Significance of cyclic AMP in the regulation of exocrine pancreas secretion

Knodell, Robert G.; Toskes, Philip P.; Reber, Howard A.; Brooks, Frank P.

doi:10.1007/bf01898480

Cited by 30 publications

(10 citation statements)

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“…After addition of synthetic COOH-terminal octapeptide of CCK (CCK-octapeptide, 10 (Table I). The inhibition of carbamylcholine-stimulated calcium outflux by atropine increased with increasing concentrations of atropine and decreased with increasing concentrations of carbamylcholine, indicating that atropine is a competitive inhibitor of carbamylcholine (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Although the sequence of morphologic changes attending pancreatic enzyme secretion has been characterized (4), the coincident sequence of biochemical events is poorly understood and the mechanism by which CCK and cholinergic agents initiate pancreatic secretion has not been characterized. Some investigators (5)(6)(7)(8)(9)(10) have suggested that stimulation of cellular accumulation of adenosine 3',5'-cyclic monophosphate (cyclic AMP) is involved in stimulation of pancreatic enzyme secretion, while others (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) have focused on changes in membrane transport of cations, in general, and of calcium in particular.…”

Section: Introductionmentioning

confidence: 99%

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Action of cholecystokinin and cholinergic agents on calcium transport in isolated pancreatic acinar cells.

Gardner¹,

Conlon²,

Kleveman³

et al. 1975

J. Clin. Invest.

155

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Action of cholecystokinin and cholinergic agents on calcium transport in isolated pancreatic acinar cells.

Gardner¹,

Conlon²,

Kleveman³

et al. 1975

J. Clin. Invest.

155

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“…cAMP levels did not change significantly. cGMP increases were maximal at 2 min then subsided by [4][5][6][7] min to a plateau about two to three times that of basal level. This plateau was maintained for the duration of the secretagogue stimulus.…”

mentioning

confidence: 95%

Cellular cyclic nucleotides and enzyme secretion in the pancreatic acinar cell.

Haymovits¹,

Scheele²

1976

Proc. Natl. Acad. Sci. U.S.A.

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Cellular levels of cAMP and cGMP were measured in guinea pig pancreatic lobules incubated in vitro, during basal or stimulated secretion. Stimulation with optimal concentrations of carbamylcholine (carbachol) (10-5 M), pancreozymin (0.1 unit/ml), and caerulein (10-9 M) resulted within seconds in a sharp rise in cGMP levels, from five to more than 20 times that of basal levels. cAMP levels did not change significantly. cGMP increases were maximal at 2 min then subsided by 4-7 min to a plateau about two to three times that of basal level. This plateau was maintained for the duration of the secretagogue stimulus. Removal of the carbachol stimulus resulted in a rapid decrease in cGMP levels to that of the basal state. The cellular cGMP levels observed within the first 2 min of stimulation correlated closely with the dose of carbachol and the secretory response. Atropine at 10-4 M blocked the cGMP elevation due to carbachol but not that due to pancreozymin, while carbonyl cyanide m-chlorophenyl hydrazone, an uncoupler of oxidative phosphorylation, blocked the response to both secretagogues. Similar though less extensive findings were observed using rabbit pancreatic lobules incubated in vitro. High concentrations (10-2-10-3 M) of the dibutyryl and 8-bromo analogues of both nucleotides were effective, though suboptimal, secretagogues. In the case of the cAMP analogues, the secretory response was associated with a rise in endogenous cGMP levels, similar to that observed during suboptimal carbachol stimulation.These findings suggest that cGMP may be an intracellular mediator in the process of stimulus secretion coupling in the acinar cell of the exocrine pancreas. Earlier attempts to define a role for cAMP in stimulus-secretion coupling in the acinar cell of the exocrine pancreas resulted in inconsistent findings (1-8 Pancreatic Lobule Preparations. Albino guinea pigs, 500 g in weight, and fed ad lib., were sacrificed by a blow to the head. The excised pancreas was immersed in cold KrebsRinger bicarbonate buffer, pH 7.4, equilibrated with 95% 02-5% CO2. Lobules were prepared as described (15). Each experimental flask contained 10 lobules (about 60 mg wet weight) supported on a nylon mesh disc (about 2 cm in diameter) in 5 ml of Krebs-Ringer buffer supplemented by physiological levels of glucose and amino acids. Secretagogues and other agents were added or omitted as indicated. Incubation was carried out in a shaker bath at 370 for varying periods of time under a 95% 02-5% CO2 atmosphere. Timed incubation was terminated by removal of the nylon mesh with the adherent lobules and instant freezing of the tissue in liquid nitrogen. Similar in vitro preparations of pancreatic lobules were made from pancreata excised from albino New Zealand rabbits 2.5 kg in weight; albino rats, 150-200 g; and mice, 25-30 g, all fed ad lib.Extraction and Measurement of Cyclic Nucleotides. The frozen tissue was suspended and homogenized in 3 ml of ice-cold 6% trichloroacetic acid. The homogenate was centrifuged at 5000 X g for 15 min; t...

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“…The dibutyryl derivative of cyclic AMP stimulates protein secretion from isolated mouse [I] and rabbit [2,3] pancreas but not from rat [4,5] and cat [6] pancreas. I n response to pancreozymin stimulation, cyclic AMP levels do not increase in guinea-pig pancreas in vitro [7] while the rise observed in vivo in the cat [S] is not clearly associated with protein release.…”

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confidence: 99%

“…Adenylate cyclase in a fresh 4000 x g pellet from rat pancreas is half-maximally stimulated by a concentration of purified pancreozymin [9] exceeding 200 times the maximal concentration which is effective on intact cells. Theophylline in vitro produces an increase in the basal output of enzymes in mouse [l], rat [5], rabbit [2,3] and cat [6], but these effects are not as evident as those noted after pancreozymin stimulation. Theophylline also potentiates slightly the effect on the pancreas of submaximal concentrations of the dibutyryl derivative of cyclic AMP in the rat [a] and of pancreozymin in rabbit [3] and cat [6].…”

mentioning

confidence: 99%

Hydrolysis of the Cyclic 3′:5′‐Monophosphates of Adenosine and Guanosine by Rat Pancreas

Robberecht

Deschodt-Lanckman

Neef

et al. 1974

European Journal of Biochemistry

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I. Crude rat pancreas homogenates had two apparent Km values for hydrolysis of adenosine 3':5'-monophosphate (cyclic AMP) of 1.9 and 32 pM with corresponding apparent V values of 147 and 1033 pmol x min-l x mg protein-l a t 30 "C. The same homogenates exhibited two apparent K, for hydrolysis of guanosine 3':5'-monophosphate (cyclic GMP) of 4 and 40 pM with apparent V values of 70 and 300 pmol x rnin-l x mg protein-I, respectively. I n comparison with liver and parotids the affinity of low-Km phosphodiesterases for cyclic nucleotides was low but the velocity of hydrolysis was higher. Cyclic GMP interfered somewhat with cyclic AMP hydrolysis but it was not possible to define Ki values. Aminophylline was a weak non-competititive inhibitor of both forms of cyclic AMP phosphodiesterases.2. A major portion (6501,) of both cyclic AMP phosphodiesterase activities and of the enzyme with a 40-pM K m €or cyclic GMP was confined to the cytosol while the remnant was partitioned among particulate fractions. The subcellular distribution of the enzyme, presenting a 4-pM Km for cyclic GMP, differred since as much as 82O/, of its activity was recovered in the cytosol.3. A secretory cycle induced in vivo by pilocarpine (30 mg/kg) did not influence phosphodiesterase activities for 3 h after the intraperitoneal injection. A 10-day adaptation to protein malnutritution tended to increase the activity of the low-Km cyclic AMP phosphodiesterase.4. It was concluded that the rat pancreas was able to hydrolyse cyclic nucleotides a t physiological concentrations and that more than one enzyme was apparently involved.Evidence for participation of adenosine 3' : 5'-monophosphate (cyclic AMP) in stimulus-secretion coupling in the exocrine pancreas is increasing rapidly. However the data are ambiguous and the physiological effect of pancreozymin and acetylcholine on adenylate cyclase is not yet definitely clarified.The dibutyryl derivative of cyclic AMP stimulates protein secretion from isolated mouse [I] and rabbit [2,3] pancreas but not from rat [4,5] and cat [6] pancreas. I n response to pancreozymin stimulation, cyclic AMP levels do not increase in guinea-pig pancreas in vitro [7] while the rise observed in vivo in the cat [S] is not clearly associated with protein release. Adenylate cyclase in a fresh 4000 x g pellet from rat pancreas is half-maximally stimulated by a concentration of purified pancreozymin [9] exceeding 200 times the maximal concentration which is effective on intact cells. These data suggest that stimulus-secretion coupling may involve a coordinated monitoring of both adenylate cyclase and cyclic AMP phosphodiesterase(s). Over 10 years ago, Butcher and Sutherland [lo] noticed the presence of an active high-Km cyclic AMP phosphodiesterase in dog pancreas. For the last 3 years, Beavo et al. [l 11 have initiated more interest in the hydrolysis of cyclic nucleotides, with concentrations closer to physiological levels and recently Uzunov and Weiss [12] were able to differentiate up to six different activities in the rat cere...

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Significance of cyclic AMP in the regulation of exocrine pancreas secretion

Cited by 30 publications

References 0 publications

Action of cholecystokinin and cholinergic agents on calcium transport in isolated pancreatic acinar cells.

Action of cholecystokinin and cholinergic agents on calcium transport in isolated pancreatic acinar cells.

Cellular cyclic nucleotides and enzyme secretion in the pancreatic acinar cell.

Hydrolysis of the Cyclic 3′:5′‐Monophosphates of Adenosine and Guanosine by Rat Pancreas

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