Phorbol ester attenuates cholecystokinin-stimulated amylase release in pancreatic acini of rats

Lee, Ping Cheung; Leung, Ying-Kit; Srimaruta, Nualanong; Cumella, James; Rossi, Thomas M.

doi:10.1016/0167-4889(87)90055-3

Cited by 15 publications

(7 citation statements)

References 27 publications

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“…Phorbol ester pretreatment of these cells also inhibited the CBCstimulated amylase secretion (18,19). The present study shows that pretreatment of rat pancreatic acini with CBC or phorbol esters for 60 min caused similar shifts to the right in the dose-response curve of amylase release in response to CBC.…”

Section: Discussionsupporting

confidence: 58%

“…Since all of these secretagogues seem to activate amylase secretion differently, and since PMA is not acting by inhibiting its own response or a process more distal than Ca2+ mobilization, these results suggest that receptor with low affinity, indicating a receptor desensitization (9). Moreover, Lee et al (19) have demonstrated that PMA pretreatment of rat pancreatic acini led to a decrease in affinity and binding capacity of the high-affinity component of the CCK receptor. In contrast, PMA pretreatment under conditions in which desensitization of CBC-induced amylase release was observed did not lead to alterations of the muscarinic receptor.…”

Section: Discussionmentioning

confidence: 85%

“…Moreover, previous studies have also shown that activation of PK-C by phorbol esters caused a down-regulation of muscarinic receptors (10) and desensitization of cyclic GMP formation mediated by muscarinic receptors (1 1) in mouse neuroblastoma cells. Inhibition of muscarinic receptor-stimulated phosphoinositide hydrolysis and [Ca"] increase was also observed in several cells following phorbol ester preexposure (12)(13)(14)(15)(16) as well as desensitization of muscarinic receptor-stimulated amylase release in guinea pig (17) and rat (18,19) pancreatic acini. However, it has also been recently shown that PK-C activation by phorbol esters had no effect on muscarinic receptor phosphorylation or agonist affinity in the chick heart nor on the ability of acetylcholine to induce desensitization of the muscarinic receptor-mediated inotropic effects (20).…”

mentioning

confidence: 75%

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Carbamylcholine and Phorbol Esters Desensitize Muscarinic Receptors by Different Mechanisms in Rat Pancreatic Acini

et al. 1990

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Pretreatment of rat pancreatic acini with phorbol 12-myristate, 13-acetate (PMA), a protein kinase C (PK-C) activator, caused the desensitization of carbamylcholine (CBC)-induced amylase release in a concentration-and time-dependent fashion. The less potent phorbol-12, 13-dibutyrate (PDBu) also provoked a desensitization, but the inactive 4-a-phorbol-12,13-didecanoate had no effect. PMA or PDBu also significantly reduced subsequent amylase release induced by caerulein or secretin in contrast to CBC, which only reduced amylase release induced by CBC or secretin. Preincubation of acini with PMA did not lead to a decrease in PMA or A23187-stimulated amylase release. A 3 h resting period did not restore the desensitization induced by PMA or PDBu. Pretreatment with PMA did not cause changes in muscarinic receptor high-and low-affinity populations as observed with CBC pretreatment. The PK-C inhibitor H-7 completely prevented the desensitization induced by PDBu but not that induced by CBC. TMB-8, another PK-C inhibitor, also completely prevented the desensitization induced by PDBu but only partially that induced by CBC. These results suggest that phorbol esters can induce desensitization of muscarinic receptor-stimulated amylase release by a different mechanism than that involved in muscarinic agonist-induced desensitization.

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 85%

mentioning

confidence: 75%

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Carbamylcholine and Phorbol Esters Desensitize Muscarinic Receptors by Different Mechanisms in Rat Pancreatic Acini

et al. 1990

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“…Beside its stimulatory effect on enzyme secretion from otherwise unstimulated acinar cells, TPA has been demonstrated to exert an inhibitory effect on CCK-induced enzyme secretion [1,9,20]. This inhibitory action of the phorbol ester was found to be paralleled by inhibition of CCK-induced inositol 1,4,5-trisphosphate production [23] and Ca 2+ mobilization [20,22,23], suggesting an effect upstream of the phospholipase-C-catalysed hydrolysis of phosphatidylinositol 4,5-bisphosphate.…”

Section: Introductionmentioning

confidence: 93%

Reduced cholecystokinin receptor phosphorylation and restored signalling in protein kinase C down-regulated rat pancreatic acinar cells

Smeets

Rao

Vries

et al. 1998

Pfl�gers Archiv European Journal of Physiology

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Receptor phosphorylation in response to agonist stimulation is a key regulatory principle in signal transduction. Previous work has suggested the concerted action of protein kinase C (PKC) and a staurosporine-insensitive receptor kinase in homologous phosphorylation of the cholecystokinin (CCK) receptor in freshly isolated rat pancreatic acinar cells [Gates, Ulrich, Miller (1993) Am J Physiol 264:G840-G847]. The present study shows that down-regulation of PKC by prolonged (2 h) treatment with 0.1 muM 12-O-tetradecanoylphorbol-13-acetate (TPA) markedly reduced basal CCK receptor phosphorylation as well as that induced by TPA (0.1 muM) and cholecystokinin-(26-33)-peptide amide (CCK8, 0.1 muM). The phosphorylation level reached was the same with both stimulants and equalled basal phosphorylation in untreated control cells. The absence of any CCK8-stimulated phosphorylation reflecting the activity of a putative staurosporine-insensitive receptor kinase raises the intriguing possibility that a basal level of PKC-mediated receptor phosphorylation is required for the action of such a receptor kinase. Immunoblot analysis revealed that the decrease in receptor phosphorylation coincided with a marked reduction of PKC-alpha and, to a lesser extent, PKC-epsilon. In addition, TPA-induced inhibition of the increase in cytosolic free Ca2+ concentration ([Ca2+]i) evoked by the high-affinity CCK receptor agonist JMV-180 was completely reversed. The time-course of recovery closely matched that of the reduction of PKC-alpha. Finally, digital imaging microscopy of individual PKC down-regulated cells revealed a marked increase in the duration of JMV-180-evoked oscillatory changes in [Ca2+]i. Taken together, the present findings are in agreement with the idea that PKC-alpha-mediated receptor phosphorylation leads to a shortening of the duration of the [Ca2+]i oscillations and eventually to inhibition of high-affinity Ca2+ signalling through the native CCK receptor in pancreatic acinar cells.

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“…TPA-pretreated pancreatic acinar cells the secretory response to calcium-mobilizing secretagogues is significantly inhibited [15,16], an effect paralleled by an impaired Ca'' response [15,17, 181. This suggests a role for protein kinase C in receptormediated desensitization.…”

mentioning

confidence: 99%

Dissimilar effects of the protein kinase C inhibitors, staurosporine and H‐7, on cholecystokinin‐induced enzyme secretion from rabbit pancreatic acini

Ederveen

Vries

Pont

et al. 1990

European Journal of Biochemistry

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The effects of two putative inhibitors of protein kinase C activity, staurosporine and H-7, on partially purified protein kinase C and amylase secretion from isolated rabbit pancreatic acini were investigated. Staurosporine dose-dependently inhibited amylase release stimulated by an optimal concentration of cholecystokinin C-terminal octapeptide. At a concentration of 100 nM, the drug inhibited the secretory response to the secretagogue by approximately 50%. At the same concentration, staurosporine inhibited 12-0-tetradecanoylphorbol 13-acetatestimulated enzyme secretion by 90%. Moreover, the potentiating effect of this phorbol ester on cholecystokinininduced amylase release was completely abolished in the presence of staurosporine. Interestingly, amylase release was decreased to the level observed with the combination of cholecystokinin and staurosporine. In contrast, H-7, potentiated rather than inhibited cholecystokinin-stimulated enzyme secretion, whereas the secretory response to 12-0-tetradecanoylphorbol 13-acetate was not affected by the drug. Both staurosporine and H-7, however, inhibited protein kinase C purified from exocrine pancreatic tissue. Kinetic analysis revealed that both compounds inhibited protein kinase C competitively with respect to ATP. The Ki value for staurosporine was 0.55 nM and for H-7 13.5 pM. Our results obtained with staurosporine are in line with a stimulatory role of protein kinase C in cholecystokinin-induced enzyme secretion from the exocrine pancreas. The results obtained with H-7 emphasize that care has to be taken in interpreting the biological effects of this drug.Protein kinase Cis an ubiquitous Ca2+-and phospholipiddependent protein kinase which is thought to play a role in a wide variety of cellular processes involved in hormone-induced cell activation [l]. In pancreatic acini, as in most tissues, the activation of the enzyme appears to be linked to the secretagogue-induced turnover of inositol phospholipids in the plasma membrane [2 -51. Interaction of a hormone, like cholecystokinin, or a neurotransmitter, such as acetylcholine, with its membrane receptor stimulates a phospholipase C activity that cleaves phosphatidylinositol 4,5-bisphosphate leading to the generation of two important second messengers, inositol 1,4,5-trisphosphate [6, 71 and diacylglycerol [8, 91. Inositol 1,4,5-trisphosphate stimulates the release of Ca2 + from intracellular stores [lo]. Diacylglycerol increases the Ca2+-affinity of protein kinase C [l, 111, leading, in conjunction with the increase in intracellular Ca", to activation of protein kinase C.Evidence for the involvement of the diacylglycerol-activated protein kinase C in the mechanism of action of calciummobilizing pancreatic secretagogues has come primarily from studies with phorbol esters. These compounds, such as 12-0-tetradecanoylphorbol 13-acetate (TPA), mimic the stimulatory effect of diacylglycerol on protein kinase C [ll] and stimulate pancreatic enzyme secretion [12 -141. However, phorbol esters can also be inhibitory active. F...

show abstract

Phorbol ester attenuates cholecystokinin-stimulated amylase release in pancreatic acini of rats

Cited by 15 publications

References 27 publications

Carbamylcholine and Phorbol Esters Desensitize Muscarinic Receptors by Different Mechanisms in Rat Pancreatic Acini

Carbamylcholine and Phorbol Esters Desensitize Muscarinic Receptors by Different Mechanisms in Rat Pancreatic Acini

Reduced cholecystokinin receptor phosphorylation and restored signalling in protein kinase C down-regulated rat pancreatic acinar cells

Dissimilar effects of the protein kinase C inhibitors, staurosporine and H‐7, on cholecystokinin‐induced enzyme secretion from rabbit pancreatic acini

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