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)

The effects of trifluoperazine hydrochloride (TFP), a calmodulin antagonist, on L-type Ca2+ currents (L-type ICa2+) and their Ca(2+)-dependent inactivation, were studied in identified Helix aspersa neurons, using two microelectrode voltage clamp. Changes in [Ca2+]i were measured in unclamped fura-2 loaded neurons. Bath applied TFP produced a reversible and dose-dependent reduction in amplitude of L-type ICa2+ (IC50 = 28 microM). Using a double-pulse protocol, we found that TFP enhances the efficacy of Ca(2+)-dependent inactivation of L-type ICa2+. Trifluoperazine sulfoxide (50 microM), a TFP derivative with low calmodulin-antagonist activity, did not have any effects on either amplitude or inactivation of L-type ICa2+. TFP (20 microM) increased basal [Ca2+]i from 147 +/- 37 nM to 650 +/- 40 nM (N = 7). The increase in [Ca2+]i was prevented by removal of external Ca2+ and curtailed by depletion of caffeine-sensitive intracellular Ca2+ stores. Since TFP may also block protein kinase C (PKC), we tested the effect of a PKC activator (12-C-tetradecanoyl-phorbol-13-acetate) on L-type Ca2+ currents. This compound produced an increase in L-type ICa2+ without enhancing Ca(2+)-dependent inactivation. The results show that 1) TFP reduces L-type ICa2+ while enhancing the efficacy of Ca(2+)-dependent inactivation. 2) TFP produces an increase in basal [Ca2+]i which may contribute to the enhancement of Ca(2+)-dependent inactivation. 3) PKC up-regulates L-type ICa2+ without altering the efficacy of Ca(2+)-dependent inactivation. 4) The TFP effects cannot be attributed to its action as PKC blocker.
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PMID:Trifluoperazine enhancement of Ca2+-dependent inactivation of L-type Ca2+ currents in Helix aspersa neurons. 1021 96

Previous biochemical, autoradiographic, and ultrastructural data have shown that, in the synaptosomal fraction of the squid optic lobe, protein synthesis is largely due to the presynaptic terminals of the retinal photoreceptor neurons (Crispino et al. [1993a] Mol. Cell. Neurosci. 4:366-374; Crispino et al. [1993b] J. Neurochem. 61:1144-1146; Crispino et al. [1997] J. Neurosci. 17:7694-7702). We now report that this process is close to its maximum at the basal concentration of cytosolic Ca++, and is markedly inhibited when the concentration of this ion is either decreased or increased. This conclusion is supported by the results of experiments with: 1) compounds known to increase the level of cytosolic Ca++, such as A23187, ionomycin, thapsigargin, and caffeine; 2) compounds sequestering cytosolic calcium ions such as BAPTA-AM; and 3) agents that block the role of Ca++ as second messenger, such as TFP and W7, which inhibit calmodulin, and calphostin, which inhibits protein kinase C. We conclude that variations in the level of cytosolic Ca++ induced in presynaptic terminals by neuronal activity may contribute to the modulation of the local synthesis of protein.
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PMID:Protein synthesis in presynaptic endings from squid brain: modulation by calcium ions. 1022 Jan 18

The vascular effect of purified baicalein from Scutellaria baicalensis Georgi (Huangqin) was examined in rat isolated mesenteric arteries. Baicalein exerts both contractile and relaxant effects on the U46619-, phenylephrine- or high K+-contracted endothelium-intact arteries. In endothelium-denuded arteries, the contractile response to baicalein (0.3-10 microM) was absent while the relaxant response to baicalein (30-300 microM) remained. Pretreatment with 100 microM N(G)-nitro-L-arginine (L-NNA) or 3 microM methylene blue abolished the baicalein-induced contraction while 10 microM indomethacin or 100 nM BQ610 had no effect. Pretreatment with baicalein (3-10 microM) significantly attenuated the relaxation induced by acetylcholine or by A23187. In contrast, baicalein did not affect the sodium nitroprusside-induced relaxation in endothelium-denuded arteries. Baicalein also concentration dependently inhibited the contractile response to 1 microM phorbol 12,13-diacetate (PDA) in Ca2+-free solution. Baicalein had little effect on the contractile response to 60 mM K+ or to 10 mM caffeine in endothelium-denuded arteries. The baicalein-induced relaxation was unaffected by 1 microM glibenclamide or by 3 mM tetraethylammonium ions in endothelium-denuded arteries. These results indicate that baicalein at low concentrations caused a contractile response and inhibited the endothelium-dependent relaxation, probably through inhibition of endothelial nitric oxide (NO) formation/release. At higher concentrations, baicalein relaxed the arterial smooth muscle partially through inhibition of the protein kinase C-mediated contractile mechanism.
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PMID:Endothelium-dependent contraction and direct relaxation induced by baicalein in rat mesenteric artery. 1042 39

The effect of elevated glucose on arterial contractions and intracellular calcium ([Ca++]i) release induced by protein kinase C (PKC) activation and potassium depolarization (KCl) was investigated. Mesenteric resistance arteries (phi < 200 microm) isolated from male Wistar rats were studied using an arteriograph system that allowed control of transmural pressure (TMP) and measurement of lumen diameter. Arteries were incubated in either 11 or 44 mmol/L glucose and the concentration-response to Indolactam V (ILV; a specific PKC activator; LC Laboratories, Woburn, MA) and KCl was determined, as well as the sensitivity to Ca++ in the presence of either agonist. An additional group of arteries were incubated in 5.5 mmol/L glucose and the concentration-response to ILV was compared versus 11 and 44 mmol/L glucose. Arteries in 44 mmol/L glucose were more sensitive to both ILV and KCl, contracting to 10.0 micromol/L ILV, 53.9 +/- 10.1% in 11 mmol/L versus 85.1 +/- 2.0% in 44 mmol/L glucose (P < .01); arteries in 5.5 mmol/L glucose responded the least to ILV, contracting only 36.0 +/- 4% to 10.0 micromol/L ILV (P < .01 v 11 and 44 mmol/L glucose). The KCl EC50 (ie, the value at which the agonist produced 50% maximal contraction) for 11 versus 44 mmol/L glucose was 41.3 +/- 4.8 versus 31.1 +/- 1.2 mmol/L (P < .05). There was no change in Ca++ sensitivity in elevated glucose for either agonist; however, Ca++ sensitivity was augmented threefold for ILV versus KCl, demonstrating an agonist-dependent modulation of Ca++ sensitivity. The Ca++ EC50 for ILV and KCl in 11 versus 44 mmol/L was 0.18 +/- 0.05 versus 0.21 +/- 0.05 and 0.59 +/- 0.09 versus 0.60 +/- 0.10 micromol/L (P < .01 v ILV). The effect of elevated glucose on [Ca++]i release from the sarcoplasmic reticulum (SR) was investigated in arteries incubated in zero Ca++ buffer containing either 11 or 44 mmol/L glucose by measuring the contraction produced by 50 mmol/L caffeine, 3.0 micromol/L ILV, or 60 mmol/L KCl. Contraction to caffeine in 11 versus 44 mmol/L glucose was comparable, constricting 42.0 +/- 6.0% in 11 mmol/L and 36.0 +/- 4.4% in 44 mmol/L glucose (P > .05), and contraction to KCl was almost undetectable in both glucose concentrations. However, contraction to ILV increased from 5.6 +/- 0.9% in 11 mmol/L to 18.7% +/- 2.2% in 44 mmol/L glucose (P < .01), indicating that although the amount of Ca++ in the SR (caffeine-sensitive stores) was not increased in elevated glucose, PKC-induced release of [Ca++]i was enhanced, a consequence that may explain the noted glucose-induced increase in contraction to PKC activation.
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PMID:Elevated glucose potentiates contraction of isolated rat resistance arteries and augments protein kinase C-induced intracellular calcium release. 1045 67

The maturation of various aspects of sperm function have been demonstrated in monkey and human epididymal sperm, including the ability to undergo the acrosome reaction. The present study aimed to investigate the maturational changes in non-human primate sperm in the signal transduction mechanisms leading to the acrosome reaction involving cyclic AMP, Ca(2+) influx, protein kinase C, and protein tyrosine phosphorylation. Sperm from the caput, corpus, and cauda epididymidis of cynomolgus monkeys were incubated in a complete medium for 2.5 hr, followed by 30 min stimulation with 1 mM dibutyryl cAMP and 1 mM caffeine, 50 microM 1, 2-dioctanoyl-sn-glycerol (DOG), and 50 microM Ca(2+)-ionophore A23187. Quantitative Western blotting revealed little difference in tyrosine phosphorylated proteins among the caput, corpus, and cauda sperm without stimulation. Incubation with cAMP increased the amount of tyrosine phosphorylated proteins up to 10-fold in the corpus and cauda sperm, but to a lower extent in the caput sperm. Ca(2+)-ionophore attenuated the cAMP stimulation but had no effect on its own. Such responses in tyrosine phosphorylated proteins were in great contrast to the responses in the acrosome reaction, where A23187 was the strongest stimulant, resulting in induction of the reaction in 50 +/- 5%, 11 +/- 5%, and 8 +/- 4% cauda, corpus and caput sperm, respectively (mean +/- sem, n = 6). DOG and cAMP in combination induced acrosome reactions in about 10% of viable cells in the cauda and corpus but not caput sperm. Caput sperm responded to cAMP with increases in percentage motility without forward progression whereas cauda sperm displayed marked kinematic changes expected of hyperactivation. Comparisons of responses suggest that the major tyrosine phosphorylated proteins detected are unlikely to be involved immediately in the precipitation of the acrosome reaction, but more related to flagellar motion. Development of signal transduction pathways is part of the epididymal maturational process.
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PMID:Responses of monkey epididymal sperm of different maturational status to second messengers mediating protein tyrosine phosphorylation, acrosome reaction, and motility. 1047 80

The presence of arginine vasopressin (AVP) V1 receptors on neonatal rat cardiomyocytes (NRCs) linked to processes capable of elevating intracellular free calcium ([Ca2+]i) is now firmly established. This study examined the sources and signaling involved in [Ca2+]i elevations evoked by AVP in NRCs. AVP promoted increases in both [Ca2+]i and 1,4,5-inositoltrisphosphate (IP3) levels in NRCs. The degree of [Ca2+]i elevation was less than that of angiotensin II, but greater than that of endothelin-1. Extracellular Mg2+ depletion led to diminution of the maximal [Ca2+]i response, with a rightward shift in the concentration-response curves to AVP. The phospholipase C inhibitors, D-609, NCDC, or U73122, and the IP3 receptor blocker, heparin, abolished the [Ca2+]i response to AVP. Neither cyclooxygenase inhibition with indomethacin nor PKC inhibition with staurosporine had any effect. Neither ryanodine nor caffeine, which deplete sarcoplasmic reticulum (SR) Ca2+ stores, nor ruthenium red, which inhibits both SR and mitochondrial Ca2+ stores, affected [Ca2+]i responses to AVP. The SR Ca2+ pump inhibitor, cyclopiazonic acid, abolished, and removal of extracellular Ca2+ attenuated, the response to AVP. These data indicate that activation of cardiac V1 receptors by AVP results in mobilization of Ca2+ from a distinct, non-SR, nonmitochondrial, intracellular Ca2+ pool that is Ca2+ pump replenished and IP3 sensitive. This process occurs secondary to phospholipase C (PLC)-mediated generation of IP3, requires the presence of Mg2+ and extracellular Ca2+, and occurs in a manner independent of PKC and cyclooxygenase activation. Such mechanisms of Ca2+ mobilization might indicate a distinct role for AVP in cardiac physiology and disease.
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PMID:Vasopressin-evoked [Ca2+]i responses in neonatal rat cardiomyocytes. 1051 Nov 29

1. The signalling pathway underlying histamine activation of non-selective cation channels was investigated in single equine tracheal myocytes. Application of histamine (100 microM) activated the transient calcium-activated chloride current (ICl(Ca)) and sustained, low amplitude non-selective cation current (ICat). The H1 receptor antagonist pyrilamine (10 microM) blocked activation of ICl(Ca) and ICat. Simultaneous application of histamine (100 microM) and caffeine (8 mM) during H1 receptor blockade activated ICl(Ca), but not ICat. Neither the H2 receptor antagonist cimetidine (20 microM) nor the H3 receptor antagonist thioperamide (20 microM) prevented activation of ICl(Ca) and ICat. 2. Intracellular dialysis of anti-Galphai/Galphao antibodies completely blocked activation of ICat by histamine, whereas ICl(Ca) was not affected. By contrast, anti-Galphaq/Galpha11 antibodies greatly inhibited ICl(Ca), but did not alter activation of ICat. 3. 1-Oleoyl-2-acetyl-sn-glycerol (OAG, 20-100 microM) did not induce any current or affect currents activated by histamine or methacholine (mACH). Simultaneous application of OAG and caffeine activated ICl(Ca), but not ICat, indicating that a rise in [Ca2+]i and stimulation of diacylglycerol-sensitive protein kinase C (PKC) is not sufficient to activate ICat. The phospholipase C inhibitor U73122 (2 microM) blocked histamine activation of ICl(Ca) and ICat, but simultaneous exposure of myocytes to histamine and caffeine restored both ICl(Ca) and ICat in the presence of U73122. 4. Histamine and mACH activated currents with equivalent I-V relationships. The currents activated by these agonists were not additive; following activation of ICat by mACH, histamine failed to induce an additional membrane current. Similarly, mACH did not induce an additional current after full activation of ICat by histamine. 5. We conclude that H1 histamine receptors activate ICat through coupling to Gi/Go proteins. Activation of ICat also requires intracellular calcium release, mediated by H1 receptors coupling to Gq/G11 proteins. This coupling is analogous to the activation of ICat by co-stimulation of M2 and M3 receptors.
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PMID:Signalling pathway for histamine activation of non-selective cation channels in equine tracheal myocytes. 1067 49

Protein kinase C appears to be involved in the regulation of airway contractility. Phorbol 12,13-diacetate (PDA; 0.01-10 microM), a protein kinase C activator, produced a transient relaxation followed by a sustained contraction of human isolated bronchus. Different protein kinase C inhibitors (calphostin C, staurosporine and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine) (H-7), nifedipine (NIF; 1 microM) or incubation with Ca(2+)-free medium, inhibited the spasmogenic response to phorbol, while ouabain (10 microM) suppressed only the initial relaxation. These results indicate that the initial relaxation, in response to PDA, is related to the activation of Na(+)/K(+)-ATPase, while the ensuing contraction depends on extracellular Ca(2+) entry.Incubation with PDA (1-5 microM) depressed the maximal relaxation to theophylline and caffeine obtained at 37 degrees C but augmented the spasmogenic responses to methylxanthines (10 mM) obtained in cooled preparations. These effects do not result apparently from increased extracellular entry of Ca(2+), but instead, from facilitation of the release of Ca(2+) from intracellular stores.
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PMID:Effects of phorbol 12,13-diacetate on human isolated bronchus. 1087 24

The present study was intended to examine the relaxant effects of berberine in rat isolated mesenteric arteries. Berberine produced a rightward shift of the concentration-response curve to phenylephrine and significantly reduced the maximal contractile response to phenylephrine. Berberine (10(-7)-3x10(-5) M) also relaxed the phenylephrine- and 9,11-dideoxy-11alpha, 9alpha-epoxy-methanoprostaglandin F(2alpha)-precontracted arteries with respective IC(50) values of 1.48+/-0.16x10(-6) and 2.23+/-0. 22x10(-6) M. Removal of a functional endothelium significantly attenuated the berberine-induced relaxation (IC(50): 4.73+/-0. 32x10(-6) M) without affecting the maximum relaxant response. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) or methylene blue reduced the relaxant effect of berberine, and L-arginine (10(-3) M) partially antagonized the effect of L-NAME. In contrast, pretreatment with 10(-6) M glibenclamide or 10(-5) M indomethacin had no effect. Berberine (10(-5) M) reduced over by 50% the transient contraction induced by caffeine or phenylephrine in endothelium-denuded rings bathed in Ca(2+)-free Krebs solution. Pretreatment with putative K(+) channel blockers, such as tetrapentylammonium ions (1-3x10(-6) M), 4-aminopyridine (10(-3) M), or Ba(2+) (3x10(-4) M), significantly attenuated the berberine-induced relaxation in endothelium-denuded arteries. In contrast, tetraethylammonium ions (3x10(-3) M), charybdotoxin (10(-7) M) or glibenclamide (10(-6) M) were without effect. Berberine reduced the high-K(+)-induced sustained contraction and the relaxant response to berberine was greater in rings with endothelium (IC(50): 4.41+/-0.47x10(-6) M) than in those without endothelium (IC(50): 8.73+/-0.74x10(-6) M). However, berberine (10(-6)-10(-4) M) did not affect the high-K(+)-induced increase of intracellular [Ca(2+)] in cultured aortic smooth muscle cells. Berberine did not affect active phorbol ester-induced contraction in Ca(2+)-free Krebs solution. In addition, berberine inhibited proliferation of cultured rat aortic smooth muscle cells with an IC(50) of 2.3+/-0.43x10(-5) M. These findings suggest that berberine could act at both endothelium and the underlying vascular smooth muscle to induce relaxation. Nitric oxide from endothelium may account primarily for the berberine-induced endothelium-dependent relaxation, while activation of tetrapentylammonium-, 4-aminopyridine- and Ba(2+)-sensitive K(+) channels, inhibition of intracellular Ca(2+) release from caffeine-sensitive pools, or a direct relaxant effect, is likely responsible for the berberine-induced endothelium-independent relaxation. Mechanisms related to either Ca(2+) influx or protein kinase C activation may not be involved. Both vasorelaxant and antiproliferative effects may contribute to a long-term benefit of berberine in the vascular system.
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PMID:Vasorelaxant and antiproliferative effects of berberine. 1088 19

The aim of this study was to determine the effect of protein kinase C (PKC) activation on intracellular Ca(2+) transient and its relation to alpha(1)-adrenoceptor (alpha(1)-AR)-stimulated negative inotropic response in rat ventricles. The electromechanical responses to phenylephrine (PE) in rat ventricular muscles were concomitantly examined using the conventional microelectrode method. The responses of intracellular Ca(2+) transient and cell contractions to PE in the absence of certain pharmacological interventions were ascertained in fura-2-loaded myocytes. The influence of PE on L-type Ca(2+) current (I(Ca,L)) was also examined using a voltage clamp in a whole-cell configuration. PE did not alter the action potential parameters during the negative inotropic phase. The negative inotropic effect (NIE) was inhibited by prazosin, chloroethylclonidine (CEC) and staurosporine, but was insensitive to pertussis toxin. Desensitization of PKC after prolonged pretreatment of rat ventricles with PDBu also abolished the NIE of PE. Caffeine modulated the NIE, but thapsigargin did not. The evoked intracellular Ca(2+) transient and cell contraction were initially decreased by PE, while I(Ca,L) was not altered. Prazosin and staurosporine significantly inhibited the responses. Our data indicated that alpha(1)AR-mediated NIE in rat ventricular muscles was due to the decrease of intracellular Ca(2+) transients by the modulation of PKC on Ca(2+)-releasing channels signaling through a CEC-sensitive alpha(1)AR subtype.
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PMID:Role of protein kinase C in mediating alpha-1-adrenoceptor-induced negative inotropic response in rat ventricles. 1097 Nov 36


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