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)

[3H]Inositol phosphate responses to histamine and a range of other agonists were studied in cultured human tracheal smooth muscle cells. Histamine (EC50 6.5 microM), bradykinin (EC50 9.7 nM), carbachol (EC50 10 microM), substance P and NaF all produced concentration dependent [3H]inositol phosphate formation in these cells. The response to histamine was inhibited by mepyramine (KA 4.3 x 10(9) M-1), indicating the involvement of the histamine H1 receptor in this response. The inositol phosphate response to histamine was apparently desensitized following prolonged agonist exposure. The response to histamine was inhibited by phorbol dibutyrate (IC50 6 nM), and this inhibitory effect was reversed by staurosporine (150 nM). Isoprenaline (1 microM), rolipram (0.1-100 microM) and 3-isobutyl-1-methylxanthine (0.1 mM) all produced small inhibitory effects upon histamine induced inositol phosphate formation. These results demonstrate that cultured human tracheal smooth muscle cells express histamine H1 receptors coupled to phosphoinositidase C and suggest that the inositol phosphate response induced by stimulation of this receptor subtype is inhibited by activation of protein kinase C and, to a lesser extent, by elevation of cell cyclic AMP content.
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PMID:Control of histamine induced inositol phospholipid hydrolysis in cultured human tracheal smooth muscle cells. 839 92

1. The regulation of the increase in the cytosolic calcium concentration ([Ca2+]c) induced by extracellular ATP in AS-30D hepatoma cells was studied. 2. Homologous desensitization involving the refilling of intracellular calcium pools and the participation of protein kinase C was found. 3. Isoproterenol, forskolin and dibutyryl-cyclic AMP also induced an increase in [Ca2+]c. 4. Interestingly, synergism was found for isoproterenol or forskolin and ATP. 5. The results suggest that there are two pathways for mobilizing [Ca2+]c in AS-30D hepatoma cells; one is activated by ATP receptors and the other by cyclic AMP.
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PMID:Modulation of the ATP induced [Ca2+]c increase in AS-30D hepatoma cells. 840 51

The ultrarapid delayed rectifier K+ current (IKur) in human atrial cells appears to correspond to Kv1.5 cloned channels and to play an important role in human atrial repolarization. Kv1.5 channels have consensus sites for phosphorylation by protein kinase A and C, suggesting possible modulation by adrenergic stimulation. The present study was designed to assess the adrenergic regulation of IKur in human atrial myocytes. Isoproterenol increased IKur in a concentration-dependent manner, with significant effects at concentrations as low as 10 nmol/L. The effects of isoproterenol were reversible by washout or by the addition of propranolol (1 mumol/L). Isoproterenol's effects were mimicked by the direct adenylate cyclase stimulator, forskolin, and by the membrane-permeable form of cAMP, 8-bromo cAMP. Isoproterenol had no effect on IKur when the protein kinase A inhibitor peptide, PKI(6-22)amide, was included in the pipette solution; in a separate set of experiments in which isoproterenol alone increased IKur by 45 +/- 9% relative to control, subsequent superfusion with isoproterenol in the presence of the protein kinase inhibitor H-7 failed to alter IKur. In contrast to isoproterenol, phenylephrine (in the presence of propranolol to block beta-adrenegic effects) induced a concentration-dependent inhibition of IKur, with significant effects observed at concentrations as low as 10 mumol/L. The inhibitory actions of phenylephrine were reversed by the addition of prazosin and prevented by coadministration with a highly selective inhibitor of protein kinase C, bisindolylmaleimide. These results indicate that beta-adrenergic stimulation enhances, whereas alpha-adrenergic stimulation inhibits, IKur and suggest that these actions are mediated by protein kinase A and protein kinase C, respectively. The modulation of IKur by adrenergic influences is a potentially novel control mechanism for human atrial repolarization and arrhythmias.
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PMID:Adrenergic modulation of ultrarapid delayed rectifier K+ current in human atrial myocytes. 862 Jun 11

The Na+/Ca2+ exchanger plays an important role in the maintenance of calcium homeostasis in the heart. Therefore, factors which regulate the exchanger have a significant impact on cardiac function. Previously, we showed that the non-hydrolysable GTP analog, 5'guanylyl imidodiphosphate [Gpp(NH)p], stimulates Na+/Ca2+ exchange activity, implying the involvement of a G protein in exchanger regulation. In this study, we examined the effect of G protein agonists on Na+/Ca2+ exchanger activity. Isoproterenol, a Gs agonist, had no effect on exchanger activity. Likewise, the Gi agonist, carbachol, did not influence Na+/Ca2+ exchanger activity. Since these G proteins couple to the adenylate cyclase system, it would appear that cAMP-linked events do not regulate the Na+/Ca2+ exchanger. We next examined the influence of Gq-linked agonists on exchanger activity. Phenylephrine, an alpha 1-adrenergic agonist, increased Na+/Ca2+ exchanger activity up to 111% with an EC50 of 21 microM. Moreover, the Na+/Ca2+ exchanger activity was enhanced by angiotensin II and endothelin 1, which caused maximal stimulation of exchanger activity up to 125% and 211%, respectively. The selective protein kinase C inhibitor chelerythrine significantly attenuated the ability of phenylephrine and angiotensin II to stimulate the Na+/Ca2+ exchanger. In addition, the protein kinase C activator, phorbol 12-myristate 13-acetate, stimulated exchanger activity by 32%, raising the possibility that all three Gq agonists mediate their actions in part through the promotion of phospholipase C activity and the subsequent activation of protein kinase C. The contribution of Na+/Ca2+ exchange to the actions of phenylephrine, angiotensin II, and endothelin 1 is discussed.
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PMID:Stimulation of the Na+/Ca2+ exchanger by phenylephrine, angiotensin II and endothelin 1. 874 10

Mechanisms involved in the regulation of hydroxyindole-O-methyltransferase (HIOMT) activity were investigated in the rat pineal. Isoproterenol, db-cAMP, PACAP or VIP had no acute (6 h) effect whereas NPY, thapsigargin and a PKC activator stimulated HIOMT activity by 30-40%. Chronic stimulation (6 days) with isoproterenol, db-cAMP, or each peptide prevented the long-term decrease of HIOMT activity. Phenylephrine had neither short- nor long-term effect on enzyme activity. These results indicate that HIOMT activity is long- and short-term regulated by various neurotransmitters.
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PMID:Adrenergic and peptidergic regulations of hydroxyindole-O-methyltransferase activity in rat pineal gland. 944 37

When cultured astrocytes are treated with agents that elevate intracellular cyclic AMP, they become process-bearing stellate cells. In the present study, we investigated possible developmental changes of astrocyte stellation induced by beta-adrenoceptor stimulaton. Cultured astrocytes were prepared from the cerebral cortices of embryonic day 18 (E18) and postnatal day 2 (P2) rats. Treatment with the beta-adrenoceptor agonist isoproterenol induced stellation in P2 astrocytes more potently and rapidly than in E18 astrocytes. Isoproterenol-stimulated increase in cellular cyclic AMP levels was very similar in E18 and P2 astrocytes. The membrane-permeable cyclic AMP analog dibutyryl cyclic AMP induced stellation in P2 astrocytes more potently and rapidly than in E18 astrocytes. Stellation induced by the protein kinase C activator phorbol ester was not different between E18 and P2 astrocytes. These results suggest that beta-adrenoceptor-mediated astrocyte stellation increases during development and that this change is attributed to the development of mechanisms downstream from cyclic AMP production.
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PMID:Developmental changes in cyclic AMP-stimulated stellation of cultured rat cortical astrocytes. 946 50

We examined some of the signalling events in the negative modulation of isoproterenol-induced stimulation of contractility in rat isolated atria. Isoproterenol-mediated positive inotropic response is accompanied by the stimulation of nitric oxide synthase (NOS) and an increase in the production of cyclic GMP (cGMP). Inhibition of NOS and guanylate cyclase increased the dose-response curve of isoproterenol on contractility. Inhibitors of calcium flux or calcium calmodulin, but not of protein kinase C, abrogated these mechanisms. The existence of a modulatory negative inotropic-cyclic GMP-mediated mechanism limiting the effect of beta-adrenergic stimulation in myocardium is discussed.
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PMID:Role of nitric oxide in cardiac beta-adrenoceptor-inotropic response. 961 82

Hyperalgesic and nociceptor sensitizing effects mediated by the beta-adrenergic receptor were evaluated in the rat. Intradermal injection of epinephrine, the major endogenous ligand for the beta-adrenergic receptor, into the dorsum of the hindpaw of the rat produced a dose-dependent mechanical hyperalgesia, quantified by the Randall-Selitto paw-withdrawal test. Epinephrine-induced hyperalgesia was attenuated significantly by intradermal pretreatment with propranolol, a beta-adrenergic receptor antagonist, but not by phentolamine, an alpha-adrenergic receptor antagonist. Epinephrine-induced hyperalgesia developed rapidly; it was statistically significant by 2 min after injection, reached a maximum effect within 5 min, and lasted 2 h. Injection of a more beta-adrenergic receptor-selective agonist, isoproterenol, also produced dose-dependent hyperalgesia, which was attenuated by propranolol but not phentolamine. Epinephrine-induced hyperalgesia was not affected by indomethacin, an inhibitor of cyclo-oxygenase, or by surgical sympathectomy. It was attenuated significantly by inhibitors of the adenosine 3',5'-cyclic monophosphate signaling pathway (the adenylyl cyclase inhibitor, SQ 22536, and the protein kinase A inhibitors, Rp-adenosine 3',5'-cyclic monophosphate and WIPTIDE), inhibitors of the protein kinase C signaling pathway (chelerythrine and bisindolylmaleimide) and a mu-opioid receptor agonist DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin). Consistent with the hypothesis that epinephrine produces hyperalgesia by a direct action on primary afferent nociceptors, it was found to sensitize small-diameter dorsal root ganglion neurons in culture, i. e., to produce an increase in number of spikes and a decrease in latency to firing during a ramped depolarizing stimulus. These effects were blocked by propranolol. Furthermore epinephrine, like several other direct-acting hyperalgesic agents, caused a potentiation of tetrodotoxin-resistant sodium current, an effect that was abolished by Rp-adenosine 3',5'-cyclic monophosphate and significantly attenuated by bisindolylmaleimide. Isoproterenol also potentiated tetrodotoxin-resistant sodium current. In conclusion, epinephrine produces cutaneous mechanical hyperalgesia and sensitizes cultured dorsal root ganglion neurons in the absence of nerve injury via an action at a beta-adrenergic receptor. These effects of epinephrine are mediated by both the protein kinase A and protein kinase C second-messenger pathways.
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PMID:Epinephrine produces a beta-adrenergic receptor-mediated mechanical hyperalgesia and in vitro sensitization of rat nociceptors. 1008 37

1. The effects of adrenergic stimulation on the ultrarapid delayed rectifier K+ current (IKur,d) of dog atrial myocytes was studied with patch-clamp methods. 2. Isoproterenol (isoprenaline) increased IKur,d in a concentration-dependent fashion with an EC50 of 7.3 +/- 0.8 nM. The effect of isoproterenol was blocked by propranolol, mimicked by forskolin and 8-bromo-cAMP, and prevented by inhibition of protein kinase A. 3. Phenylephrine (in the presence of propranolol) increased IKur,d with an EC50 of 0.49 +/- 0.06 microM. The effect of phenylephrine was blocked by prazosin, prevented by inhibition of protein kinase C, and mimicked by activation of protein kinase C with phorbol ester. 4. Phenylephrine significantly abbreviated canine atrial action potential duration in the absence of tetraethylammonium (TEA). When TEA was present under both control conditions and in the presence of phenylephrine, phenylephrine failed to alter canine atrial repolarization. 5. We conclude that beta- and alpha-adrenergic stimulation increase IKur,d via protein kinase A and C, respectively, and that the induced changes in IKur,d may play a role in adrenergic control of canine atrial repolarization.
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PMID:Adrenergic control of the ultrarapid delayed rectifier current in canine atrial myocytes. 1008 39

Whole-cell [(32)P]-protein phosphorylation assays and two-dimensional gel electrophoresis (2-DGE) were applied to the analysis of the beta-adrenoceptor (betaAR)-linked signal transduction pathway. Rat C6 glioma cells were stimulated with isoproterenol and the protein lysates were resolved by 2-DGE. Two dimensional [(32)P]-phosphoprotein 'maps' were generated depicting the modulation of intracellular proteins after isoproterenol stimulation versus unstimulated cells. A total of 274 distinct phosphoprotein spots were detected, of which 200 were up-regulated, 69 were down-regulated, and 5 remained unchanged. An evaluation of isoproterenol's activity across several kinase pathways was performed using a computer-generated 2-DGE template incorporating the location and identification of individual signaling phosphoprotein intermediaries. The template served as a 'reference map' for drug treatment comparisons. We observed a significant increase in the phosphorylation states of several nuclear transcription factors, notably CREB-1, ATF-1, NFkappaB/IkappaBalpha and ELK-1, but not c-Jun. A parallel series of radioimmunoprecipitation studies confirmed our 2-DGE findings. Moreover, isoproterenol increased the phosphorylation state of PKC and of several MAPK-dependent pathway kinases which correlated with a significant increase in their endogenous kinase activity. Isoproterenol's effects on PKA, PKC and ERK-dependent activities were blocked by propranolol, a betaAR antagonist. In conclusion, an acute isoproterenol stimulus induced multiplex pathway modulation via the betaAR in the C6 glioma cell indicating that signaling pathway cross-talk is an essential feature for the regulation of cellular function. Moreover, the immediate advantages of the 2-DGE analytical approach were apparent, and further development of the protein database will provide a valuable tool to screen for broad-based drug-mediated signaling activities.
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PMID:Probing for drug-induced multiplex signal transduction pathways using high resolution two-dimensional gel electrophoresis: application to beta-adrenoceptor stimulation in the rat C6 glioma cell. 1040 86


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