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)

1. The effects of leukotriene D4 (LTD4) on the mechanical properties of smooth muscle cells from the guinea-pig basilar artery were investigated in whole and chemically skinned muscle strips. 2. In strips with an intact endothelium, 5-hydroxytryptamine (5-HT; 10 microM), LTD4 and LTC4 (1 microM), STA2 (1 nM-10 nM) and high K+ (30 mM-128 mM) generated contractions. These comprised an initial phasic and subsequently generated tonic response with different amplitudes. Acetylcholine (ACh, 0.1-10 microM) inhibited and methylene blue (1-10 microM) enhanced the tonic component of these contractions in endothelium-intact muscle strips. In endothelium-denuded tissues, methylene blue had no effect on mechanical responses and ACh produced a further contraction in the presence of LTD4. 3. When the endothelium was removed, the amplitude of contractions induced by all tested stimulants markedly increased. In intact muscle strips, the order of potency for the production of a maximum response was; 128 mM K+ greater than STA2 greater than LTD4 = LTC4 = 5-HT. Following removal of the endothelium; STA2 greater than 128 mM K+ greater than LTD4 = LTC4 much greater than 5-HT. 4. In endothelium-denuded strips, the selective LTD4 antagonists, ONO-RS-411 and FPL 55712 inhibited the LTD4-induced contraction. In contrast, guanethidine, prazosin, yohimbine, atropine and mepyramine had no effect. Indomethacin and a thromboxane A2(TXA2) antagonist, ONO-3708 also had no effect on LTD4-induced contractions in endothelium-denuded strips. 5. In endothelium-denuded strips, nifedipine inhibited the tonic contraction induced by LTD4 but not the phasic component. In Ca2+-free solution containing 2 mM EGTA, LTD4 produced only the phasic contractions. 6. In saponin-treated chemically skinned muscle strips, LTD4 had no effect on either the pCa-tension relationship or on the release of Ca2+ from intracellular stores. However, inositol 1,4,5-triphosphate released Ca2+ from the stores and 1,2-diolein, an activator of protein kinase C, enhanced the contractions induced by 0.3 microM Ca2+. 7. It was concluded that LTD4 acts on both the endothelium and on the smooth muscle cells of the guinea-pig basilar artery. It stimulates the release of endothelium-derived relaxing factor (EDRF) which tends to inhibit the LTD4-induced contraction. It also interacts with receptors on the smooth muscle and produces a contraction as a result of an increase in both voltage-dependent and receptor-activated Ca2+ influx and, in part, the release of Ca2+ from cellular storage sites.
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PMID:Some effects of leukotriene D4 on the mechanical properties of the guinea-pig basilar artery. 325 45

Muscarinic receptor stimulation in the hippocampus has been associated with inositol phospholipid breakdown. In other systems this leads to the formation of inositol trisphosphate and diacylglycerol, which promotes the activation of protein kinase C. Phorbol esters, which directly activate protein kinase C, exhibit high and specific binding in the hippocampus. This, along with the advantages of the hippocampal slice preparation, including direct pharmacological access to a cell population (CA1 pyramidal cells) having clearly defined muscarinic responses, makes this an ideal preparation to examine whether protein kinase C serves as the intracellular signal for muscarinic receptor occupation. Like muscarinic agonists, phorbol esters abolish the slow calcium-activated potassium afterhyperpolarizing potential (AHP) and its underlying current without reducing calcium action potentials. Those phorbol analogs that do not activate kinase C have no effect, suggesting that activation of this enzyme is required to reduce the AHP. The accommodation of spike discharge normally seen during a long depolarizing stimulus is also markedly reduced by phorbol esters as well as by muscarinic receptor activation. However, unlike muscarinic agonists, phorbol esters have no effect on the muscarine-sensitive, voltage-dependent, potassium current termed IM, nor do they consistently cause an increase in input resistance. Moreover, unlike ACh, they do not appear to have a presynaptic inhibitory action on the fast EPSP elicited by orthodromic stimulation. The slow cholinergic EPSP was blocked by phorbol esters, but this could be accounted for by a postsynaptic action. Thus, if inositol phospholipid turnover is involved in mediating muscarinic responses in the hippocampus, the activation of protein kinase C can account for only part of the electrophysiological response.
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PMID:Phorbol esters mimic some cholinergic actions in hippocampal pyramidal neurons. 345 34

The vasoconstrictor effects of 9,11-epithio-11,12-methano-thromboxane A2 (STA2) on smooth muscle strips of the rabbit coronary artery have been investigated in vitro. Right coronary artery (RCA) was more responsive to STA2 than either the left anterior descending or the circumflex coronary artery. On endothelium-denuded RCA strips, the sensitivity and responsiveness to STA2 were greater than observed on intact muscle strips. A thromboxane(Tx)-antagonist, (9,11), (11,12)-dideoxa-9 alpha, 11 alpha-dimethylmethano-11,12-methano-13,14-dihydro-13-aza-14-oxo-15 - cyclopenthyl-16,17,18,19,20-pethanol-15-epi-TxA2 (ONO-3708), inhibited the STA2-induced contraction, whereas atropine or prazosin had no effect. Nifedipine partly inhibited the STA2-induced contraction, one half of which was still evoked in Ca2+-free solution. When acetylcholine was applied prior to the application of STA2 in Ca2+-free solution, the STA2-vasoconstriction disappeared. In saponin-treated chemically skinned muscle strips, STA2 itself had no effect on either the pCa-tension relation or on the release of Ca2+ from intracellular stores. However, inositol 1,4,5-trisphosphate released Ca2+ from such stores, and 12-o-tetradecanoyl phorbol-13-acetate (TPA) and 1,2-diolein, activators of protein kinase C, enhanced the contraction induced by 0.3 microM Ca2+. It is concluded that STA2 acts on the TxA2 receptor and produces contraction due to an increase in both voltage- and agonist(receptor)-dependent Ca2+ influx. STA2 also releases Ca2+ from ACh- and caffeine-sensitive storage sites.
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PMID:Mechanisms of vasoconstriction induced by 9,11-epithio-11,12-methano-thromboxane A2 in the rabbit coronary artery. 358 48

We have developed the coexpression system of both delta-opioid receptor (DOR1) and M2-muscarinic receptor (M2) which mediate agonist-evoked currents due to common post-receptor mechanisms including Gi1 and phospholipase C (PLC) activation in Xenopus oocytes reconstituted with Gi1 alpha. The DOR1-currents by 100 nM D-Ser2-leu-enkephalin-Thr6 (DSLET) were selectively desensitized by 10 nM phorbol 12-myristate 13-acetate (PMA). The PMA-desensitization of DSLET-currents was abolished in the presence of calphostin C, a protein kinase C inhibitor, or reversed by an intracellular injection of calcineurin, a protein phosphatase 2B. When a higher concentration (3 microM) of DSLET was used, DSLET-currents were rapidly desensitized by repeated challenges of DSLET itself. However, repeated challenges of 10 microM ACh caused no influence on such DSLET- or M2-currents. The desensitization of DSLET-currents was selectively reversed by protein kinase C inhibitors. Similar results were also obtained with various delta-opioid agonists. These results suggest that protein kinase C is involved in the homologous desensitization of delta-opioid receptors.
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PMID:Protein kinase C involvement in homologous desensitization of delta-opioid receptor coupled to Gi1-phospholipase C activation in Xenopus oocytes. 747

The modulation of acetylcholine-activated current (IACh) by protein kinase C (PKC) was studied in Xenopus laevis oocytes microinjected with either mRNA extracted from C2C12 myotubes (C2C12 mRNA) or RNAs encoding murine alpha beta gamma delta subunits of the nicotinic ACh receptor (nAChR). Voltage-clamped oocytes were treated for 90 sec with 12-O-tetradecanoylphorbol-13-acetate (TPA, 300 nM), a potent PKC activator. Transient increase in the amplitude and acceleration in the decay of IACh were invariably observed within minutes of TPA application, and were independent of extracellular Ca2+ concentration. Both parameters recovered to control within 20-30 min; then a slight depression of IACh developed. By this time, an initial PKC down regulation was observed. At the peak of TPA-induced potentiation, dose-response relations suggested an increased binding affinity of nAChR for the neurotransmitter. 4 alpha-phorbol 12,13-didecanoate (300 nM), a biologically inactive analogue of TPA, did not affect IACh, while staurosporine (5-10 microM), a potent inhibitor of PKC activity, suppressed the action of TPA on IACh. In oocytes co-injected with C2C12 mRNA and with rat brain mRNA, IACh was potentiated by 5-hydroxy-tryptamine (10 microM), whose receptors are coupled to phosphoinositide hydrolysis. The nAChR-channel activity in cell-attached patches increased when TPA was applied to the oocytes. In 50% of the oocytes examined, a sustained depression of the single channel activity followed. We conclude that in Xenopus oocytes an endogenous PKC system regulates the function of embryonic-type muscle nAChRs.
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PMID:Protein kinase C modulates exogenous acetylcholine current in Xenopus oocytes. 747 75

Cyclic GMP (cGMP) production in rat superior cervical sympathetic ganglia (SCG) was markedly increased (ca. 7-9-fold) by the addition of either acetylcholine (ACh; 0.1 mM) or a muscarinic agonist, carbachol (Carb; 0.1 mM), in the presence of an inhibitor (3-isobutyl-1-methylxanthine) for cGMP hydrolytic enzyme during in vitro aerobic incubation at 37 degrees C for 5 min. The ACh-induced accumulation of cGMP in SCG was effectively blocked (-73%) by the further addition of atropine (10 microM), a muscarinic antagonist, whereas a nicotinic blocker, hexamethonium (10 microM) partially antagonized (-41%) this ACh stimulation. The inhibitory effect of hexamethonium on ACh-evoked ganglionic cGMP production was effectively augmented (-83%) by addition of NG-monomethyl-L-arginine (L-NMMA, 50 microM), a compound that inhibits nitric oxide (NO) synthesis from L-arginine. Comparable inhibition of cGMP formation was observed following application of L-NMMA to the SCG upon stimulation of Carb. In contrast, L-NMMA had no effect on the decreased level of ACh-evoked cGMP production caused by the muscarinic antagonist. The Carb-induced elevation of ganglionic cGMP synthesis was significantly reduced within 1 min of incubation in the medium containing hemoglobin (Hb; 20 microM), an agent that scavenges only the extracellular fraction of NO. Thereafter, the tissue cGMP formation attenuated to the control level by subsequent incubation for several minutes. Addition of protein kinase C (PKC) activator, 12-O-tetradecanoylphorbol 13-acetate (TPA; 1 microM) to the medium significantly decreased Carb-evoked cGMP synthesis (-61%) in SCG, whereas superoxide dismutase (SOD; 30 U/ml) only slightly suppressed the Carb stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The intercellular communication via nitric oxide and its regulation in coupling of cyclic GMP synthesis upon stimulation of muscarinic cholinergic receptors in rat superior cervical sympathetic ganglia. 752 17

Acetylcholine (ACh) is one of the factor which induces vasodilation through the release of endothelium-derived relaxing factor. The aim of this study was to clarify whether endothelial cells can synthesize ACh and the types of substance which regulate the synthesis of ACh in endothelial cells. We determined the ACh content of endothelial cells isolated from porcine cerebral microvessels and of the culture medium. ACh was detected in the medium after 12 h incubation in the presence of diisopropylfluorophosphate, a non-specific cholinesterase inhibitor, and increased linearly up to 24 h. Phorbol 12-myristate 13-acetate (PMA, 10(-7) M) increased the ACh content of the medium in a dose-dependent manner. The effect of PMA was most apparent between 12 and 24 h after treatment, and was inhibited by cycloheximide. Calphostin C, a specific inhibitor of protein kinase C (PKC), did not inhibit the effect of PMA. Dioctanoyl glycerol, a specific activator of PKC, did not increase the intracellular ACh content or the amount released into the culture medium. ACh synthesis was not inhibited by bromoacetylcholine, a specific inhibitor of choline acetyltransferase (ChAT). PMA treatment did not affect the specific activity of ACh synthesis in endothelial cells. These data show that endothelial cells are able to synthesize ACh, and that ACh synthesis is up-regulated by PMA through the PKC independent mechanism via protein induction. The enzyme which synthesizes ACh in endothelial cells is not ChAT. The increase in ACh synthesis induced by PMA may not be due to induction of the ACh synthetic enzyme.
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PMID:Phorbol ester stimulates acetylcholine synthesis in cultured endothelial cells isolated from porcine cerebral microvessels. 752 25

Torpedo acetylcholine receptor (AChR) has a protein kinase C (PKC) phosphorylation site, which modulates channel properties, on the alpha and delta subunit. The effect of a potent PKC activator, PDBu on AChR expressed into Xenopus oocytes was examined by whole cell voltage clamp recordings. The pretreatment with 4-beta-PDBu reversely accelerated desensitization of ACh-elicited membrane currents and the same effect was shown by co-application of 4-beta-PDBu and ACh without pre-incubation. Treatment with the inactive stereoisomer of phorbol ester, 4-alpha-PDBu also demonstrated an acceleration of desensitization. Furthermore, 4-beta-PDBu enhanced the rate of desensitization in mutant AChR deleting PKC phosphorylation sites on the alpha and delta subunit. These results indicate that phorbol ester directly acts on the AChR channel independent of PKC activation.
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PMID:Direct action of 4-beta-phorbol-12,13-dibutyrate (PDBu) on nicotinic acetylcholine receptor channel independent of protein kinase C activation. 754 Jul 39

The role of protein kinase C (PKC) in the muscarinic excitation of chromaffin cells freshly isolated from rat adrenal medullae was examined by the patch-clamp recording method. Acetylcholine and McN-A-343, a M1-receptor agonist, depolarized the cell and induced action potentials. Phorbol 12,13-dibutyrate (PDBu), an activator of PKC, increased acetylcholine-induced firing concomitant with a persistent depolarization. Under voltage-clamp recording, both McN-A-343 and PDBu decreased the cesium-sensitive K+ current, which was induced by shifting the membrane potential between -140 mV and -40 mV. These results suggested that the stimulation of muscarinic M1-receptors by cholinergic drugs activated phospholipase C to degrade phosphoinositide, consequently producing diacylglycerol, and diacylglycerol activates PKC to induce excitation of adrenal chromaffin cells.
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PMID:Effects of protein kinase C on the muscarinic excitation of rat adrenal chromaffin cells. 768 90

1. Effects of cholinergic agonists on the cultured chick cochlear ganglion (CG) neurone were examined using the whole-cell patch-clamp method. 2. Acetylcholine (ACh, 0.1-100 microM) and its non-hydrolysable form, carbamylcholine (CCh, 0.1-300 microM), suppressed the outward current. The CCh-sensitive current was activated at membrane potentials more positive than -70 mV. 3. The CCh-sensitive current slowly activated after step depolarization with a time constant from 20 to 150 ms. The activation time constant decreased monotonically with depolarization of the membrane. 4. The reversal potential of CCh-sensitive current changed as a function of the external K+ concentration (-79, -65 and -44 mV in 5, 10 and 25 mM, respectively) and was approximately equal to the potassium equilibrium potential (-89, -71 and -48 mV in 5, 10 and 25 mM, respectively). The CCh-sensitive current is concluded to be K+ selective. 5. The CCh-sensitive current showed a sigmoid log dose vs. response relationship with an apparent dissociation constant (KD) of 1.4 microM and a Hill coefficient of 1.0. When ACh was applied, an apparent KD of 1.8 microM and a Hill coefficient of 1.0 was measured. 6. The suppression of K+ current by CCh was blocked by atropine (3 microM) and pirenzepine (3 microM), suggesting that the current is mediated by an M1 muscarinic receptor. 7. The CCh suppression of the K+ current was enhanced by GTP-gamma-S (0.1 mM), suggesting that a GTP-binding protein is involved. 8. The CCh suppression of the K+ current was mimicked by protein kinase C activators, 1-oleoyl-2-acetyl-sn-glycerol (OAG, 100 microM), phorbol dibutyrate (PDBu, 2 microM) and phorbol 12-myristate 13-acetate (PMA, 1 microM). The protein kinase inhibitor, staurosporine (0.2 microM) applied internally blocked the CCh suppression of the K+ current which suggests an involvement of protein kinase C.
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PMID:Suppression of the slow K+ current by cholinergic agonists in cultured chick cochlear ganglion neurones. 769 17


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