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)

Previous studies of enzyme secretion from isolated pancreatic acinar cells and of isolated zymogen granules (ZG) have reported that both a Cl- and a K+ permeability are present on the ZG membrane. It has been suggested that ion influx via these permeability pathways, followed by water movement is required for granular swelling which appears to be intimately related to exocytosis. However, little is known about the regulation of these pathways by secretagogues. Evidence suggests that cAMP-protein kinase A and diacylglycerol-protein kinase C are second messengers in stimulation of exocytosis. In the present study we have examined ion permeability pathways in ZG isolated from control cells and from cells pretreated with the acetylcholine analog carbachol (Cch), with the peptide hormone cholecystokinin (CCK) and with second messengers of hormone action such as cAMP and the diacylglycerol analog 12-O-tetradecanoyl phorbol-13-acetate (TPA). Ion and water influx rates in ZG and consequent swelling and lysis of granules was monitored by measuring changes in optical densities of ZG suspensions at 540 nm following additions of the electrogenic or electroneutral ionophores valinomycin and nigericin, respectively. The data show that both a Cl- conductance and an anion exchange pathway are present in the granule membrane. Both pathways are activated by pretreatment of isolated cells with CCK or of isolated permeabilised cells with cAMP, whereas only the Cl- conductance is increased by pretreatment with Cch or with TPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Secretagogue and second messenger-activated Cl- permeabilities in isolated pancreatic zymogen granules. 256 Jan 64

1. Coexisting with oxytocin or vasopressin in the cell bodies and nerve terminals of the hypothalamic-neurohypophysial system are smaller amounts of other peptides. For a number of these "copeptides" there is strong evidence of corelease with the major magnocellular hormones. Guided by the location of their specific receptors we have studied the effects of three copeptides, dynorphin, cholecystokinin (CCK), and corticotropin releasing hormone (CRH), on the secretion of oxytocin and vasopressin from isolated rat neural lobe or neurointermediate lobe preparations in vitro. 2. Dynorphin is coreleased with vasopressin from neural lobe nerve terminals and acts on neural lobe kappa-opiate receptors to inhibit the electrically stimulated secretion of oxytocin. Naloxone augments oxytocin release from the neural lobe in a manner directly proportional to the amount of vasopressin (and presumably dynorphin) released. 3. Cholecystokinin, coreleased with oxytocin by neural lobe terminals, has been shown to have high-affinity receptors located in the NL and to stimulate secretion of both oxytocin and vasopressin. CCK's secretagogue effect was independent of electrical stimulation and extracellular Ca2+ and was blocked by an inhibitor of protein kinase C. 4. CRH, coreleased with OT from the neural lobe, has receptors in the intermediate lobe of the pituitary, but not in the neural lobe itself. CRH stimulates the secretion of oxytocin and vasopressin from combined neurointermediate lobes but not from isolated neural lobes. Intermediate lobe peptides, alpha and gamma melanocyte stimulating hormone, induced secretion of oxytocin and vasopressin from isolated neural lobes. Their effect was, like that of CCK, independent of electrical stimulation and extracellular Ca2+ and blocked by an inhibitor of protein kinase C. 5. Among the CRH-producing parvocellular neurons of the paraventricular nucleus, in the normal rat, approximately half also produce and store vasopressin. After removal of glucocorticoid influence by adrenalectomy, virtually all of the CRH neurons contain vasopressin. 6. The two subtypes of CRH neurosecretory cells found in the normal rat possess different topographical distributions in the paraventricular nucleus, suggesting the possibility of differential innervation. Stress selectively activates the vasopressin containing subpopulation of CRH neurons, indicating that there are separate channels of regulatory input controlling the two components of the parvocellular CRH neurosecretory system.
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PMID:Coexisting peptides in hypothalamic neuroendocrine systems: some functional implications. 257 30

This paper reviews our work on the modulation of voltage-dependent Ca currents in identified snail neurons. Ca currents of snail neurones are enhanced or decreased by neurotransmitters. Serotonin and acetylcholine enhance the Ca current of identified neurons, the effect of serotonin being mediated by cGMP and cGMP-dependent protein kinase. Cholecystokinin (CCK8) and dopamine both decrease the Ca current of identified neurons. The effect of CCK8 is irreversible and involves the activation of protein kinase C. The dopamine-induced decrease in Ca current is reversible and involves an alpha 40 subunit of a snail G protein immunologically and functionally related to alpha o of mammalian brain.
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PMID:Intracellular mechanism of neurotransmitter-induced modulations of voltage-dependent Ca current in snail neurons. 257 63

The effect of monooleoylglycerol on cholecystokinin- and tolbutamide-induced insulin secretion was examined in isolated perifused rat islets. In the presence of 5.5 mmol/l glucose, addition of 10 nmol/l cholecystokinin or 50 mumol/l tolbutamide had practically no effect on insulin secretion. Combined tolbutamide and cholecystokinin led to a biphasic insulin secretory response which was significantly enhanced by addition of 50 mumol/l monooleoylglycerol, an inhibitor of diacylglycerol kinase. Monooleoylglycerol (50 mumol/l) alone had a minimal stimulatory effect on insulin release in the presence of 5.5 mmol/l glucose. Perifusion of islets with 1 mumol/l forskolin had no significant effect on basal insulin secretion in the presence of 5.5 mmol/l glucose, but markedly enhanced the responses to both cholecystokinin plus tolbutamide, and to the combination of cholecystokinin, tolbutamide and monooleoylglycerol. Lowering the glucose level to 2.75 mmol/l abolished the profound stimulatory effect to these agonist combinations on insulin release. Finally, monooleoylglycerol also enhanced the first and second phase insulin secretory responses induced by 20 mmol/l glucose. These results are discussed in relationship to the possible role of protein kinase C in mediating insulin secretion.
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PMID:The effect of monooleoylglycerol on insulin secretion from isolated perifused rat islets. 266 83

Cholecystokinin (CCK) and its receptors are abundantly represented in the central nervous system. However, a specific role or mechanism of action for CCK in this context has not been established. CCK coexists with oxytocin in magnocellular neurons of the hypothalamic-neurohypophysial system, sharing common neurosecretory vesicles with oxytocin in the neural lobe of the pituitary. The neural lobe, which consists primarily of oxytocin- and vasopressin-containing axons and nerve terminals and their surrounding glia, provides a relatively simple model system allowing for the study of the regulation of neurosecretion at the nerve terminal level, free from the complex array of synaptic effects present throughout the rest of the central nervous system. In this paper, we demonstrate the presence of high-affinity CCK binding sites in the rat neural lobe and show that activation of these receptors by the sulfated octapeptide, CCK-8, and related peptides causes potent secretion of oxytocin and vasopressin from the isolated nerve terminals. The secretagogue action of CCK-8, which is blocked by a CCK receptor antagonist (L-364,718), is independent of electrical stimulation and extracellular calcium and is blocked by an inhibitor of protein kinase C. Thus, the action of CCK on the neural lobe provides an example of peptide ligand-induced neurosecretion apparently mediated by second messengers rather than depolarization-induced calcium influx.
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PMID:Cholecystokinin evokes secretion of oxytocin and vasopressin from rat neural lobe independent of external calcium. 274 Mar 51

Isolated rabbit pancreatic acinar cells, permeabilized by saponin treatment and incubated in the presence of 0.1 microM free Ca2+, accumulated 0.9-1.5 nmol of Ca2+/mg acinar protein in an energy-dependent pool. Uptake into this pool was not altered by pretreatment of acinar cells with the Ca2+ mobilizing secretagogues carbamylcholine and cholecystokinin-octapeptide or the phorbol ester 12-O-tetradecanoylphorbol 13-acetate, indicating that the Ca2+ pump of the internal Ca2+ store was not affected by prolonged activation of the Ca2+ messenger system. Inositol 1,4,5-trisphosphate (1,4,5-IP3) caused a rapid decrease in Ca2+ content of the internal Ca2+ store. The response was maximal within 30 s following addition of 1,4,5-IP3 and no reuptake of Ca2+ was observed over the next 60 s. Up to 55% of the amount of Ca2+ stored in the energy-dependent pool was 1,4,5-IP3 releasable with an EC50 of 1.0 microM. Pretreatment of acinar cells with carbamylcholine or cholecystokinin-octapeptide significantly reduced the effectivity of 1,4,5-IP3 to release Ca2+ from the internal store. The dose-response curve for 1,4,5-IP3-induced release of actively stored Ca2+ from carbamylcholine-treated acinar cells showed both a rightward shift (EC50 value of 1.7 microM) and a decreased maximal response (maximal release value of 44%), which suggests that the affinity of 1,4,5-IP3 for its receptor as well as the number of 1,4,5-IP3 receptors or 1,4,5-IP3-operated Ca2+ channels was reduced upon prolonged activation of the Ca2+ messenger system. Moreover, analysis of the release values in a Hill plot suggested positive cooperativity for 1,4,5-IP3-induced Ca2+ release from the internal store (n values of 1.3 and 1.7 for saline- and carbamylcholine-treated permeabilized acinar cells, respectively). Pretreatment of acinar cells with 12-O-tetradecanoylphorbol 13-acetate partly mimicked the inhibitory effect of carbamylcholine on 1,4,5-IP3-induced release of actively stored Ca2+ in that the dose-response curve was shifted to the right but the maximal response was not affected, suggesting that the effects of carbamylcholine were at least in part mediated by protein kinase C.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Inhibition of inositol 1,4,5-trisphosphate-induced Ca2+ release in permeabilized pancreatic acinar cells by hormonal and phorbol ester pretreatment. 278 96

We have explored the hypothesis that the apparent greater efficiency of cholecystokinin (CCK-8) receptor-second messenger coupling compared with that of muscarinic receptor in Flow 9000 cells is due to differential feedback inhibitory control mechanisms. Pretreatment of Flow 9000 cells with the tumour-promoting protein kinase C (PKC)-activating agent 12-O-tetradecanoylphorbol 13-acetate (TPA) produced a time- and dose-dependent inhibition of CCK-8 and acetylcholine (ACh) stimulation of inositol phosphate production. The inhibition by TPA of ACh-induced PI (phosphoinositide) response involved reduction of the maximal response, but no change in the concentration of ACh required to evoke a half-maximal response. In contrast, TPA inhibition of CCK-8 responses could be overcome by increasing the CCK-8 concentrations. Flow 9000 cells pretreated with TPA exhibited a 52-68% reduction in [3H]quinuclidinyl benzilate ([3H]QNB) binding capacity, whereas [125I]CCK-8 binding was unchanged. In saponin-permeabilized Flow 9000 cells, TPA pretreatment had no effect on guanosine 5'-[gamma-thio]triphosphate (GTP[S])-induced inositol phosphate formation, indicating that G-protein linkage to phosphoinositidase C (PIC) was not affected. However, TPA significantly inhibited the potentiating effect of GTP[S] on CCK-8 and ACh activation of PI response, suggesting that the coupling between the receptors and the G-protein was impaired. The PKC-activator 1-oleoyl-2-acetylglycerol (OAG), a diacylglycerol analogue, also significantly reduced CCK-8 and ACh stimulation of inositol phosphate accumulation in these cells. Our results are consistent with the hypothesis that muscarinic activation of PI hydrolysis is subjected to rapid feedback inhibition via the 1,2-diacylglycerol-PKC pathway. CCK-receptor activation of PI turnover is modulated to a lesser extent, and this may partially explain apparent differences in the efficiency of receptor-second messenger coupling. It is proposed that TPA acting through PKC exerts its inhibitory action on muscarinic-agonist-mediated PI response mainly at the receptor level, whereas the inhibitory effect on CCK-8 response is at a site close to the receptor-G-protein coupling step.
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PMID:Differential regulation of cholecystokinin- and muscarinic-receptor-mediated phosphoinositide turnover in Flow 9000 cells. 284 62

We and others have suggested previously that the binding of somatostatin to its receptors in the pancreas is regulated by not only somatostatin analogs but also cholecystokinin analogs in proportion to their known biological potencies. To clarify the precise mechanism by which unrelated peptides modulate somatostatin binding, the effect of a phorbol ester, 12-O-tetradecanoylphorbol 13-acetate (TPA), or a synthetic diacylglycerol analog, 1-oleyl-2-acetylglycerol (OAG), on [125I-Tyr1]somatostatin binding to pancreatic acinar cell membranes was examined. Pretreatment of pancreatic acini for 120 min at 37 degrees C with 100 ng/ml TPA maximally reduced subsequent labeled somatostatin binding to acinar membranes. The inhibitory effect of TPA on the somatostatin binding was dependent on the dose used or the time and temperature of pretreatment. These effects of TPA were almost mimicked by the treatment of acini with OAG. Scatchard analysis of [125I-Tyr1]somatostatin binding demonstrated that the decrease in the labeled somatostatin binding induced by TPA or OAG pretreatment was due to the decrease in the maximum binding capacity without a significant change in the binding affinity. A specifically labeled single band of Mr = 90,000 obtained with a photoaffinity cross-linking study indicates that the somatostatin-binding sites are the same somatostatin receptor as previously described. Moreover, the intensity of the Mr = 90,000 band was dramatically decreased when acini were treated with increasing concentrations of TPA, a finding consistent with TPA-induced decrease in binding capacity. Such an inhibitory effect of TPA was abolished when pretreatment of acini with TPA was performed in the presence of Ca2+-chelating compounds such as EDTA and EGTA or phospholipid-interacting drugs such as chlorpromazine and tetracaine. Interestingly, the combined treatment of TPA and Ca2+ ionophore A23187 caused synergistic inhibition of the subsequent labeled somatostatin binding to acinar membranes, although Ca2+ ionophore itself almost failed to affect the somatostatin binding. These results suggest, therefore, that TPA or OAG can modulate somatostatin binding to its receptors on rat pancreatic acinar cell membranes, presumably through activation of Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C); and the activated protein kinase C and intracellular Ca2+ mobilization presumably act to modulate the pancreatic acinar somatostatin receptors synergistically.
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PMID:Phorbol ester or diacylglycerol modulates somatostatin binding to its receptors on rat pancreatic acinar cell membranes. 286

To clarify the precise mechanism by which unrelated peptides, cholecystokinin or carbamylcholine, modulate the somatostatin binding, the effect of a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) or a synthetic diacylglycerol analog, 1-oleyl-2-acetylglycerol (OAG) on [125I-Tyr1]somatostatin binding to pancreatic acinar cell membranes was examined. Pretreatment of pancreatic acini for 120 min at 37 degrees C with 100 ng/ml TPA maximally reduced subsequent labeled somatostatin binding to acinar membranes. The inhibitory effect of TPA on the somatostatin binding was dependent on the dose used, or the time and temperature of pretreatment. These effects of TPA were almost mimicked by the treatment of acini with OAG. Scatchard analysis of [125I-Tyr1]somatostatin binding demonstrated that the decrease in the labeled somatostatin binding induced by TPA or OAG pretreatment was due to the decrease in the maximum binding capacity without a significant change in the binding affinity. A specifically labeled single band of the Mr = 90 K obtained with a photoaffinity cross-linking study indicates that the somatostatin binding sites are the same somatostatin receptor as previously described. Moreover, the intensity of the Mr = 90 K band was dramatically decreased when acini were treated with increasing concentrations of TPA, a finding consistent with TPA-induced decrease in binding capacity. Such an inhibitory effect of TPA was abolished when pretreatment of acini with TPA was performed in the presence of Ca2+ chelating compounds such as EDTA and EGTA. Interestingly, the combined treatment of TPA and Ca2+ ionophore A23187 caused synergistic inhibition of the subsequent labeled somatostatin binding to acinar membranes, although Ca2+ ionophore itself almost failed to affect the somatostatin binding. These results suggest, therefore, that TPA or OAG can modulate somatostatin binding to its receptors on rat pancreatic acinar cell membranes, presumably through activation of Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C) and the activated protein kinase C and intracellular Ca2+ mobilization presumably act to modulate pancreatic acinar somatostatin receptors synergistically.
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PMID:[Phorbol ester or diacylglycerol modulates somatostatin binding to its receptors on rat pancreatic acinar cell membranes]. 287 6

Development of an enriched cultured cell system allowed us to investigate the mechanism of cholinergic inhibition of somatostatin release stimulated by adenosine 3',5'-cyclic monophosphate (cAMP) and Ca2+-protein kinase C-dependent pathways of cell activation. After a 24-h culture on rat tail collagen, D-cells, quantified by immunohistochemistry, were 18-fold enriched compared with unelutriated dispersed cells. Somatostatin release from cultured cells was expressed as a percent of the somatostatin released by a specific stimulus in control cells. Under basal conditions release of somatostatin was 2.3 +/- 0.6% of the total cell content. Epinephrine (1 microM) and cholecystokinin octapeptide (10 nM) increased somatostatin release to 6.98 +/- 1.25 and 10.72 +/- 1.64%, respectively. Carbachol (1 microM) completely inhibited somatostatin release stimulated by epinephrine and reduced cholecystokinin octapeptide-stimulated release to 75% of control levels. Carbachol inhibition of the response to both epinephrine and cholecystokinin octapeptide was totally prevented by 5 h of treatment of the cells with pertussis toxin (300 ng/ml). Somatostatin release in response to the diterpene forskolin (10 microM), dibutyryl cAMP (300 microM), the phorbol ester beta-phorbol 12-myristate 13-acetate (0.1 microM), and the calcium ionophore A23187 (1 microM) was also inhibited by carbachol and prevented by pertussis toxin pretreatment. The ADP-ribosylase inhibitor isonicotinamide (1 mM) selectively blocked the effect of pertussis toxin without altering other stimulatory or inhibitory responses. These data are consistent with the view that carbachol inhibits somatostatin release at guanyl nucleotide-binding protein and/or another pertussis toxin-sensitive site.
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PMID:Pertussis toxin-sensitive cholinergic inhibition of somatostatin release from canine D-cells. 290 2


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