP levels at any concentration tested (P less than 0.05), in contrast to the adenylate cyclase activator forskolin, 10(-5) M, which caused a 6- to 37-fold increase (P less than 0.05). TFP, 2 X 10(-4) did not increase LDH levels significantly (P less than 0.05). Thus a calmodulin inhibitor, TFP, paradoxically stimulates PS. This stimulatory effect of TFP is not cAMP-dependent and is not accompanied by a nonspecific release of LDH into the medium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Paradoxical effect of trifluoperazine, a calmodulin antagonist, on pepsinogen secretion. 301 66

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

(Thr28,Nle31)CCK(23-33) (CCK-9) and gastrin(1-17)I (gastrin) inhibited adenylate cyclase activity in membranes from the tumoral rat pancreatic acinar cell line AR 4-2J through a Bordetella pertussis toxin-sensitive mechanism. This contrasted with the stimulatory effect exerted by CCK-9 on adenylate cyclase activity in membranes from normal rat pancreas. The relative potency of CCK-9, gastrin, and related peptides in inhibiting adenylate cyclase, when confronted with previous evidence, suggests that 'non-selective CCK-gastrin CCK-B receptors' predominating over 'selective CCK-A receptors' in the AR 4-2J cell line, favored the coupling of the first receptors to adenylate cyclase through Gi, while CCK-A receptors capable of stimulating the enzyme through Gs were detected only after Bordetella pertussis toxin pretreatment.
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PMID:CCK and gastrin inhibit adenylate cyclase activity through a pertussis toxin-sensitive mechanism in the tumoral rat pancreatic acinar cell line AR 4-2J. 320 44

CCK release elicited by 40 mM potassium from slices of rat caudato-putamen (cp) was inhibited by VIP. The effect of VIP was maximal at 10(-7) M. VIP does not inhibit CCK release from cerebral cortex at either 10(-7) or 10(-6) M. VIP is known to elevate levels of cAMP in rat brain. VIP inhibition of CCK release appears to be independent of activation of adenylate cyclase because treatment of cp slices with forskolin (2 X 10(-6) to 10(-4) M) does not mimic the inhibitory action of VIP.
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PMID:Vasoactive intestinal polypeptide (VIP) inhibits potassium-induced release of cholecystokinin (CCK) from rat caudato-putamen but not from cerebral cortex. 378 88

ATP-dependent 45Ca2+ uptake was investigated in purified plasma membranes from rat pancreatic acinar cells. Plasma membranes were purified by four subsequent precipitations with MgCl2 and characterized by marker enzyme distribution. When compared to the total homogenate, typical marker enzymes for the plasma membrane, (Na+,K+)-ATPase, basal adenylate cyclase and CCK-OP-stimulated adenylate cyclase were enriched by 43-fold, 44-fold, and 45-fold, respectively. The marker for the rough endoplasmic reticulum was decreased by fourfold compared to the total homogenate. Comparing plasma membranes with rough endoplasmic reticulum, Ca2+ uptake was maximal with 10 and 2 mumol/liter free Ca2+, and half-maximal with 0.9 and 0.5 mumol/liter free Ca2+. It was maximal at 3 and 0.2 mmol/liter free Mg2+ concentration, at an ATP concentration of 5 and 1 mmol/liter, respectively, and at pH 7 for both preparations. When Mg2+ was replaced by Mn2+ or Zn2+ ATP-dependent Ca2+ uptake was 63 and 11%, respectively, in plasma membranes; in rough endoplasmic reticulum only Mn2+ could replace Mg2+ for Ca2+ uptake by 20%. Other divalent cations such as Ba2+ and Sr2+ could not replace Mg2+ in Ca2+ uptake. Ca2+ uptake into plasma membranes was not enhanced by oxalate in contrast to Ca2+ uptake in rough endoplasmic reticulum which was stimulated by 7.3-fold. Both plasma membranes and rough endoplasmic reticulum showed cation and anion dependencies of Ca2+ uptake. The sequence was K+ greater than Rb+ greater than Na+ greater than Li+ greater than choline+ in plasma membranes and Rb+ greater than or equal to K+ greater than or equal to Na+ greater than Li+ greater than choline+ for rough endoplasmic reticulum. The anion sequence was Cl greater than or equal to Br greater than or equal to 1 greater than SCN greater than NO3 greater than isethionate greater than cyclamate greater than gluconate greater than SO2(4) greater than or equal to glutarate and Cl- greater than Br greater than gluconate greater than SO2(4) greater than NO3 greater than 1 greater than cyclamate greater than or equal to SCN, respectively. Ca2+ uptake into plasma membranes appeared to be electrogenic since it was stimulated by an inside-negative K+ and SCN diffusion potential and inhibited by an inside-positive diffusion potential. Ca2+ uptake into rough endoplasmic reticulum was not affected by diffusion potentials. We assume that the Ca2+ transport mechanism in plasma membranes as characterized in this study represents the extrusion system for Ca2+ from the cell that might be involved in the regulation of the cytosolic Ca2+ level.
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PMID:Electrogenic calcium transport in plasma membrane of rat pancreatic acinar cells. 399 24

The time course of activation and deactivation and the degree of activation at steady state [Ea]/[Etot] of adenylate cyclase, in semi-purified rate pancreatic plasma membranes, were compatible with a simple two-state model with three rate constants, so that [Ea]/[Etot] = k+1/(k+1 + k2 + k-1). The hormone CCK-8 increased k+1 with GTP in a dose-dependent manner, from 0.2 to 10.9 min-1; k-1 increased from 0.01 to 0.3 min-1, i.e. in proportion, but k2 was unaltered at 7 min-1, so that [Ea]/[Etot] increased 15-fold, from 4 to 61%. A similar activation was obtained after cholera toxin pretreatment by a different mechanism. The toxin pretreatment exerted a major inhibitory effect on the value of k2 and on the corresponding GTPase activity. A pretreatment at the high cholera toxin concentration (10 micrograms/ml) exerted two additional effects that became evident when p[NH]ppG rather than GTP was used as activating nucleotide: (a) a relatively large increase in k-1 from an unmeasurably low control value to 0.3 min-1, and (b) a four-fold increase in the p[NH]ppG activation rate, k+1. This contrasted with the action of CCK-8, which increased k-1 and k+1 in proportion.
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PMID:Determining steps in the regulatory GTPase cycle of rat pancreatic adenylate cyclase. 612 39


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