Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholecystokinin is a regulatory peptide, that acts through two subtypes of receptors, 1 and 2. RT-PCR demonstrated the expression of both cholecystokinin receptors 1 and 2 genes in the zona glomerulosa, but not the zona fasciculata-reticularis, of rat adrenals. Autoradiography demonstrated the presence of abundant [(125)I]cholecystokinin-binding sites in the zona glomerulosa, but not the zona fasciculata-reticularis, which were displaced by both cholecystokinin receptor 1- and 2-selective antagonists (cholecystokinin 1-A and 2-A). Cholecystokinin increased basal aldosterone secretion from dispersed zona glomerulosa cells without affecting corticosterone secretion from zona fasciculata-reticularis cells. The aldosterone response to cholecystokinin was blunted by cholecystokinin 1-A and 2-A, which when added together abolished it. ACTH-stimulated aldosterone production was not affected by cholecystokinin; in contrast, cholecystokinin potentiated aldosterone response to both angiotensin II and K(+). Cholecystokinin enhanced cAMP, but not IP(3), release by dispersed zona glomerulosa cells. The aldosterone response to cholecystokinin was abolished by the adenylate cyclase inhibitor SQ-22536 and the PKA inhibitor H-89, but not by either the PLC inhibitor U-73122 or the PKC inhibitor calphostin C. In conclusion, our study provides evidence that cholecystokinin, acting through cholecystokinin receptors 1 and 2 coupled with the adenylate cyclase/PKA cascade, exerts a sizeable secretagogue action on rat zona glomerulosa cells.
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PMID:Cholecystokinin stimulates aldosterone secretion from dispersed rat zona glomerulosa cells, acting through cholecystokinin receptors 1 and 2 coupled with the adenylate cyclase-dependent cascade. 1156 81

In order to develop a model system for identifying signaling pathways and cell cycle events involved in gastrin-mediated mitogenesis, we have used high efficiency retroviral-mediated transfection of cholecystokinin (CCK)(B)/gastrin receptor into Swiss 3T3 cells. The retrovirally-transfected CCK(B)/gastrin receptor binds 125I-CCK-8 with high affinity (Kd = 1.1 nM) and is functionally coupled to intracellular signaling pathways including rapid and transient increase in Ca2+ fluxes, protein kinase C-dependent protein kinase D activation, and MEK-dependent ERK1/2 activation. In the presence of insulin, CCK-8 or gastrin induced a 66.5 +/- 8.8-fold (mean +/- SEM, n = 24 in eight independent experiments) increase in cellular DNA synthesis, reaching a level similar to that achieved by stimulation with a saturating concentration of fresh serum, and much greater than the response to each agonist added alone. CCK-8 also induced a striking increase in the expression of cyclins D1, D3, and E and hyperphosphorylation of Rb acting synergistically with insulin. Similar effects were observed when CCK(B)/gastrin receptor was activated in the presence of EGF or bombesin. Our results demonstrate that activation of CCK(B)/gastrin receptor retrovirally-transfected into Swiss 3T3 induces a potent synergistic effect on DNA synthesis, accumulation of cyclins D1, D3, and E and hyperphosphorylation of Rb in combination with insulin, EGF, or bombesin. Thus, the CCK(B)/gastrin receptor transfected into Swiss 3T3 cells provides a novel model system to elucidate mitogenic signal transduction pathways and cell cycle events activated via this receptor.
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PMID:CCK(B)/gastrin receptor mediates synergistic stimulation of DNA synthesis and cyclin D1, D3, and E expression in Swiss 3T3 cells. 1174 87

Recently, we cloned a novel serine/threonine kinase termed protein kinase D2 (PKD2). PKD2 can be activated by phorbol esters both in vivo and in vitro but also by gastrin via the cholecystokinin/CCK(B) receptor in human gastric cancer cells stably transfected with the CCK(B)/gastrin receptor (AGS-B cells). Here we identify the mechanisms of gastrin-induced PKD2 activation in AGS-B cells. PKD2 phosphorylation in response to gastrin was rapid, reaching a maximum after 10 min of incubation. Our data demonstrate that gastrin-stimulated PKD2 activation involves a heterotrimeric G alpha(q) protein as well as the activation of phospholipase C. Furthermore, we show that PKD2 can be activated by classical and novel members of the protein kinase C (PKC) family such as PKC alpha, PKC epsilon, and PKC eta. These PKCs are activated by gastrin in AGS-B cells. Thus, PKD2 is likely to be a novel downstream target of specific PKCs upon the stimulation of AGS-B cells with gastrin. Our data suggest a two-step mechanism of activation of PKD2 via endogenously produced diacylglycerol and the activation of PKCs.
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PMID:Mechanism of activation of protein kinase D2(PKD2) by the CCK(B)/gastrin receptor. 1205 27

Over-expression of cyclooxygenase-2 (COX-2) has been demonstrated to be tumorigenic in transgenic mice. Chronic treatment with NSAIDs is chemoprotective for colorectal cancer. Gastrin is a growth factor for gastric mucosa and has been shown to promote proliferation of colorectal cells. Recent studies suggest that COX-2 expression levels could mediate the growth effects of gastrin. Here, we report that gastrin increased PGE2 secretion in Swiss 3T3 cells expressing the CCK2 receptor. Gastrin dose dependently induced COX-2 protein levels in a time dependent manner. COX-2 mRNA levels were rapidly induced by a dose dependent increase in gastrin. Prior treatment of the cells with the CCK2 receptor specific antagonist, L365,260, inhibited gastrin-induced COX-2 protein and mRNA expression. Pretreatment with L364,714, the CCK1 receptor specific antagonist did not block COX-2 induction by gastrin. Inhibition of de novo protein synthesis by cycloheximide did not block COX-2 mRNA induction by gastrin. Also, gastrin-dependent COX-2 expression did not require PKC activity, activation of ERK, or transactivation of EGFR. However, co-stimulation with EGF and gastrin synergistically induced COX-2 protein and mRNA expression and PGE2 secretion. Measurements of COX-2 mRNA stability and COX-2 gene transcription reveal that EGF significantly increased the half-life of COX-2 mRNA with only a slight increase in the COX-2 transcription rate. Conversely, gastrin significantly increased COX-2 gene transcription rates but did not enhance COX-2 mRNA stability.
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PMID:Gastrin and EGF synergistically induce cyclooxygenase-2 expression in Swiss 3T3 fibroblasts that express the CCK2 receptor. 1289 2

A large number of neuroanatomical, neurophysiologic, and neurochemical mechanisms are thought to contribute to the development and maintenance of neuropathic pain (NP). As a result, a corresponding wide range of treatments have been employed to treat patients with NP, including antiepileptic drugs, opioid analgesics, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, N-methyl-D-aspartate receptor antagonists, cholecystokinin receptor antagonists, adenosine, lipoic acid, cannabinoids, isosorbide dinitrate, dronabinol, capsaicin, protein kinase C inhibitors, aldose reductase inhibitors, and VR-1 receptor modulators. Many of these compounds are limited by marginal efficacy and clinically significant adverse events; few have been evaluated in well-controlled, large-scale clinical trials. At present, the only agents approved for the treatment of painful diabetic peripheral neuropathy and postherpetic neuralgia are lidocaine patches 5%, duloxetine, gabapentin, and pregabalin. Of these, only pregabalin is indicated for both conditions.
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PMID:New and emerging treatment options for neuropathic pain. 1677 59

CCK is a brain-gut peptide that is abundantly distributed in both gastrointestinal tract and mammalian brain. The sulfated octapeptide fragment of cholecystokinin (CCK-8S) has been shown to be involved in numerous physiological functions such as behavior, anxiety, learning/memory processes and neuropathic pain. CCK-8S is one of the strongest endogenous anti-opioid substances and suppresses opioid peptides-mediated 'pre-synaptic inhibition' of gamma-aminobutyric acid (GABA) release. Here we provide evidence that CCK-8S modulates GABA-evoked membrane depolarization in rat dorsal root ganglion (DRG) neurons using intracellular recording technique. Bath application CCK-8S-induced membrane depolarization in most of the rat DRG neurons. The depolarization was blocked by prolumide but not LY225910. Pretreatment with CCK-8S suppressed the GABA-evoked depolarization in a concentration-dependent manner. The CCK-8S inhibition was also time-dependent and reached the peak at about 2 min. The inhibitory effect of CCK-8S was strongly suppressed by pre-incubation of CCK-B receptor antagonist LY225910, phospholipase C inhibitor U73122, protein kinase C inhibitor chelerythrine and calcium chelator BAPTA-AM, respectively. The protein kinase A inhibitor H-89 did not affect CCK-8S effect. The results suggest that CCK-8S inhibits GABA-A receptor function by activation of CCK-B receptor followed by activation of intracellular PLC-Ca(2+)-PKC cascade. Thus, CCK-8S might enhance nociceptive information transmission through inhibition of the "pre-synaptic inhibition" evoked by GABA, which may explain its role in modulation of primary sensory information (especially pain).
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PMID:Modulatory effect of CCK-8S on GABA-induced depolarization from rat dorsal root ganglion. 1705 64

Trefoil family factor 2 (TFF2) is expressed in gastrointestinal epithelial cells where it serves to maintain mucosal integrity and promote epithelial repair. The peptide hormone, gastrin, stimulates acid secretion but also induces proliferation of the acid-secreting mucosa. Because the relationship between these peptides of overlapping function is not understood, we chose to investigate the regulatory effect of gastrin on TFF2 expression. The expression of mRNA and protein of TFF2 was determined by RT-PCR and immunohistochemical staining, respectively. A series of truncated and mutant murine TFF2 promoter constructs was generated. Promoter activity was assessed using dual luciferase reporter assays. Gastrin-responsive DNA-binding sites in the TFF2 promoter were evaluated by electrophoretic mobility shift assay. Gastrin significantly increased the level of endogenous mRNA of TFF2 in the gastrin receptor-expressing AGS-E gastric cancer cell line in a time- and dose-dependent manner. TFF2 protein expression in the gastric fundus was elevated in hypergastrinemic (INS-GAS) transgenic mice and reduced in gastrin-deficient mice. Gastrin treatment increased TFF2 promoter activity through cis-acting regions, containing CCAATA- and GC-rich enhancers. Pretreatment with Y-F476, a gastrin/CCK(B) receptor antagonist, abolished gastrin-dependent promoter activity. Inhibitors of protein kinase C (PKC), mitogen/extracellular signal-regulated kinase (MEK1), and phosphatidylinositol 3-kinase (PI 3-kinase) reduced gastrin-dependent TFF2 promoter activity, whereas an epithelial growth factor receptor (EGFR) inhibitor had no effect. We found that gastrin regulates TFF2 transcription through a GC-rich DNA-binding site and a PKC-, MEK1- and PI 3-kinase-dependent but EGFR-independent pathway. Regulation of TFF2 by gastrin may play a role in the maintenance and repair of the gastrointestinal mucosa.
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PMID:Gastrin regulates the TFF2 promoter through gastrin-responsive cis-acting elements and multiple signaling pathways. 1733 76

Regulation of the cholecystokinin receptor is accomplished by biochemical and cell biological mechanisms. The major mechanism for biochemical regulation involves phosphorylation of serine and threonine residues within the receptor's intracellular third loop and carboxyl-terminal tail. This form of rapid desensitization is achieved by protein kinase C, a kinase activated in the normal signaling cascade of this Gq-coupled receptor, and/or a member of the G protein-coupled receptor kinase family that recognizes the active conformation of the receptor. Conversely, a type 2A serine protein phosphatase has been shown to selectively act on this receptor in an agonist-regulated manner, resulting in receptor dephosphorylation and resensitization. Cell biological mechanisms for desensitization involve the net removal of receptors from exposure to circulating hormone via insulation within a specialized plasma membrane domain or internalization into the cell within endocytic compartments. Internalization has been shown to occur by both clathrin-dependent and clathrin-independent mechanisms, the latter believed to represent potocytosis in caveolae, that lead to recycling of receptors to the plasma membrane for resensitization or shuttling of receptors to lysosomes for degratory down-regulation. Interestingly, receptor phosphorylation has been shown to affect intracellular domain accessibility and receptor trafficking, although the specific proteins regulating this have not yet been identified. The cholecystokinin receptor can exist in the plasma membrane as oligomeric superstructures, namely as homomers with themselves or as heteromers with closely related class I G protein-coupled receptors. Agonist occupation results in oligomer dissociation, but the functional significance of this observation has yet to be defined.
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PMID:Biochemical and cell biological mechanisms of cholecystokinin receptor regulation. 1758 38

Our previous work revealed that gastrin regulates chromogranin A (CgA) transcription through enhanced binding of Sp1, CREB and Egr-1 to a proximal gastrin-responsive promoter element (Gas-RE). Here, we provide a detailed characterization of the signalling pathways transmitting the effect of gastrin on the CgA promoter. Gastrin treatment of gastric AGS-B cells potently stimulated MEK-1 as well as MAP kinases ERK-1/-2, JNK and p38 in a time-dependent manner. Interruption of ERK-1/-2/MEK-1 pathways abolished the transactivating effect of gastrin, whereas blockade of JNK or p38 activity was without effect. Functional promoter analysis revealed that the minimal element CgA-85/-64 was sufficient and necessary to confer MEK-1/ERK responsiveness. Analysis of proximal signalling pathways showed that activation of the MEK-1/ERK-1/2 module by gastrin does not require Ras, PI3-kinase or intracellular calcium signals, but depends on activation of kinases of the PKC family. This report demonstrates that a pathway comprising PKCs>Raf-1>MEK-1>ERK-1/-2 mediates the effect of gastrin on the CgA promoter, and strongly suggests that enhanced phosphorylation of Sp1 and CREB is crucial for CgA transactivation through the G protein-coupled CCK-B/gastrin receptor.
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PMID:Gastrin transactivates the chromogranin A gene through MEK-1/ERK- and PKC-dependent phosphorylation of Sp1 and CREB. 1788 8

The gastrin/CCK receptor (CCK2R) mediates the physiological functions of gastrin in the stomach, including stimulation of acid secretion and cellular proliferation and migration, but little is known about the factors that regulate its expression. We identified endogenous CCK2R expression in several cell lines and used luciferase promoter-reporter constructs to define the minimal promoter required for transcription in human gastric adenocarcinoma, AGS, and rat gastric mucosa, RGM1, cells. Consensus binding sites for SP1, C/EBP and GATA were essential for activity. Following serum withdrawal from RGM1 and AR42J cells, endogenous CCK2R mRNA abundance and the activity of a CCK2R promoter-reporter construct were significantly elevated. Transcription of CCK2R was also increased in AGS-G(R) and RGM1 cells by gastrin through mechanisms partly dependent upon protein kinase C (PKC) and mitogen/extracellular signal-regulated kinase (MEK). Gastrin significantly increased endogenous CCK2R expression in RGM1 cells, and CCK2R protein expression was elevated in the stomach of hypergastrinaemic animals. In mice with cryoulcers in the acid-secreting mucosa, CCK2R expression increased progressively in the regenerating mucosa adjacent to the ulcer repair margin, evident at 6 days postinjury and maximal at 13 days. De novo expression of CCK2R was observed in the submucosa beneath the repairing ulcer crater 6-9 days postinjury. Many of the cells in mucosa and submucosa that expressed CCK2R in response to cryoinjury were identified as myofibroblasts, since they coexpressed vimentin and smooth muscle alpha-actin but not desmin. The data suggest that increased CCK2R expression might influence the outcome of epithelial inflammation or injury and that the response may be mediated in part by myofibroblasts.
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PMID:Regulation of mammalian gastrin/CCK receptor (CCK2R) expression in vitro and in vivo. 1793 65


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