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)

The human erythroleukemia cell line (HEL) has been used as a model system for studying signal transduction processes as they might relate to platelet/megakaryocyte function. We were interested in examining the role of thrombin in the regulation of adenylyl cyclase in this cell line. As opposed to its predominantly inhibitory effects on cyclic AMP production in platelets or in membranes from HEL cells, our initial experiments in intact HEL cells revealed that thrombin markedly potentiated the cyclic AMP response to prostaglandin E1 (2.9 +/- 0.2-fold), prostacyclin (1.9 +/- 0.2-fold) and carbacyclin (2.5 +/- 0.5-fold), measured either by radioimmunoassay or by the [3H]adenine preloading procedure. Thrombin, although ineffective alone, also potentiated cyclic AMP production stimulated by vasoactive intestinal peptide (1.6 +/- 0.2-fold), cholera toxin (3.0 +/- 0.6-fold) and AIF4- (2.3 +/- 0.6-fold), but not by forskolin (0.9 +/- 0.1-fold). The thrombin effect 1) produced an increase in the efficacy of the prostaglandins with no change in potency; 2) was long-lived; 3) required the proteolytic activity of thrombin; 4) was insensitive to pertussis toxin; and 5) was at least partially mimicked by trypsin, extracellular ATP and UTP, platelet activating factor and activators of protein kinase C. Down-regulation of protein kinase C or pre-exposure to the protein kinase inhibitor staurosporine blocked the potentiating effect. Together, these results suggest that in HEL cells, the mechanism of thrombin potentiation of cyclic AMP production may involve alterations in the interaction between stimulatory guanine nucleotide binding protein and the catalytic subunit of adenylyl cyclase, possibly involving protein kinase C-mediated phosphorylation.
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PMID:Potentiation of cyclic adenosine monophosphate production by thrombin in the human erythroleukemia cell line, HEL. 133 12

Phorbol-myristate-acetate (PMA) induced in lymphocytes the production or reactive oxygen intermediates in a process which was stimulated by the presence of vasoactive intestinal peptide (VIP) in a dose-dependent response at VIP concentrations in the range 10(-11)-10(-8) M. The dissociation constant for the high-affinity receptors of VIP agreed with the ID50 of the activation of adenylate cyclase, and the ID50 for the stimulation by VIP of PMA-induced chemiluminescence, which were close to 0.2 nM VIP. Forskolin produced in lymphocytes an effect quite similar to VIP. A comparison of the response to VIP and forskolin of lymphocytes and monocytes showed that, in contrast to forskolin, VIP failed to induce the above described effect in monocytes. A possible mechanism involving protein kinase C, which is activated by PMA, and an intracellular signal linked to VIP receptors is pointed out. This study further supports a role for VIP as a mediator in the neuroimmune system.
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PMID:Vasoactive intestinal peptide enhances phorbol myristate acetate-induced chemiluminescence in human lymphocytes. 133 43

The effects of alterations in the membrane lipid environment on vasoactive intestinal peptide (VIP) binding and VIP-stimulated cyclic AMP accumulation have been analyzed by arachidonic acid treatment of prostatic epithelial cells from rats at puberty and maturity, two critical developmental periods with characteristic lipidic and androgenic statuses. Treating cells with 0.1 mM arachidonic acid for 15 min at 37 degrees C increased the affinity of VIP receptors and the potency of the neuropeptide (up to five times) in the formation of cyclic AMP at maturity, but not at puberty. The average plasma membrane fluidity (as measured by fluorescence polarization of diphenylhexatriene) remained unmodified after arachidonic acid treatment of cells. The modifications observed in mature rats were specific for the VIP receptor/effector system, since cyclic AMP stimulation by isoproterenol or forskolin was not affected by cell treatment with arachidonic acid. These results are compatible with the existence of a particular lipidic microdomain surrounding the VIP receptor in the cell membrane that would be altered by exposure to arachidonic acid (either directly or through conversion of arachidonic acid to its metabolites, as suggested by experiments on inhibition of the arachidonic acid cascade). This would make it possible for the activation of protein kinase C to phosphorylate VIP receptors in cells from mature rats, but not in those from pubertal animals with a very different membrane lipid composition (as suggested by the corresponding values of membrane fluidity and transition temperature).
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PMID:Differential effect of arachidonic acid on the vasoactive intestinal peptide receptor/effector system in rat prostatic epithelium during sexual maturation. 133 77

The muscarinic agonist carbachol (CCh) was shown to elicit both stimulatory and inhibitory actions on Cl- secretion in T84 cells. These effects were observed in cells that had been prestimulated with adenosine 3',5'-cyclic monophosphate (cAMP) agonists. The addition of CCh to cells treated with submaximal concentrations (1-10 nM) of the receptor-mediated agonist prostaglandin (PG) E2 resulted in a biphasic effect on short-circuit current (Isc) involving a transient synergistic rise followed by a slower and sustained attenuation of the PGE2-activated Isc response. In contrast at higher PGE2 concentrations (greater than 10 nM) or with nonreceptor-mediated cAMP agonists (forskolin, dibutyryl cAMP) CCh elicited a prolonged synergistic response. Both effects of CCh could be reproduced by selective activation of the Ca2+ pathway. Increasing cytosolic Ca2+ with ionophore A23187 partially mimicked the "early" stimulation of secretion, though there was evidence that a combination of A23187 and the protein kinase C activator phorbol 12,13-dibutyrate (PDB) was required for full expression of the secretory response. In contrast, treatment with PDB alone closely mimicked the CCh-induced inhibition of PGE2-stimulated Isc. The antisecretory effects of CCh were associated with a marked attenuation of cAMP production in response to receptor-mediated agonists, including PGE2 and vasoactive intestinal peptide. This effect could also be closely mimicked by PDB. Pretreatment with pertussis toxin partially inhibited the ability of CCh to inhibit cAMP production. CCh potentiated the cAMP response to the nonreceptor agonist forskolin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulatory and inhibitory actions of carbachol on chloride secretory responses in human colonic cell line T84. 165 58

In rat pinealocytes, ethanol has been shown recently to inhibit the alpha 1-adrenergic potentiation of vasoactive intestinal peptide (VIP)-stimulated cyclic AMP (cAMP) and cyclic GMP (cGMP) responses, with the cGMP response being more sensitive to the inhibition. Two intracellular events known to be of importance to the potentiation mechanism are activation of protein kinase C and elevation of intracellular calcium [( Ca2+]i). In this study, we examined the effects of ethanol on these two intracellular mechanisms with an activator of protein kinase C, and two agents that elevate [Ca2+]i, depolarizing concentrations of K+ and A23187. Using dispersed pinealocytes, ethanol (up to 175 mM) was found to have no effect on the 4 beta-phorbol 12-myristate 13-acetate (PMA, an activator of protein kinase C) potentiated VIP-stimulated cAMP response. As for the cGMP response, full potentiation requires both activation of protein kinase C and simultaneous elevation of [Ca2+]i. This could be achieved by stimulating the VIP-treated cells with a combination of PMA and 15 mM K+. In the presence of ethanol, the amplification effect of PMA and K+ on the VIP-stimulated cGMP response was inhibited with an IC50 value of 125 mM. In contrast, similar concentrations of ethanol had no effect on the corresponding cAMP response. These findings suggest that the potentiation of cAMP response by protein kinase C is not affected by ethanol. When depolarizing concentrations of K+ were used to potentiate the VIP-stimulated cAMP and cGMP accumulation, ethanol inhibited the K+ potentiation of VIP-stimulated cAMP and cGMP responses with IC50 values of 50 and 30 mM, respectively. The A23187 potentiation of VIP-stimulated cGMP response was also sensitive to the inhibitory effect of ethanol with an IC50 value of 120 mM. In comparison, the corresponding IC50 value for the cAMP response was greater than 175 mM. Based on our findings, we conclude that ethanol likely inhibits a Ca(2+)-dependent event(s) that is critical to the alpha 1-adrenergic-mediated potentiation of VIP-stimulated cAMP and cGMP responses.
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PMID:Inhibitory effects of ethanol on the calcium-dependent potentiation of vasoactive intestinal peptide-stimulated cAMP and cGMP accumulation in rat pinealocytes. 165 91

We showed previously that TRH down-regulates TRH receptor (TRH-R) mRNA in GH3 cells by a mechanism that appears to be mediated by protein kinase C. Here we show that vasoactive intestinal peptide (VIP) down-regulates TRH-R mRNA and present evidence that this action is mediated by protein kinase A. In GH3 cells, VIP caused a time- and concentration-dependent decrease in TRH-R mRNA. This VIP effect was simulated by 8-(4-chlorophenylthio)-cAMP, forskolin, cholera toxin and 1-methyl-3-isobutylxanthine. When cells were incubated with agents that elevate cAMP and TRH or phorbol 12-myristate 13-acetate, the decrease in TRH-R mRNA was greater than with either agent alone. When cells were pre-incubated with H-7 [1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride], an inhibitor of protein kinases, the effects of VIP, TRH and phorbol 12-myristate 13-acetate were inhibited. We suggest that VIP, via protein kinase A, and TRH, via protein kinase C, dually regulate TRH-R mRNA.
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PMID:Evidence for dual regulation by protein kinases A and C of thyrotropin-releasing hormone receptor mRNA in GH3 cells. 165 32

Heterologous expression of the rat 5-HT1A receptor in stably transfected GH4C1 rat pituitary cells (clone GH4ZD10) and mouse Ltk- fibroblast cells (clone LZD-7) (Albert, P.R., Zhou, Q.-Y., VanTol, H.H.M., Bunzow, J.R., and Civelli, O. (1990) J. Biol. Chem. 265, 5825-5832) was used to characterize the cellular specificity of signal transduction by the 5-HT1A receptor. We demonstrate that the 5-HT1A receptor, acting via pertussis toxin-sensitive G proteins, can change its inhibitory signaling phenotype and become a stimulatory receptor, depending on the cell type, differentiation state, or intracellular milieu of the cell in which it is expressed. When expressed in pituitary GH4ZD10 cells, activation of 5-HT1A receptors decreased both basal and vasoactive intestinal peptide-enhanced cAMP accumulation and blocked (+/-)-Bay K8644-induced influx of calcium, inhibitory responses which are typical of neurons which endogenously express this receptor. Similarly, 5-hydroxytryptamine (5-HT) also inhibited adenylyl cyclase in fibroblast LZD-7 cells, reducing the forskolin-induced enhancement of cAMP levels by 50%, but did not alter basal cAMP levels. In contrast to GH4ZD10 cells, where 5-HT had no effect on basal or thyrotropin-releasing hormone-induced phosphatidylinositol turnover, 5-HT enhanced the accumulation of inositol phosphates and induced a biphasic increase in [Ca2+]i in LZD-7 cells. These dominant stimulatory actions of 5-HT, as well as the inhibitory effects, were absent in untransfected cells and displayed the potency and pharmacological specificity of the 5-HT1A receptor, indicating that the 5-HT1A subtype coupled to both inhibitory and stimulatory pathways in the fibroblast cell. The actions of 5-HT in GH and L cells were blocked by 24-h pretreatment with pertussis toxin, suggesting that inhibitory G proteins (Gi/G(o)) mediate both inhibitory and stimulatory signal transduction of the 5-HT1A receptor. However, the 5-HT-induced stimulatory pathway in fibroblasts was blocked selectively by acute (2-min) pretreatment with TPA, an activator of protein kinase C. This action of protein kinase C was potentiated by activation of protein kinase A, indicating that the expression of the stimulatory pathway of the 5-HT1A receptor in LZD-7 cells is modulated by second messengers.
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PMID:Cell-specific signaling of the 5-HT1A receptor. Modulation by protein kinases C and A. 166 Aug 81

In recent years evidence has accumulated indicating the presence of functional receptors for most neurotransmitters on astrocytes. In particular, receptors coupled to adenylate cyclase have been demonstrated, in primary astrocyte cultures, for vasoactive intestinal peptide (VIP), noradrenaline (NA) and adenosine. Here we provide, in primary cultures of cerebral cortical astrocytes prepared from neonatal mice, a detailed characterization of a cAMP-dependent process elicited by VIP, NA and adenosine, i.e. the hydrolysis of glycogen. The EC50s for the glycogenolytic effect of VIP, NA and adenosine are 3, 20 and 800 nM, respectively. The initial rate of glycogen hydrolysis is, in nmol/mg prot/min, 9.1 for VIP and 7.5 for NA. The effect of NA is predominantly mediated by beta-adrenoceptors, although an alpha 1-adrenergic component, acting most likely through protein kinase C activation, is also present. The action of VIP is mimicked by peptides sharing sequence homologies such as PHI and secretin. Glutamate, GABA, carbachol and the peptides NPY and somatostatin do not influence glycogen levels. The glycogen content of the cultures can be markedly increased by anabolic factors present in fetal calf serum, by high (e.g. 25 mM) glucose in the medium and by 48-h pretreatment of the cultures with dibutyryl cAMP. These results indicate that the glycogen content of astrocytes is under the dynamic control of various factors, including certain neurotransmitters. They also further stress the notion of a functional interaction between neurons and glial cells aimed at maintaining local energy metabolism homeostasis.
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PMID:Characterization of the glycogenolysis elicited by vasoactive intestinal peptide, noradrenaline and adenosine in primary cultures of mouse cerebral cortical astrocytes. 166 73

First incubating guinea pig pancreatic acini with carbachol reduced the subsequent stimulation of amylase release caused by carbachol, cholecystokinin octapeptide (CCK-8), and bombesin but not that caused by vasoactive intestinal peptide, substance P, 8-bromoadenosine 3',5'-cyclic monophosphate, A23187, or 12-O-tetradecanoylphorbol-13-acetate. Carbachol also reduced the subsequent binding of N-[3H]methylscopolamine, 125I-CCK-8, and 125I-[Tyr4]bombesin. Pancreatic acini possess a high-affinity class of cholinergic receptors and a low-affinity cholinergic receptors appears to produce the reduction in carbachol-stimulated amylase release and binding of N-[3H]methylscopolamine. First incubating acini with carbachol caused a complete loss of high-affinity cholinergic receptors with no change in the number or affinity of low-affinity cholinergic receptors. Carbachol occupation of low-affinity cholinergic receptors appears to produce the reduction in CCK-8- and bombesin-stimulated amylase release and in binding of 125I-CCK-8 and 125I-[Tyr4]bombesin. Acini possess two classes of CCK receptors. One class has a high affinity for CCK-8; the other class has a low affinity for CCK-8. First incubating acini with carbachol caused a 60% decrease in the number of high-affinity CCK receptors with no change in the number of low-affinity receptors or the affinities of either class of receptors for CCK-8. Acini possess a single class of bombesin receptors, and first incubating acini with carbachol caused a 40% decrease in the number of bombesin receptors with no change in their affinity for bombesin. 12-O-tetradecanoyl phorbol-13-acetate reproduced the action of carbachol on binding of N-[3H]methylscopolamine and 125I-CCK-8 but not on binding of 125I-[Tyr4]bombesin, suggesting that carbachol activation of protein kinase C may in some way mediate the effect of carbachol on receptors for carbachol and those for CCK but not that on receptors for bombesin.
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PMID:Carbachol desensitizes pancreatic enzyme secretion by downregulation of receptors. 168 17

Cholecystokinin (CCK) and cholinergic agonists are both major stimulants of pancreatic enzyme secretion and both utilize a common calcium-phosphoinositide-mediated receptor coupling system. In this study we investigated the modulation of pancreatic acinar CCK receptors by the muscarinic agonist carbachol (CCh) and investigated the intracellular mechanisms involved in the modulation. Acini were isolated from rat pancreas and dispersed in N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-Ringer solution. Preincubation with 0.1 mM carbachol for 60 min reduced the CCK octapeptide (CCK-8; 100 pM)-stimulated amylase release by 43 +/- 5%. Binding of 125I-Bolton-Hunter-labeled CCK-8 (125I-BH-CCK-8) revealed two classes of CCK receptors, a high affinity with a dissociation constant (Kd) of 20 pM and a low affinity with a Kd of 2.3 nM. Pretreatment with 100 microM CCh decreased total binding by 35 +/- 6%, affecting the binding capacity of the high-affinity site, without change in the maximal binding capacity of the low-affinity site and no change in the Kd of either site. Preincubation of acini with 12-O-tetradecanoylphorbol 12,13-acetate (TPA, 1 microM), an activator of protein kinase C (PKC), decreased subsequent CCK-8-stimulated amylase release, and total binding of 125I-BH-CCK-8 to a similar extent as with pretreatment with CCh. The inhibitory effect of TPA or CCh on CCK-8-stimulated amylase release was reversed by simultaneous preincubation with H-7, an inhibitor of PKC. Pretreatment of acini with the calcium ionophore A23187, vasoactive intestinal peptide, or 8-bromoadenosine 3',5'-cyclic monophosphate had no effect on 125I-BH-CCK-8 binding. After CCh or TPA preincubation, CCK-8-stimulated production of [3H]inositol phosphates was inhibited by at least 49%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Carbachol acts through protein kinase C to modulate cholecystokinin receptors on pancreatic acini. 172 47


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