Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Cytoplasmic Ca2+ ([Ca2+]i) responses were studied in guinea-pig pancreatic acinar cells during stimulation with cholecystokinin octapeptide (CCK-8), substance P (SP) and carbachol. 2. Individual cells exhibited [Ca2+]i responses to all three agonists. 3. In the absence of external Ca2+, all the agonists initiated [Ca2+]i peaks which, particularly at high agonist concentrations, rapidly declined. 4. SP induced repetitive monophasic [Ca2+]i transients which started from basal [Ca2+]i even after elevation of the external Ca2+ concentration. 5. CCK-8 triggered similar oscillations, which particularly at high agonist concentration or after elevating external Ca2+ became superimposed upon a sustained elevation of [Ca2+]i. 6. Carbachol-induced oscillations were more complex with [Ca2+]i transients superimposed on slower waves. 7. At high carbachol concentrations or elevation of external Ca2+ the slow waves fused into a sustained increase of [Ca2+]i. 8. The protein kinase C (PKC) activator 12-O-tetradecanoylphorbol-13-acetate attenuated the agonist-induced [Ca2+]i responses, and this effect was reversed by the PKC activator staurosporine. 9. The results indicate that oscillations of [Ca2+]i induced by SP, CCK-8 and carbachol involve intracellular mobilization of Ca2+. 10. CCK-8 and carbachol also cause a rise of [Ca2+]i by a mechanism more directly dependent on the presence of extracellular Ca2+. 11. In the case of carbachol the latter component is subject to oscillatory control. 12. The transition from oscillatory [Ca2+]i to sustained increase may be associated with inhibition of amylase release.
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PMID:Calcium oscillations in guinea-pig pancreatic acinar cells exposed to carbachol, cholecystokinin and substance P. 172 99

Canine jejunal epithelial cells were isolated and maintained in short-term culture to study cholecystokinin (CCK) release. Sequential digestion of jejunal mucosa with collagenase and ethylenediaminetetraacetic acid was followed by counterflow elutriation to enrich CCK-containing cells. After 40 hours in culture on collagen-coated plates, 8.4% of the initially seeded cells were attached; 8.7% of them stained positive with a C-terminal CCK/gastrin antibody and 2.5% stained positive with a gastrin-specific antibody. Basal release of CCK into the culture medium amounted to 1.3% of total cell content over 105 minutes. Receptor-independent stimulation of protein kinase C by the phorbol ester beta-phorbol-12-myristate-13-acetate caused significant CCK release. The inactive form, 4 alpha-phorbol-12-myristate-13-acetate, had no effect. Activation of adenylate cyclase by 10(-5) mol/L forskolin evoked a 2.5-fold increase in CCK concentrations, which was completely abolished by 10(-8) mol/L somatostatin. L-phenylalanine stimulated CCK release at 20 and 50 mmol/L, whereas D-phenylalanine caused significant hormone output only at 50 mmol/L. L-tryptophan had no effect. Cholecystokinin release stimulated by L-phenylalanine was not influenced by the addition of either somatostatin or somatostatin antibody. In conclusion, a system of isolated canine jejunal epithelial cells was developed in short-term culture. This preparation proved suitable for the study of CCK release on a cellular basis.
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PMID:Cholecystokinin release from isolated canine epithelial cells in short-term culture. 172 60

Cholecystokinin (CCK) is a potent neuropeptide hormone with activity on various gastrointestinal organs during the digestive process. It was recently suggested that CCK may also act on the immune system. In this study we investigated the effect of CCK on the human mucosal immune system as represented by colonic lamina propria lymphocytes (LPL). Our results demonstrated that CCK at concentrations of 10(-13) M to 10(-7) M inhibits thymidine incorporation into Con A-stimulated LPL DNA by up to 40%. Moreover, this inhibitory effect was reversed by the specific CCK receptor antagonist, L-364718, at concentrations of 10(-8) M to 10(-5) M. In addition, CCK did not affect DNA synthesis of LPL stimulated with phorbol ester (PDB) and calcium ionophore (ionomycin). It is postulated that the CCK effect may involve intracellular metabolic steps proximal to protein kinase C activation and calcium flux. Our results suggest that CCK may play a role in modulating the human mucosal immune system during digestion and thus, should be added to the list of the neuropeptides that affect the mucosal immune system.
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PMID:The inhibition effect of cholecystokinin in human colonic lamina propria lymphocyte proliferation, and reversal by the cholecystokinin receptor antagonist L-364718. 179 24

The effects of cholecystokinin (CCK) and other pancreatic secretagogues on phosphatidylcholine (PC) synthesis were studied in isolated rat pancreatic acini. When acini were incubated with [3H] choline in the presence of 1 nM CCK-octapeptide (CCK8) for 60 min, the incorporations of [3H] choline to both water soluble choline metabolites and PC in acini were reduced by CCK8 to 74% and 41% of control, respectively. Pulse-chase study revealed that CCK reduced both the disappearance of phosphocholine and the synthesis of PC. Ca(2+)-mobilizing secretagogues such as carbamylcholine and Ca2+ ionophore A23187 also reduced PC synthesis to the same extent as CCK8. By contrast, neither cAMP-dependent secretagogues such as secretin and dibutyryl cAMP nor a phorbol ester had any effect on PC synthesis in acini. These results suggest that CCK inhibits PC synthesis by inducing both the reduction of choline uptake into acini and the inhibition of CTP: phosphocholine cytidylyltransferase activity. This hormonal regulation of PC synthesis via CDP-choline pathway appears to be mediated by Ca(2+)-dependent pathway but not by cAMP- or protein kinase C-dependent pathway.
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PMID:[The inhibitory effect of cholecystokinin on phosphatidylcholine synthesis in isolated rat pancreatic acini]. 192 Sep

In isolated rat pancreatic islets, the possible involvement of protein kinase C in cholecystokinin-8-stimulated insulin secretion was investigated. In islets exposed for 24 hours to the phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (500 nmol l-1), a procedure known to down-regulate islet protein kinase C-activity, the insulinotropic effect of cholecystokinin-8 (10(-7) mol l-1) was partially reduced (by 34 +/- 8%, P less than 0.001). In contrast the insulinotropic response to acute exposure to 12-O-tetradecanoyl phorbol 13-acetate (10(-6) mol l-1) was totally abolished (P less than 0.001), whereas the insulin response to glucose (8.3 mmol l-1) was not affected. In normal islets, the protein kinase C-inhibitor, staurosporine, inhibited 12-O-tetradecanoyl phorbol 13-acetate- and glucose-stimulated insulin secretion (P less than 0.01), but was without effect on cholecystokinin-8-stimulated insulin release. Furthermore, in normal islets, cholecystokinin-8 had no effect on insulin release at a low glucose level (3.3 mmol l-1). However, at this low glucose level, cholecystokinin-8 clearly potentiated insulin release induced by acute exposure to 12-O-tetradecanoyl phorbol 13-acetate (10(-8) -10(-6) mol l-1, P less than 0.001). This potentiating effect was abolished by the removal of extracellular Ca2+. It is concluded that the insulinotropic effect of cholecystokinin-8 in rat islets is partially mediated by the protein kinase C pathway. Furthermore, the lack of effect of cholecystokinin-8 on insulin secretion at a low glucose level might be explained by an insufficient activation of protein kinase C under these conditions.
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PMID:Cholecystokinin-stimulated insulin secretion and protein kinase C in rat pancreatic islets. 192 52

The messenger role of Ca+2, cyclic nucleotides and inositol triphosphates in the stimulation of pepsinogen and mucous secretion were studied using isolated pig [correction of nug] gastric chief cells and guinea pig mucous cells, resp. Pepsinogen secretion was stimulated by agents either working at the postreceptor adenylate cyclase (AC) level (db-cAMP, forskolin) or after 12-o-tetradecanoyl-phorbol-13-acetate (TPA) stimulation of protein kinase C (PK C). Similar secretory effects were observed with histamine (H), carbachol (C) and cholecystokinin (CCK). [Ca-2] in was elevated by C and by CCK, but not by H in both types of cells. Like TPA, both C and CCK, but not H, stimulated the Ca+2-sensitive particulate PK C. H increased the activity of cAMP-dependent PK A. PGE2, C and CCK were found to increase inositol-1,4,5-triphosphate content in mucous cells. The findings indicate that two pathways of the regulation of pepsinogen and mucous secretion (AC-cAMP-PK C and phosphoinositol breakdown cascade) can act synergistically.
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PMID:[Secondary messengers in the hormonal regulation of the functional activity of the main and mucoid cells in the stomach]. 198 55

The present study was undertaken to determine if the cholecystokinin (CCK) receptor may be phosphorylated, and to gain insight into its regulation. For this, the ATP pool of rat pancreatic acini was prelabeled with 32P, and the cells were stimulated with various secretagogues. CCK receptors from treated cells were enriched by sequential fractionation to produce plasmalemma, and subsequent solubilization and lectin-affinity chromatography. This protocol detected a phosphorylated Mr = 85,000-95,000 plasma membrane glycoprotein with features similar to the CCK receptor. Phosphorylation of this protein occurred rapidly (less than 2 min) and in a concentration-dependent manner in response to CCK, and was inhibited by the CCK receptor antagonist L-364,718. Further evidence that this represented the CCK receptor included comigration of phosphorylated and CCK radioligand affinity-labeled proteins on sodium dodecyl sulfate-polyacrylamide gels, both in native forms and after endoglycosidase F deglycosylation, and the specific adsorption of the phosphoprotein to a CCK analogue affinity resin. Phosphorylation occurred predominantly on serine residues of the receptor protein. Phosphorylation of this protein was also enhanced in response to other secretagogues which, like CCK, stimulate a cascade leading to protein kinase C activation, and in response to direct activation of this enzyme by 12-O-tetradecanoylphorbol 13-acetate. Thus, the pancreatic CCK receptor is phosphorylated in a regulated manner, in response to both homologous and heterologous secretagogues, and to protein kinase C activation.
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PMID:Agonist-regulated phosphorylation of the pancreatic cholecystokinin receptor. 198 91

Receptor-activated cytoplasmic calcium (Ca2+) oscillations have been investigated in single pancreatic acinar cells by microfluorimetry (Fura-2 as indicator). At submaximal concentrations of the agonists acetylcholine (ACh) and cholecystokinin octapeptide (CCK-8), both give rise to oscillatory changes in the cytosolic free calcium concentration ([Ca2+]i). The patterns of oscillations are markedly and consistently different for each of these two agonists. The ACh induced oscillations are superimposed upon a median elevation in background [Ca2+]i. The CCK-8 induced oscillations are of longer duration with [Ca2+]i returning to prestimulus levels between the discrete spikes. The ACh induced oscillations are rapidly abolished upon removal of extracellular Ca2+ while the CCK-8 induced oscillations persist for many minutes in the absence of external Ca2+. The CCK-8, but not the ACh, induced oscillations are increased in duration by the protein kinase C (PKC) inhibitor staurosporine and abolished by the PKC activating phorbol ester PMA. It is clear that CCK-8 and ACh do not activate receptor transduction mechanisms in an identical manner to generate oscillating [Ca2+]i signals.
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PMID:Acetylcholine and cholecystokinin induce different patterns of oscillating calcium signals in pancreatic acinar cells. 205 90

We examined the effect of cholecystokinin (CCK) on the receptors for vasoactive intestinal peptide (VIP) and secretin in rat pancreatic acini. CCK decreased the specific binding of 125I-VIP and 125I-secretin by 42 and 51%, respectively. This CCK-induced inhibition was caused by an apparent decrease in the capacity of high-affinity binding sites of VIP and secretin receptors. CR 1409, a specific antagonist of CCK, abolished CCK-induced binding inhibition, whereas 12-O-tetradecanoylphorbol-13-acetate, A23187, and cycloheximide did not affect the binding of the radioligands. Both N2,O2-dibutyryl guanosine 3',5'-cyclic monophosphate (Bt2cGMP) and nitroprusside inhibited the specific binding of 125I-VIP. This inhibition, however, was because of an apparent decrease in the capacity of low-affinity binding sites on VIP receptors. CCK-induced downregulation of VIP and secretin receptors was associated with the diminished acinar response to VIP or secretin-induced adenosine 3',5'-cyclic monophosphate accumulation and amylase secretion, whereas neither Bt2cGMP nor nitroprusside affected VIP-induced amylase secretion. Data suggest that CCK-induced downregulation is mediated by the initial interaction of CCK with CCK receptors followed by some postreceptor process, which appears unrelated to protein kinase C, calcium mobilization, decrease in protein synthesis, or cellular cGMP increases. This downregulation, at least in part, accounts for CCK-induced restricted stimulation of amylase secretion by VIP and secretin.
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PMID:Cholecystokinin downregulates receptors for vasoactive intestinal peptide and secretin in rat pancreatic acini. 215 42

Mechanisms by which various classes of extracellular signals regulate insulin secretion are discussed regarding their cellular and molecular actions. Under physiological circumstances, the small postprandial changes in plasma glucose concentrations (approximately 4.4-6.6 mM) primarily serve as a conditioned modifier of insulin secretion and dramatically alter the responsiveness of islets to a combination of neurohormonal agonists. These agonists have two functions. Cholecystokinin (CCK) and acetylcholine activate the hydrolysis of polyphosphoinositides, and gastric inhibitory polypeptide (GIP) and glucagonlike peptide 1 activate adenylate cyclase. These two functional classes of neurohumoral agonists act synergistically to enhance insulin secretion when plasma glucose is greater than 6.0 mM but not when it is less than or equal to 4 mM. On the other hand, an increase in plasma glucose concentration to 8-10 mM induces an increase in insulin secretory rate in the absence of any of the neurohormonal agonists. Remarkably, high glucose leads to an increase in the same intracellular signals, as does a combination of acetylcholine and GIP. On the basis of these data, a model of how insulin secretion is regulated under physiological circumstances is proposed. This model emphasizes that the regulation of insulin secretion occurs in three stages: cephalic, early enteric, and later enteric. In this view, the crucial event occurring during the first two phases is the agonist-induced, translocation of protein kinase C (PKC) to the plasma membrane under conditions in which an increase in Ca2+ influx does not occur. PKC is now in a cellular location and a Ca2(+)-sensitive conformation such that an increase in Ca2+ influx rate occurring during the third phase leads to its immediate activation and an enhanced rate of insulin secretion. Furthermore, under physiological circumstances, an optimal insulin secretory response is dependent on a correct temporal pattern of signals arising from neural and enteric sources. If this pattern is deranged, an abnormal pattern of insulin secretion is observed. An important new insight is provided by the observation that agonists (e.g., CCK or acetylcholine) that act to stimulate the hydrolysis of phosphatidylinositides, when acting for a short period (10-20 min), induce an enhanced responsiveness of islets to glucose, i.e., proemial sensitization. However, when acting unopposed for several hours, these agonists will induce a time-dependent suppression of responsiveness to glucose and other agonists. The latter observation implies that optimal insulin secretion is dependent on periodic rather than a continuous exposure to the correct pattern of extracellular signals.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Physiology and pathophysiology of insulin secretion. 219 49


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