Effects of the immunosuppressants cyclosporin A and FK 506 on exocytosis in the rat exocrine pancreas <i>in vitro</i>

Waschulewski, Ingo H.; Hall, Douglas; Kern, Horst F.; Edwardson, J. Michael

doi:10.1111/j.1476-5381.1993.tb13483.x

Cited by 25 publications

(20 citation statements)

References 29 publications

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“…Moreover, minimal changes in serum amylase level or pancreatic histology were seen after administration of CsA or FK506, making a toxic effect on the pancreas unlikely. Previous reports (9,48) suggest the potential harmful effect of these agents in rat pancreas. These differences may occur from Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Groblewski et al (20,21) demonstrated that CCK treatment of dissociated pancreatic acini activated CN in that a specific protein substrate, calcium-regulated heat-stable protein of 24 kDa (CRHSP-24), was dephosphorylated after CCK stimulation, and this effect was blocked by CsA or FK506. These inhibitors also had a modest effect in inhibiting pancreatic amylase secretion, leading to the suggestion that CN may play a role in stimulus-secretion coupling in pancreatic acinar cells (20,48). Recent studies in other tissues, however, have shown that CN plays a critical role in experimental models of cardiac (34,36,45) or skeletal muscle (11,32,42) hypertrophy.…”

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confidence: 99%

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Calcineurin mediates pancreatic growth in protease inhibitor-treated mice

Tashiro¹,

Samuelson²,

Liddle³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Calcineurin mediates pancreatic growth in protease inhibitor-treated mice. Am J Physiol Gastrointest Liver Physiol 286: G784-G790, 2004. First published December 18, 2003 10.1152/ ajpgi.00446.2003.-CCK acts on pancreatic acinar cells to increase intracellular Ca 2ϩ leading to secretion of digestive enzymes and, in the long term, pancreatic growth. Calcineurin (CN) is a serine/ threonine-specific protein phosphatase activated by Ca 2ϩ and calmodulin that recently has been shown to participate in the growth regulation of cardiac and skeletal myocytes. We therefore tested the effect of two different CN inhibitors, cyclosporine A (CsA) and FK506, on mouse pancreatic growth induced by oral administration of the synthetic protease inhibitor camostat, a known stimulator of endogenous CCK release. Mice were fed a powdered diet with or without 0.1% camostat. Pancreatic wet weight, protein, and DNA were increased in response to camostat in a time-dependent manner over 10 days in ICR mice but not in CCK-deficient mice. Both CsA (15 mg/kg) and FK506 (3 mg/kg) given twice daily blocked the increase in pancreatic wet weight and protein and DNA content induced by camostat. The increase in plasma CCK induced by camostat was not blocked by CsA or FK506. Camostat feeding also increased the relative amount of CN protein, whereas levels of MAPKs, ERKs, and p38 were not altered. In summary, 1) CCK released by chronic camostat feeding induces pancreatic growth in mice; 2) this growth is blocked by treatment with both CsA and FK506, indicating a role for CN; 3) CCK stimulation also increases CN protein. In conclusion, activation and possibly upregulation of CN may participate in regulation of pancreatic growth by CCK in mice.cholecystokinin; camostat; FK506; cyclosporine A A VARIETY OF GASTROINTESTINAL peptides have been implicated in the regulation of proliferation and differentiation in the mature gastrointestinal tract and the pancreas (30,56). It is well known that feeding initiates pancreatic protein synthesis and secretion and that adaptation to a high-protein diet results in pancreatic growth (17, 18). More detailed studies have shown that among gastrointestinal peptides, CCK is released in response to dietary protein leading to pancreatic growth. Injection of CCK increases pancreatic wet weight and protein and DNA content in vivo over 4-10 days (8,37,40,43). Oral administration of soybean trypsin inhibitor (5, 44) or the synthetic protease inhibitor camostat (10,15,37,52,55), as well as pancreaticobiliary diversion (13, 39), increase the release of endogenous CCK into the blood and induce pancreatic growth. Moreover, CCK-A receptor antagonists that block the action of exogenous and endogenous CCK inhibit pancreatic growth (10, 13, 37, 39, 52). Therefore, most of the studies of pancreatic growth have been focused on CCK as a key regulator.In pancreatic acinar cells, the intracellular mechanisms of enzyme secretion have been well documented. CCK activates the release of intracellular Ca 2ϩ and the influx of Ca 2ϩ and generate...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Calcineurin mediates pancreatic growth in protease inhibitor-treated mice

Tashiro¹,

Samuelson²,

Liddle³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…An important target of Ca 2ϩ is Ca 2ϩ /calmodulin-dependent serine/threonine phosphatase 2B (protein phosphatase 2B or calcineurin). In the exocrine pancreas, the Ca 2ϩ -calcineurin pathway is required for acinar cell growth (33,39) and may have a modest effect on enzyme secretion (5,11,43). However, the role of calcineurin in early pancreatitis events is not known.…”

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confidence: 99%

Caerulein-induced intracellular pancreatic zymogen activation is dependent on calcineurin

Husain¹,

Grant²,

Gorelick³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Aberrant cytosolic Ca2+ flux in pancreatic acinar cells is critical to the pathological pancreatic zymogen activation observed in acute pancreatitis, but the downstream effectors are not known. In this study, we examined the role of Ca2+-activated protein phosphatase 2B (or calcineurin) in zymogen activation. Isolated pancreatic acinar cells were stimulated with supraphysiological caerulein (100 nM) with or without the calcineurin inhibitors FK506 or cell-permeable calcineurin inhibitory peptide (CiP). Chymotrypsin activity was measured as a marker of zymogen activation, and the percent amylase secretion was used as a measure of enzyme secretion. Cytosolic Ca2+ changes were recorded in acinar cells loaded with the intermediate Ca2+-affinity dye fluo-5F using a scanning confocal microscope. A 50% reduction in chymotrypsin activity was observed after pretreatment with 1 μM FK506 or 10 μM CiP. These pretreatments did not affect amylase secretion or the rise in cytosolic Ca2+ after caerulein stimulation. These findings suggest that calcineurin mediates caerulein-induced intra-acinar zymogen activation but not enzyme secretion or the initial caerulein-induced cytosolic Ca2+ signal.

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“…Using CsA and FK506 as inhibitors, our laboratory previously identified a novel calcineurin substrate of unknown function named calcium-regulated heat-stable protein of 24 kDa (CRHSP-24), based on its calcium regulation, heat stability, and apparent molecular weight of 24 kDa (22). Whereas high concentrations of CsA were found to inhibit amylase secretion (21,56), it is not clear whether FK506 inhibits pancreatic exocrine secretion (13,56) or not (unpublished observations). More recently, both FK506 and CsA were found to block pancreatic growth in response to chronic elevation of CCK induced by feeding trypsin inhibitor to mice (55), indicating a possible role for calcineurin in pancreatic growth.…”

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confidence: 99%

“…The endogenous phosphatase inhibitors 1 and 2, as well as chemical inhibitors of PP1 and PP2A, fail to inhibit calcineurin, whereas immunosuppressants do not block these other phosphatases (48). The use of FK506 and CsA has implicated calcineurin in a number of cellular processes, including pancreatic endocrine (14,23) and exocrine secretion (13,21,56); calcium-stimulated gene transcription (11,24); cell growth (19,36); cell cycle regulation (33); apoptosis (53); endocytosis (12); cytoskeletal organization (26); and neurite outgrowth (30). Moreover, study of the side effects of CsA and FK506 in organ transplant therapy has implicated calcineurin in the protein synthesis mechanisms of some tissues, including kidney and liver (7,8).…”

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confidence: 99%

Calcineurin is required for translational control of protein synthesis in rat pancreatic acini

Sans¹,

Williams²

2004

American Journal of Physiology-Cell Physiology

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Sans, Maria Dolors, and John A. Williams. Calcineurin is required for translational control of protein synthesis in rat pancreatic acini. Am J Physiol Cell Physiol 287: C310 -C319, 2004. First published March 24, 2004 10.1152 10. /ajpcell.00534.2003creases the rate of net protein synthesis in rat pancreatic acini by activating initiation and elongation factors required for translation. The immunosuppressant FK506 inhibits the Ca 2ϩ -calmodulin-dependent phosphatase calcineurin in pancreatic acinar cells and blocks pancreatic growth induced by chronic CCK treatment. To test a requirement for calcineurin in the activation of the translational machinery stimulated by CCK, we evaluated the effects of FK506 on protein synthesis and on regulatory initiation and elongation factors in rat pancreatic acini in vitro. CCK acutely increased protein synthesis in acini from normal rats with a maximum increase at 100 pM CCK to 170 Ϯ 11% of control. The immunosuppressant FK506 dosedependently inhibited CCK-stimulated protein synthesis over the same concentration range that blocked calcineurin activity, as assessed by dephosphorylation of the calcineurin substrate calciumregulated heat-stable protein of 24 kDa. Another immunosuppressant, cyclosporin A, inhibited protein synthesis, but its effects appeared more complex. FK506 also inhibited protein synthesis stimulated by bombesin and carbachol. FK506 did not significantly affect the activity of the initiation factor-2B, or the phosphorylation of the initiation factor-2␣, ribosomal protein protein S6, or the mRNA cap binding protein eukaryotic initiation factor (eIF) 4E. Instead, blockade of calcineurin with FK506 reduced the phosphorylation of the eIF4E binding protein, reduced the formation of the eIF4F complex, and increased the phosphorylation of eukaryotic elongation factor 2. From these results, we conclude that calcineurin activity is required for protein synthesis, and this action may be related to an effect on the formation of the mRNA cap binding complex and the elongation processes. exocrine pancreas; cholecystokinin; translation initiation factors; protein phosphatase 2B; immunosuppressants CALCINEURIN, ALSO KNOWN AS protein phosphatase 2B (PP2B), is a serine/threonine protein phosphatase (48) that is highly regulated by Ca 2ϩ

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Effects of the immunosuppressants cyclosporin A and FK 506 on exocytosis in the rat exocrine pancreas in vitro

Cited by 25 publications

References 29 publications

Calcineurin mediates pancreatic growth in protease inhibitor-treated mice

Calcineurin mediates pancreatic growth in protease inhibitor-treated mice

Caerulein-induced intracellular pancreatic zymogen activation is dependent on calcineurin

Calcineurin is required for translational control of protein synthesis in rat pancreatic acini

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