Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study shows the presence of seven different low-molecular-weight GTP binding proteins (smg proteins) with molecular masses between 18 and 27 kDa in subfractions of rat pancreatic acinar cells. After stimulation of isolated intact and permeabilized pancreatic acinar cells with cholecystokinin octapeptide (CCK-OP), the diacylglycerol (DG) analogue 12-O-tetradecanoylphorbol 13-acetate (TPA), vasoactive intestinal peptide (VIP), adenosine 3',5'-cyclic monophosphate (cAMP), or guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S), [alpha-32P]GTP binding to 21- to 22-kDa smg protein(s) in microsomal membranes (MM) was reduced, whereas the [alpha-32P]GTP binding to 23-kDa protein(s) was enhanced. In addition, prestimulation of permeabilized cells with GTP gamma S caused enhancement of [alpha-32P]GTP binding to a 19-kDa protein in MM [immunologically identified as the ADP-ribosylation factor (arf)]. In the presence of cytosol, direct addition of GTP gamma S to isolated MM resulted in an apparent translocation of the 19-kDa protein (arf) from the cytosol to membranes. This indicates increased association of arf with the membrane in its GTP-bound state. In CCK-OP-prestimulated acinar cells, [alpha-32P]GTP binding to plasma membrane-located 21- to 22-kDa proteins (immunologically identified as p21ras proteins) was enhanced, suggesting that there is an interrelationship between p21ras proteins and CCK receptors. Our results give evidence for a role of 19-kDa, 21- to 22-kDa, and 23-kDa smg proteins in cAMP-protein kinase A- and DG-protein kinase C-mediated stimulation of intracellular pathways in pancreatic acinar cells.
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PMID:Effects of agonists on p21ras and ras-related proteins in rat pancreatic acinar cells. 141 52

Recordings of [Ca2+]i in single AR42J cells loaded with Fura 2 were used to study regulation of [Ca2+]i oscillation. Continuous stimulation with the cholecystokinin analogue, (t-butyloxycarbonyl-Tyr-(SO3)-norleucine-Gly-Trp-Nle-Asp-2-phenylethyl ester) or carbachol evoked long lasting oscillation in [Ca2+]i. Removal of CCK-JMV-180 after brief stimulation did not abruptly stop the oscillation. Rather, removal of CCK-JMV-180 resulted in time-dependent reduction in amplitude with little change in frequency of oscillation. The patterns of [Ca2+]i oscillation were affected by activation of protein kinase C and protein kinase A. However, down-regulation of protein kinase C activity did not prevent stimulation of [Ca2+]i oscillation. Hence, we conclude that an active protein kinase C pathway is not crucial for [Ca2+]i oscillation in this cell line. Variation in extracellular Ca2+ concentration (Ca2+out) was used to further characterize the oscillation. Reducing Ca2+out to approximately 10 microM resulted in a time dependent inhibition of [Ca2+]i oscillation. Subsequent step increases in Ca2+out up to 2-3 mM resulted in increased amplitude and frequency of oscillation. Further increase in Ca2+out or an increase in plasma membrane permeability to Ca2+, brought about by an increase in pHo, resulted in increased amplitude, decreased frequency, and modified shape of the [Ca2+]i spikes. These observations point to the existence of regulatory mechanisms controlling the duration of Ca2+ release and entry during [Ca2+]i oscillation.
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PMID:Regulation of intracellular Ca2+ oscillation in AR42J cells. 170 Nov 71

In this study we have examined the effects of prostaglandin E2 (PGE2), the cyclooxygenase inhibitor, indomethacin, and a protein kinase A inhibitor (PKA-I) on the Cl- conductance in isolated zymogen granules (ZG) from cholecystokinin octapeptide (CCK-8) pre-stimulated pancreatic acini. The Cl- conductance in isolated ZG from CCK-8 pre-stimulated rat pancreatic acini increases with increasing CCK-8 concentrations and decreases at supramaximal CCK-8 concentrations. The basal and CCK-8-stimulated Cl- conductance in ZG is inhibited by pretreatment of acini with PGE2 (10(-6) M). This PGE2-induced inhibition is abolished in the presence of PKA-I (20 U/ml). Furthermore, pretreatment of acini with indomethacin (10(-5) M) or PKA-I (20 U/ml) abolishes the decrease in the CL- conductance at supramaximal CCK-8 concentrations (10(-9) M). We conclude that the inhibition of the CL- conductance in isolated ZG at high CCK-8 concentrations is mediated by an enhanced production of PGE2, and that PGE2 operates by stimulating adenylate cyclase (AC) with a consequent rise in cAMP and activation of PKA.
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PMID:PGE2 regulates cholecystokinin-octapeptide (CCK-8)-stimulated Cl- conductance in isolated zymogen granules from rat pancreas. 172 67

The sulphated octapeptide of cholecystokinin (CCK-8S) was found to cause a dose-dependent increase in the basal release of aspartate, glycine, and gamma-aminobutyric acid from the striatum and the ventromedial nucleus of the hypothalamus (VMH). No effect on amino acid release was observed after electrical (VMH) or potassium (striatum) stimulation. Experiments performed using the CCKB-selective antagonist L-365,260 and the CCKA-selective antagonist L-364,718 suggested that this action of CCK-8S was mediated via the CCKB receptor. The ability of CCK-8S to evoke amino acid release was not dependent on the presence of extracellular calcium, though the effect was abolished by tetrodotoxin. Inhibition of protein kinase activity by staurosporine prevented the excitatory effects of CCK-8S on amino acid release.
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PMID:Effect of cholecystokinin octapeptide on endogenous amino acid release from the rat ventromedial nucleus of the hypothalamus and striatum. 200 50

Figure 4 summarizes the steps by which Ca2+ and cyclic AMP-mediated secretagogues activate enzyme secretion in the pancreatic acinar cell. CCK and acetylcholine bind to specific plasma membrane receptors and through an as yet incompletely understood mechanism give rise to an elevation in free cytoplasmic Ca2+. A question central to this scheme is whether receptor binding leads to intracellular Ca2+ mobilization through generation of a diffusable mediator. Clues to answering this question may come from a) determining whether Ca2+ is released from the plasma membrane in addition to one or more intracellular organelles, and b) examining the role (if any) of membrane phosphatidylinositol metabolism in Ca2+ mobilization. A second class of secretagogues, represented by VIP and secretin, bind to their specific receptors and cause the accumulation of cyclic AMP. Cyclic AMP potentiates Ca2+ in activating secretion, and in some species, cyclic AMP may activate secretion independently of Ca2+. Ca2+ may act by regulating the activity of calmodulin dependent protein kinase(s) and phosphatase(s) and a phospholipid dependent kinase (protein kinase C) which has also been shown to be activated by diacylglycerol; cyclic AMP activates a distinct kinase termed protein kinase A. These kinases and phosphatases then alter the phosphorylation of specific proteins which are presumed to play structural or regulatory roles in exocytosis. Potentiation may thus result from interaction of Ca2+ and cyclic AMP at the level of a protein kinase, phosphatase or protein substrate.
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PMID:Stimulus-secretion coupling in pancreatic acinar cells. 609 80

In hog terminal bile duct cholecystokinin peptides caused an activation of cyclic AMP-dependent protein kinase (A-PK) with cyclic AMP, followed by increase in Ca uptake of sarcoplasmic reticulum fraction (SR-F). By contrast, papaverine showed no activation of A-PK-induced Ca uptake by SR-F with cyclic AMP. The Ca uptake by SR-F was dependent on ATP and Mg2+, but the component phosphorylated was not the phosphoenzyme intermediate in Ca2+-ATPase. The effect of Ca uptake was blocked by the inclusion of a protein inhibitor of A-PK. The correlation coefficient between cyclic AMP-dependent SR-F phosphorylation and stimulated Ca uptake by the phosphorylated SR-F was 0.731 (P less than 0.01). These results suggest that one of the mechanisms by which CCK-4, CCK-8, and CCK-33 peptides relax isolated Oddi's sphincters of terminal bile ducts is activation of A-PK-induced Ca uptake by sarcoplasmic reticulum fraction and possibly also by plasma membrane.
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PMID:Relationship between cyclic AMP-dependent protein kinase activation and Ca uptake increase of sarcoplasmic reticulum fraction of hog biliary muscles relaxed by cholecystokinin-C-terminal peptides. 629 7

We examined the effects of FK506 on amylase secretion and intracellular pathway in stimulus secretion coupling in isolated pancreatic acini. Amylase release from isolated acini in response to cholecystokinin octapeptide (CCK-8) was suppressed by exposing acini to FK506. The suppressing effect of FK506 on amylase release from acini was dependent on the concentration of FK506 and the time of exposure to FK506. Amylase releases in response to 8-bromo-cAMP and vasoactive intestinal peptide and phorbol ester (12-O-tetradecanoylphorbol 13-acetate) were not suppressed when acini were exposed to FK506, suggesting that the cAMP-dependent protein kinase pathway and protein kinase C pathway were not affected by FK506. However, amylase release in response to calcium ionophore (4-bromo-A23187) was suppressed by FK506, whereas the increase in cytosolic free calcium concentration caused by 4-bromo-A23187 was not affected by FK506. These results suggest that FK506 suppressed secretagogue-stimulated amylase release in acini by altering Ca(++)-mediated intracellular pathways. Further, the property of CCK-8 binding site, CCK-8 stimulated inositol phosphates formation, rises in cytosolic free calcium concentration, and calcium efflux from acini were not suppressed by exposing acini to FK506. These findings indicate that FK506 suppresses amylase release by affecting postreceptor intracellular pathways that are mediated by Ca++ in stimulus secretion coupling.
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PMID:Biochemical characterization of the effects of FK506 on signal transduction in exocytotic function of rat pancreatic acini. 767 38

In order to establish a regulatory role for phosphoproteins in the process of receptor-stimulated Ca2+ mobilization, isolated pancreatic acinar cells, loaded with fura-2, were stimulated with cholecystokinin-octapeptide (CCK8) in the presence of either staurosporine, a general inhibitor of protein kinase activity, or 12-O-tetradecanoylphorbol 13-acetate (TPA), an activator of protein kinase C. Staurosporine alone did not affect the average free cytosolic Ca2+ concentration ([Ca2+]i,av) in a suspension of acinar cells. However, in the presence of 1.0 microM staurosporine the stimulatory effect of submaximal concentrations of CCK8 was significantly enhanced. The potentiating effect of the inhibitor was paralleled by the increased production of inositol 1,4,5-trisphosphate. In addition, staurosporine evoked a transient increase in [Ca2+]i,av in cells prestimulated with a submaximal concentration of CCK8. The data obtained with staurosporine indicate that CCK8-stimulated phosphorylations exert a negative feedback role in the process of receptor-mediated Ca2+ mobilization. The involvement of protein kinase C was investigated by studying the effects of TPA on CCK8-induced Ca2+ mobilization. The phorbol ester induced a rightward shift of the dose/response curve for the CCK8-evoked increase in [Ca2+]i,av, which, in contrast to the unlimited shift obtained with the receptor antagonist D-lorglumide, reached a maximum of approximately one order of a magnitude at 10 nM TPA. The inhibitory effect of TPA was completely overcome by CCK8 at concentrations at or beyond 10 nM. This observation has led to the hypothesis that protein kinase C, directly or indirectly, converts the CCK receptor from a high-affinity state to a low-affinity state. Substantial evidence in favour of this hypothesis was provided by the observation that the increase in [Ca2+]i,av evoked by the CCK8 analogue JMV-180, which acts as an agonist at the high-affinity receptor, was completely blocked by TPA pretreatment. TPA also evoked a rightward shift of the dose/response curve for the carbachol-induced increase in [Ca2+]i,av, indicating that the protein-kinase-C-mediated transition of the affinity state of receptors is a more general phenomenon. In the presence of submaximal CCK8 concentrations, TPA dose-dependently decreased the poststimulatory elevated [Ca2+]i,av to the prestimulatory level, indicating that protein kinase C also inhibits the process of sustained Ca2+ mobilization. The effects of TPA were counteracted by staurosporine, suggesting that the effects of the inhibitor itself were indeed due to inhibition of the receptor-mediated activation of protein kinase C.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Receptor-evoked Ca2+ mobilization in pancreatic acinar cells: evidence for a regulatory role of protein kinase C by a mechanism involving the transition of high-affinity receptors to a low-affinity state. 769 87

cGMP-dependent protein kinase (cGMP kinase) has been implicated in the regulation of the cytosolic calcium level ([Ca2+]i). In Chinese hamster ovary (CHO) cells stably transfected with the cGMP kinase I alpha (CHO-cGK cells), cGMP kinase suppressed the thrombin-induced increase in inositol 1,4,5-trisphosphate and [Ca2+]i (Ruth, P., Wang, G.-X., Boekhoff, I., May, B., Pfeifer, A., Penner, R., Korth, M., Breer, H., and Hofmann, F. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 2623-2627). Cholecystokinin activated intracellular calcium release via a pertussis toxin (PTX)-insensitive pathway in CHO-cGK cells. cGMP kinase did not attenuate the CCK-stimulated [Ca2+]i. In contrast, cGMP kinase suppressed calcium influx stimulated by insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) via PTX-sensitive pathways. The effects of PTX and cGMP kinase on [Ca2+]i were not additive. 8-Bromo-cGMP had no effect on [Ca2+]i stimulated by IGF-1 or IGF-2 in wild type CHO cells. These results suggested that cGMP kinase inhibited the different signaling pathways by the phosphorylation of a PTX-sensitive G protein. cGMP kinase phosphorylated the alpha subunits of Gi1, Gi2, and Gi3 in vitro. Phosphorylation stoichiometry was 0.4 mol of phosphate/mol of G alpha i1 after reconstitution of heterotrimeric Gi1 in phospholipid vesicles. The alpha subunit of Gi was also phosphorylated in vivo. These results show that cGMP kinase blocks transduction of distinct hormone pathways that signal via PTX-sensitive Gi proteins.
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PMID:Cyclic GMP-dependent protein kinase blocks pertussis toxin-sensitive hormone receptor signaling pathways in Chinese hamster ovary cells. 772 18

In the course of examining the actions of the cholecystokinin octapeptide (CCK-8) on pancreatic acini we found that CCK-8 can stimulate release of the large-molecular-weight cytoplasmic protein, lactate dehydrogenase (LDH) by as much as 6-fold. CCK-8-stimulated LDH release is mediated by a CCK-preferring receptor, detectable at 100 pM CCK-8, maximal at 100 nM CCK-8, constant for up to 30 min, reversible, not desensitized, and dependent on oxidative metabolism and incubation temperature but not on calcium in the extracellular medium. This action of CCK-8 is blocked by inhibitors of protein kinases, staurosporine, H-7, H-8 and H-9, but not by calmodulin antagonists, chlorpromazine, trifluoperazine or W-7. This action of CCK-8 on LDH release is not reproduced by TPA, 8Br-cAMP or A23187. Thus, it appears to be mediated by a previously uncharacterized protein kinase or an isoform of protein kinase C that is not maximally stimulated by TPA.
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PMID:A newly recognized action of cholecystokinin on pancreatic acini-release of lactate dehydrogenase. 849 90


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