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)

Previous results from our laboratory (White and Carrier, Enhanced Vascular Alpha-Adrenergic Neuroeffector System in Diabetes: Importance of Calcium. Am. J. Physiol. 255: H1036-1042, 1988) demonstrated that mesenteric arteries from streptozotocin (STZ)-diabetic rats exhibit an enhanced responsiveness to alpha adrenergic agonists. The present study demonstrates that this enhanced responsiveness is dependent upon the presence of extracellular calcium. Arteries from STZ-diabetic (10-12 weeks) rats developed greater contractile force in response to norepinephrine or KCl. Development of these effects was prevented by daily insulin treatment, indicating these alterations are related to the diabetic state. Similarly, the contractile response to extracellular calcium in the presence of norepinephrine (3 x 10(-6) M) or KCl (60 mM) was greater in arteries from STZ-diabetic animals. BAY K 8644, a calcium channel agonist, induced greater contraction in arteries from STZ-diabetic animals, as did activation of protein kinase C by phorbol dibutyrate. In contrast, contraction induced by release of calcium from intracellular sources (alpha-1 adrenoceptor-mediated or caffeine-induced) was unaltered by diabetes. These findings indicate that enhanced vascular contraction in STZ-diabetes is of a nonspecific nature, i.e., the contractile response to any agent which induces extracellular calcium-dependent contraction should be enhanced in diabetes. We propose that STZ-diabetes enhances the activity and/or number of calcium ion channels in vascular smooth muscle.
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PMID:Vascular contraction induced by activation of membrane calcium ion channels is enhanced in streptozotocin-diabetes. 169 42

1. Membrane currents were recorded by a patch-clamp pipette technique in cultured cells from rat portal vein using the whole-cell mode. 2. Noradrenaline (NA, 10(-5) M) and phorbol-12,13-dibutyrate (PDBu, 10(-7) M) produced an increase in voltage-dependent inward current carried by barium (5 mM), but their effects were not additive. Calcium-activated chloride current was evoked by NA but not by PDBu. 3. The NA-induced increase in peak voltage-dependent inward current was inhibited by intracellular application of GDP-beta-S (10(-3) M) while the effect of PDBu was unchanged. GDP-beta-S blocked the NA-induced chloride current but had no effect on the caffeine-induced chloride current. 4. Inclusion of GTP-gamma-S (10(-5)-10(-4) M) in the pipette solution increased the voltage-dependent inward current and inhibited the NA- or PDBu-induced increase in peak current. GTP-gamma-S potentiated the effect of NA on calcium-activated chloride current. At higher concentrations (10(-3) M), GTP-gamma-S activated the chloride current and prevented the effects of NA or caffeine on this current. 5. The combination of 10(-5) M-aluminium chloride and 10(-2) M-sodium fluoride had an effect similar to that of high concentrations of GTP-gamma-S on both inward current and calcium-activated chloride current. In contrast, arachidonic acid (10(-3) M) had no effect on calcium and chloride conductances activated by NA. 6. Cells responded normally to NA after pre-treatment for 4-30 h with 10 micrograms ml-1 pertussis toxin (PTx). 7. It is concluded that the stimulation of calcium and chloride conductances by NA is mediated through activation of a PTx-insensitive GTP-binding protein. This effect may involve activation of phospholipase C enzyme and production of both D-myo-inositol 1,4,5-trisphosphate which depletes calcium stores and diacylglycerol which activates protein kinase C.
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PMID:GTP-binding proteins mediate noradrenaline effects on calcium and chloride currents in rat portal vein myocytes. 170 Jan 11

We assessed the specificity of staurosporine, a putative protein kinase C inhibitor, for the enzyme in intact porcine coronary arteries by examining its effects on changes in intracellular free calcium level ([Ca++]i) and force induced by a phorbol ester, high KCl and caffeine. [Ca++]i was measured simultaneously with force by the fura-2 microfluorimetric method. Phorbol 12,13-dibutyrate (PDBu, 10(-6) M) produced a slowly developing and sustained contraction; however, [Ca++]i only increased slightly and transiently in the initial phase and then decreased gradually. On the other hand, 90 mM KCl elicited a contraction with a sustained increase in [Ca++]i. Staurosporine (10(-10) to 10(-7) M) applied 20 min before the addition of PDBu inhibited the PDBu-induced changes in [Ca++]i and force in a concentration-dependent manner. In contrast, staurosporine only at 10(-7) M reduced an increase in [Ca++]i and contractile force produced by 90 mM KCl. The inhibitory effects of staurosporine on PDBu- and KCl-induced contractions depended on exposure time. The [Ca++]i-force relationship obtained with variable concentrations of KCl was shifted slightly to the right by staurosporine at 10(-7) M. Furthermore, staurosporine even at 10(-7) M did not affect an increase in [Ca++]i by caffeine (25 mM), although it slightly attenuated a caffeine-induced contraction. These results suggest that staurosporine is a relatively specific inhibitor of protein kinase C in intact arteries at lower concentrations. At higher concentrations it may have actions unrelated to its inhibitory effect of protein kinase C, which include the inhibition of calcium influx into smooth muscle cells through the voltage-dependent Ca++ channel.
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PMID:Is staurosporine a specific inhibitor of protein kinase C in intact porcine coronary arteries? 176 58

1. Endothelin-1 (ET-1) caused a concentration-dependent contraction of helical strips from rat thoracic aorta in the absence of extracellular Ca2+. The Ca(2+)-depleted muscle strips, prepared by three repeated applications of 10(-2) M caffeine or 10(-6) M noradrenaline in Ca(2+)-free buffer, were contracted by 10(-8) M ET-1 in the same manner as non-treated strips. 2. In the absence of extracellular Ca2+, 10(-7) M phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, induced a small but sustained contraction of the rat thoracic aorta strips within 60 min. Preincubation of the strips with 10(-7) M PMA for 60 min in Ca(2+)-free buffer, did not affect the 10(-8) M ET-1-induced contraction, but decreased the 5 x 10(-8) M phorbol 12,13-dibutyrate (PDB)-, or the 10(-7) M PMA-induced contraction, and potentiated the contraction induced by 10(-8) M urotensin II. Preincubation with 10(-8) M ET-1 (which induced maximum contraction) for 25 min in Ca(2+)-free buffer did not change the subsequent contraction induced by PMA (10(-7) M) or urotensin II (10(-8) M) but gave a somewhat lower maximum tension than in non-treated strips. 3. Calyculin-A, a potent inhibitor of phosphatase, also induced a contraction of the Ca(2+)-depleted muscle strips in Ca(2+)-free buffer. Preincubation of the strips with ET-1 (10(-8) M) or PMA (10(-7) M) decreased the calyculin-A (3 x 10(-8) M)-induced contraction.4. These results suggest that ET-1 may induce phosphorylation of an unknown protein either without an increase in myoplasmic Ca2 + concentration or, alternatively, with mobilization of intracellular Ca2+ from noradrenaline- and caffeine-insensitive Ca2 + sources, through a mechanism different from that of phorbol ester.
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PMID:Contraction of rat thoracic aorta strips by endothelin-1 in the absence of extracellular Ca2+. 181 May 98

In single NIH-3T3 fibroblasts loaded with fura-2, bombesin induced one of three patterns of increase in the concentration of intracellular free Ca2+ [( Ca2+]i): a single transient increase, a sustained increase, or repetitive transient increases in [Ca2+]i. Foetal-calf serum and ATP also gave these three patterns of response, although a lower proportion of cells gave repetitive Ca2+ transients in response to ATP. An increase in the concentration of bombesin from 1 to 25 nM increased the proportion of cells which exhibited repetitive Ca2+ transients. At 25 nM-bombesin, the proportion of cells which exhibited repetitive Ca2+ transients increased as the extracellular Ca2+ (Ca2+o) concentration was increased from 1 to 5 mM. Removal of Ca2+o by addition of EGTA, or inhibition of Ca2+ inflow by treatment of cells incubated in the presence of Ca2+o with verapamil or an activator of protein kinase C, abruptly terminated repetitive Ca2+ transients, with only one transient observed after the cessation of Ca2+ inflow. Repetitive Ca2+ transients were not observed in cells incubated in the absence of Ca2+o and in the presence of EGTA. Addition of Ca2+o to cells previously incubated in the presence of EGTA caused a resumption of repetitive Ca2+ transients. Addition of thapsigargin alone induced a large transient increase in [Ca2+]i, whereas much smaller transient increases in [Ca2+]i were induced in about 30% of cells tested by caffeine or carbonyl cyanide m-chlorophenylhydrazone (CCCP) plus oligomycin. Thapsigargin or the combination of CCCP plus oligomycin completely inhibited bombesin-induced repetitive Ca2+ transients, whereas caffeine had no effect. It is concluded from the studies of the role of Ca2+o that NIH-3T3 cells differ from other cell types in the anatomical or chemical links between extracellular Ca2+ and the intracellular stores involved in the generation of Ca2+ transients, whereas the results of the experiments with inhibitors indicate that the generation of repetitive Ca2+ transients in NIH-3T3 cells is unlikely to involve Ca(2+)-induced Ca2+ release from caffeine-sensitive stores.
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PMID:Inhibition of Ca2+ inflow causes an abrupt cessation of growth-factor-induced repetitive free Ca2+ transients in single NIH-3T3 cells. 191 Mar 37

The M current, IM, a voltage-dependent non-inactivating K current, was recorded in NG108-15 neuroblastoma x glioma hybrid cells, using the whole-cell mode of the patch-clamp technique. We studied inhibition of the M current by bradykinin, phorbol dibutyrate (PDBu), an activator of protein kinase C (PKC), and methylxanthines. Focal application of 0.1-5 microM bradykinin inhibited IM by about 60%; 5 nM bradykinin inhibited by about 40%. Bath application of 0.1 microM and 1 microM PDBu diminished IM to about half of the control value. Staurosporine, a PKC inhibitor, applied for 35-43 min in a concentration of 0.3 microM significantly reduced the effect of 1 microM PDBu. M current blockage by PDBu could be partly reversed by bath application of H-7 (51-64 microM), another PKC inhibitor. These observations suggest that the PDBu effect is really due to activation of PKC. The findings are compatible with the view [Brown DA, Higashida H (1988) J Physiol (Lond) 397:185-207] that the bradykinin effect on IM is mediated by PKC. However, three further observations suggest that this is only true for part of the bradykinin effect. When the suppression of IM by 1 microM PDBu was fully developed, 0.1 microM bradykinin produced a further inhibition of IM. Down-regulation of PKC by long-term treatment with PDBu reduced the effect of 0.1 microM bradykinin significantly but did not abolish it. Staurosporine (0.3 microM, applied for 31-46 min) failed to reduce the effect of 5 nM bradykinin significantly. The M current could be reversibly blocked by methylxanthines (caffeine, isobutyl-methylxanthine, theophylline) in the millimolar range, probably because of a direct action on the M channels.
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PMID:Inhibition of the M current in NG 108-15 neuroblastoma x glioma hybrid cells. 194 51

A wide variety of nonexcitable cells generate repetitive transient increases in cytosolic calcium ion concentration ([Ca2+]i) when stimulated with agonists that engage the phosphoinositide signalling pathway. Current theories regarding the mechanisms of oscillation disagree on whether Ca2+ inhibits or stimulates its own release from internal stores and whether inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DG) also undergo oscillations linked to the Ca2+ spikes. In this study, Ca2+ was found to stimulate its own release in REF52 fibroblasts primed by mitogens plus depolarization. However, unlike Ca2+ release in muscle and nerve cells, this amplification was insensitive to caffeine or ryanodine and required hormone receptor occupancy and functional IP3 receptors. Oscillations in [Ca2+]i were accompanied by oscillations in IP3 concentration but did not require functional protein kinase C. Therefore, the dominant feedback mechanism in this cell type appears to be Ca2+ stimulation of phospholipase C once this enzyme has been activated by hormone receptors.
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PMID:Generation of calcium oscillations in fibroblasts by positive feedback between calcium and IP3. 198 13

1. In the present study we investigated desensitization phenomena of guinea-pig jejunal longitudinal smooth muscle responses after stimulation with 100 microM histamine or methacholine, using a superfusion method. 2. Histamine H1-receptor-mediated contractions appear to be rapidly reduced after application of 100 microM histamine. Muscarinic responses were not affected following desensitization with 100 microM histamine, indicating a homologous desensitization. 3. Initial contractions to 0.3 microM histamine were reduced by 90%, recovered quickly, but did not reach control levels within 1 h. Desensitization of histamine responses could be separated into two phases; a rapid, but transient, desensitization and a more sustained desensitization. As a consequence of this sustained effect the pD2 for histamine shifted from 6.7 +/- 0.1 (control) to 6.1 +/- 0.1 (desensitized). 4. Desensitization with 100 microM methacholine caused a heterologous desensitization, reflected by the development of a refractory period, in which neither histamine nor methacholine was able to elicit a contraction. After a few minutes responses to both agents recovered to control levels. 5. During the refractory period after methacholine desensitization, muscle strips were still responsive to 40 mM KCl but did not contract in response to 10 mM caffeine, suggesting that the heterologous desensitization is caused by a modification of an intracellular Ca2(+)-store, which is used by both histamine and methacholine. 6. The recovery of the responses after methacholine desensitization was not dependent on extracellular Ca2+, suggesting that the recovery is not dependent on refilling of the intracellular Ca2+ store with extracellular Ca2+. 7. The protein kinase C activator, phorbol-12,13-dibutyrate, concentration-dependently inhibited histamine- and methacholine-induced contractions. Protein kinase C seems therefore not to be implicated in the observed homologous H,-receptor desensitization. 8. These data suggest that different forms of desensitization can be distinguished in this model, each with a different time course and dependent on the applied stimulus.
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PMID:Different profiles of desensitization dynamics in guinea-pig jejunal longitudinal smooth muscle after stimulation with histamine and methacholine. 208 11

Endothelin-1 is a powerful inotropic peptide for the rat atrium. Its action can develop in the absence of L-type Ca2+ channel activity provided that the external Ca2(+)-concentration has been raised to supraphysiological concentrations. Endothelin stimulates phosphatidylinositol hydrolysis in new born rat atrial cells via a mechanism that is insensitive to pertussis toxin. The diacylglycerol/protein kinase C signaling pathway cannot account for the contractile action of endothelin but its activation by phorbol esters induces a partial desensitization of phospholipase C activity. Endothelin-1 and the related peptides, endothelin-2, endothelin-3, and sarafotoxin S6b, raise intracellular Ca2+ levels in rat atrial cells. The actions of endothelin-1, endothelin-2, and sarafotoxin on [Ca2+]i are mutually exclusive, suggesting that they act at the same receptor site. The rise in [Ca2+]i induced by endothelins results both from the mobilization of intracellular stores and from Ca2+ entry through the sarcolemma via a pathway that is not voltage-dependent L-type Ca2+ channels. The Ca2+ store that is mobilized in response to endothelin retains its Ca2+ content when cells were incubated for long periods of time in a 50 nM Ca2+ solution. It is insensitive to caffeine and ryanodine. These two properties distinguish it from the sarcoplasmic reticulum. Contraction experiments in which the pacing rate has been altered to favor Ca2+ accumulation into terminal cisternae of the sarcoplasmic reticulum also suggest that the Ca2+ load of the sarcoplasmic reticulum is increased in endothelin treated rat atria.
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PMID:Endothelin mobilizes Ca2+ from a caffeine- and ryanodine-insensitive intracellular pool in rat atrial cells. 215 11

Front surface fluorometry and porcine coronary arterial strips loaded with fura-2 were used to investigate the effect of endothelin on cytosolic Ca concentrations, [Ca]i, and on contractile force, the objective being to elucidate the mechanism of action. Both in the presence and absence of extracellular Ca, endothelin induced rapid and dose-dependent increases in [Ca]i and in contraction. When caffeine-sensitive and histamine-sensitive intracellular Ca stores were depleted, in Ca-free medium, a transient contraction but no increase in [Ca]i followed the subsequent application of endothelin. This Ca-independent component was largely inhibited by the relative protein kinase C inhibitor, H-7, but not inhibited by W-7, calmodulin antagonist. This component is probably linked to activation of protein kinase C.
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PMID:Endothelin-induced Ca-independent contraction of the porcine coronary artery. 249 31


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