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 interaction between an active phorbol ester, 4-beta-phobol-12,13-dibutyrate (PDBu), and muscarinic cholinergic receptor (MAChR) agonists on the electrically evoked neurotransmitter release was studied in the striatal and prefrontal cortex (PFC) of the rabbit. MAChR agonists (carbachol and oxotremorine), physostigmine and PDBu enhanced dopamine (DA) release from striatum and prefrontal cortex. Pretreatment with PDBu antagonized the increase in DA release produced by MAChR agonists (M1 receptors). Pretreatment with MAChR agonists and physostigmine also inhibited the action of PDBu on DA release. The inhibition of ACh release from the striatum induced by MAChR agonists (M2 receptors) and by apomorphine (D2-DA receptors) was antagonized by PDBu. MAChR agonists, however, did not antagonize the effects of the D2 agonist on ACh release. In the prefrontal cortex, PDBu produced greater facilitation of DA release than in the striatum, and MAChR agonists were less effective in inhibiting the effects of PDBu on DA release. This study suggests that the facilitation of DA release induced by the MAChR agonists and that induced by PDBu occur via a similar mechanism: stimulation of protein kinase C. PDBu induces a broad-spectrum loss of responsiveness to M1-MAChR and M2-MAChR and to D2-DA release-modulatory receptors, which is probably due to massive protein kinase C stimulation, signaling cell overstimulation. MAChR agonists, on the other hand, would stimulate the protein kinase C in close proximity to the M1 ACh receptor, facilitating DA release but failing to induce broad-spectrum desensitization.
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PMID:Differential effects of muscarinic receptor agonists and phorbol ester on muscarinic and D2-dopamine release-modulatory receptors. 876 17

Muscarinic, cholinergic inputs, largely from the medial septum, have pronounced effects on hippocampal cell excitability. A major effect of synaptically released ACh is block of the slow Ca(2+)-dependent potassium current, called IAHP. Protein kinase C exists in the hippocampus in high concentrations, its activation blocks IAHP, and it has been suggested as a mediator of the muscarinic-receptor-(mAChR)-mediated actions. Using conditions that produce a stable postspike afterhyperpolarizing current (IAHP) in whole-cell recordings from CA1 hippocampal pyramidal neurons in the slice preparation, we have investigated the role of PKC in the cholinergic inhibition of IAHP mediated by mACHRs. Bath application of the general kinase inhibitor, H7, had no effect on inhibition of IAHP by carbachol, although H7 dramatically reduced inhibition of IAHP by the phorbol ester, phorbol-12, 13-diacetate (PDA). Another muscarinic response thought to be mediated by PKC-inhibition of GABAB-mediated hyperpolarization-was reduced by extracellular H7 treatment, suggesting that the coupling between mAChRs and protein kinase activity was maintained in whole-cell recordings. We also discovered that PDA does not mediate its effects on IAHP directly. Intracellular perfusion of high concentrations of H7 (10 mM) or the specific PKC inhibitor, PKCI(19-31) (1 mM), did not prevent inhibition of IAHP by PDA. These results are consistent with an indirect, presynaptic action of phorbol esters on IAHP, possibly mediated through enhanced release of neurotransmitter from surrounding cells.
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PMID:Whole-cell voltage-clamp investigation of the role of PKC in muscarinic inhibition of IAHP in rat CA1 hippocampal neurons. 879 18

1. Cholinergic regulation of L-type Ca2+ channels was investigated in freshly dissociated guinea-pig gastric and tracheal smooth muscle cells. Acetylcholine (ACh, 50 microM) decreased Ca2+ channel current (ICa) by 37 +/- 3% (mean +/- S.E.M., 46 cells). 2. ACh reduced ICa at all voltages, with no shift in the current-voltage relationship. Effects of ACh were rapid (within 5 s) and repeatable, with multiple applications reproducibly inhibiting ICa in the continued presence of extracellular Ca2+ and in the presence of protein kinase C inhibitors. 3. The involvement of Ca2+ stores in this inhibition was investigated using Ca(2+)-free solution or cyclopiazonic acid (CPA) to deplete the stores. ACh initially inhibited ICa in the Ca(2+)-free solution (Na+ as charge carrier, 53 +/- 4% decrease, 18 cells) with subsequent responses significantly attenuated (n = 9). CPA (1 microM) reduced, then abolished, the effects of ACh on ICa (n = 5). 4. When studied in cell-attached patches (Ba2+ as charge carrier), ACh reduced Ca2+ channel open probability in twenty-two of thirty-six cells, consistent with the involvement of a diffusible cytosolic messenger. 5. ACh also inhibited ICa in tracheal muscle cells (reduction of 38 +/- 6% in 1 mM Ca2+, 4 cells; 77 +/- 3% in Ca(2+)-free solution, 7 cells). Furthermore, in cells where ACh elicited oscillating Ca(2+)-activated Cl- current, oscillatory inhibition of ICa was also observed (3 cells). 6. In summary, ACh causes rapid and reversible inhibition of ICa in gastric and tracheal muscles. Ca2+ stores were required to initiate this effect, with the rapid onset and oscillatory inhibition consistent with Ca2+ inhibition of the channel. Suppression of ICa would reduce Ca2+ entry during cholinergic excitation.
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PMID:Cholinergic inhibition of Ca2+ current in guinea-pig gastric and tracheal smooth muscle cells. 886 56

We observed the movement of insulin granules in living transformed hamster pancreatic beta-cells (HIT T15) with a light microscope, where secretory granules are moving in the cytoplasmic space. Velocity of the typical granule movement was approximately 1.5 microns/sec. A stimulatory concentration of glucose activated the movement of the secretory granules. Forskolin, an activator of adenylate cyclase, increased the movement, resulting in changes in intracellular localization of the granules. Acetylcholine also activated the granule movement, whereas high K+ and tolbutamide, which cause Ca2+ influx through the voltage-dependent Ca2+ channel, had only little effect. The movement was abolished by BAPTA, the intracellular Ca2+-chelator. Activation of protein kinase C by 12-O-tetradecanoyl-phorbol 13-acetate failed to affect this movement. The motile events were inhibited by the calmodulin antagonist, W-7, and dramatically increased by okadaic acid, an inhibitor of protein phosphatases 1 and 2A. These results suggest protein phosphorylation by Ca2+/calmodulin- and cAMP-dependent protein kinases play a positive role in the control of the insulin granule movements, which results in potentiation of insulin release from the pancreatic beta-cell.
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PMID:Ca2+/calmodulin and cyclic 3,5' adenosine monophosphate control movement of secretory granules through protein phosphorylation/dephosphorylation in the pancreatic beta-cell. 889 28

1. Interlobular ducts were isolated from the rat pancreas and maintained in short-term tissue culture. Fluid secretion from these isolated ducts was measured using micropuncture techniques, intracellular calcium concentration ([Ca2+]i) by fura-2 microspectrofluorimetry, and cyclic AMP by radioimmunoassay. 2. Applying secretin and ACh simultaneously to ducts caused either a stimulation or an inhibition of fluid secretion depending on the doses employed. 3. The inhibitory effect of secretin and ACh could be relieved by atropine, and by the protein kinase C (PKC) inhibitors staurosporine and 1-(5-isoquinolinylsulphonyl)-2-methyl-piperazine (H-7). 4. Activation of PKC by 12-O-tetradecanoylphorbol-13-acetate (TPA) and phorbol 12, 13-dibutyrate (PDBu) inhibited secretin-evoked fluid secretion. 5. ACh and TPA also inhibited fluid secretion stimulated by the adenylate cyclase activator, forskolin. 6. Neither secretin nor the PKC activators and inhibitors had any effect on either the increase in [Ca2+]i evoked by ACh or the increase in intracellular cyclic AMP evoked by secretin and forskolin. 7. We conclude that the inhibitory effect of combined doses of secretin and ACh on ductal fluid secretion is probably mediated by PKC at a point in the secretory mechanism distal to the generation of intracellular messengers.
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PMID:Interactions between secretin and acetylcholine in the regulation of fluid secretion by isolated rat pancreatic ducts. 891 Feb 14

This study used a beta-escin-permeabilized canine tracheal smooth muscle preparation to test the hypothesis that the volatile anesthetic halothane decreases myofilament Ca2+ sensitivity by inhibiting the membrane receptor-linked second messenger systems that regulate myofilament Ca2+ sensitivity and not by inhibiting Ca(2+)-calmodulin activation of the contractile proteins. Acetylcholine (ACh) caused a GTP-dependent increase in force at constant submaximal cytosolic Ca2+ concentration. ACh, guanosine-5'-O-(3-thiotriphosphate), and the protein kinase C agonist 12,13-phorbol dibutyrate each significantly decreased the concentration of free Ca2+ producing a half-maximal response from 0.77 +/- 0.09 microM (Ca2+ alone) to 0.16 +/- 0.01, 0.19 +/- 0.02, and 0.37 +/- 0.03 microM, respectively, demonstrating an increase in myofilament Ca2+ sensitivity. Halothane (0.92 +/- 0.12 mM) had no effect on the free Ca2+ concentration-response curves generated by Ca2+ alone. However, in the presence of 3 microM ACh plus 10 microM GTP to maximally activate muscarinic receptors, halothane significantly increased the EC50 for free Ca2+ from 0.17 +/- 0.01 microM to 0.38 +/- 0.03 microM. These findings suggest that halothane decreases myofilament Ca2+ sensitivity in beta-escin-permeabilized canine tracheal smooth muscle by inhibiting the membrane receptor-linked second messenger systems that regulate myofilament Ca2+ sensitivity.
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PMID:Halothane reduces myofilament Ca2+ sensitivity during muscarinic receptor stimulation of airway smooth muscle. 894 14

1. Activation of muscarinic K+ (KACh) channels by P2-purinergic agonists, such as ATP, decreases monotonically in the continued presence of agonist. We investigated the mechanisms underlying this process of decline in guinea-pig atrial myocytes using the patch-clamp technique. 2. External ATP reversibly depressed the acetylcholine (ACh, 5.5-11 microM)-induced KACh current in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50) of 5.4 microM. 3. External ATP irreversibly reduced guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S)-induced KACh current both in control and pertussis toxin (PTX)-pretreated cells, suggesting (i) that the ATP-induced inhibition of KACh current occurred at some step(s) downstream from the activation of the PTX-sensitive G protein, GK, and (ii) that a PTX-insensitive G protein was involved in the signal transduction pathway. 4. The potency order of ATP analogues in reducing KACh current was ATP > or = 2-methylthio-ATP > or = alpha, beta-methylene-ATP, indicating involvement of a P2Y-type purinoceptor. 5. In the cell-attached patch recording, ATP (100 microM) applied to the bath solution reduced the activity of the KACh channels activated by ACh in the pipette, in two out of eight experiments, suggesting the possible involvement of cytosolic second messengers in the inhibition of KACh channels. 6. The ATP-induced reduction of KACh current was not affected by a protein kinase C inhibitor, 1-(5-isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride (H-7), suggesting that this response was not mediated by the activation of protein kinase C. 7. These results demonstrate that, in addition to the membrane-delimited activation through GK, external ATP causes an inhibition of the KACh channel probably by activating a PTX-insensitive G protein and cytosolic second messenger(s), which may underlie the monotonic decrease of the ATP-activated KACh current.
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PMID:Modulation of the muscarinic K+ channel by P2-purinoceptors in guinea-pig atrial myocytes. 896 Nov 82

Platelet-activating factor (PAF), a phospholipid mediator exhibiting potent biological activities, has been shown to stimulate amylase release from the pancreas and salivary glands. The capacity of salivary glands for PAF biosynthesis in response to stimulation has also been demonstrated. To elucidate the role of PAF in salivary glands, we studied the regulation of platelet-activating factor synthesis by the autonomic nervous system in canine salivary glands. Acetylcholine and ionomycin stimulated PAF production in dispersed cells from parotid, submandibular, and sublingual glands of dogs. Norepinephrine and phenylephrine, but not isoproterenol, also stimulated PAF production in submandibular gland cells. Norepinephrine-induced PAF production was blocked by phentolamine but not by propranolol. Acetylcholine and norepinephrine increased both the PAF production and liberation of [14C]arachidonic acid from cells pre-labeled with [14C]arachidonic acid in the presence of Ca2+ in the medium. These stimulants increased [14C]arachidonic acid liberation without the accompanying production of PAF in Ca(2+)-deprived medium. No activators or inhibitors of protein kinase C produced or affected acetylcholine-induced PAF production. Lyso-PAF:acetyl-CoA acetyltransferase was activated in the cells treated with acetylcholine, norepinephrine, isoproterenol, and 8Br-cyclic AMP. Deprivation of Ca2+ in the medium markedly reduced acetylcholine-induced activation of the transferase, but little affected norepinephrine-, isoproterenol-, and 8Br-cyclic AMP-induced activation. Dithiothreitol-insensitive cholinephosphotransferase activity was also increased by acetylcholine, norepinephrine, isoproterenol, and 8Br-cyclic AMP, and the deprivation of Ca2+ in the medium further increased the activation of the enzyme activity by these agents. These results suggest that PAF synthesis in canine salivary glands is under the control of muscarinic cholinergic and alpha-adrenergic systems via Ca(2+)-dependent remodeling pathways, and that the independent activation of either phospholipase A2 or acetyltransferase is insufficient for PAF production in submandibular gland cells, i.e., the concurrent activation of these enzymes is required.
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PMID:Stimulation of platelet-activating factor synthesis by neurotransmitters in salivary glands. 904 79

The action of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), the potent stimulator of protein kinase C (PKC), on acetylcholine-activated currents (I(Ach)) was investigated in voltage clamped Xenopus laevis oocytes injected with RNAs encoding murine embryonic nicotinic acetylcholine receptor (AChR) subunits. Comparable potentiation and acceleration of decay of I(ACh) were observed within minutes of phorbol ester application in oocytes injected with various RNA subunit combinations: (i) alpha beta gamma delta; (ii) alpha beta gamma; (iii) alpha beta delta; and (iv) alpha beta gamma delta(AAA), a mutant of the delta subunit with serine residues 360-361-362 mutated to alanine. Our findings indicate that the effects on I(ACh) induced by PKC stimulation are independent of both gamma and delta subunits and, accordingly, of the presence of PKC phosphorylation sites on delta subunit. It is here suggested a novel PKC-dependent modulatory mechanism of cholinergic receptor which does not involve direct phosphorylation of the AChR and requires phosphorylation of intermediate regulatory protein(s).
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PMID:Phorbol ester modulation of both delta-mutant and subunit-omitted nicotinic receptors expressed in Xenopus oocytes. 911 92

The present study aimed to investigate the possible role of endothelium in contractile response to phorbol 12,13-diacetate (PDA) by measuring the contractile force in rat isolated aortic rings. PDA at low concentrations induced small and sustained tension in arteries with intact endothelium. N(G)-Nitro-L-arginine (100 microM), a nitric oxide synthase inhibitor and methylene blue (10 microM), an O2-generator induced a large increase in tension in the presence of PDA. The magnitude of contractions in response to N(G)-Nitro-L-arginine was related to concentrations of PDA. Staurosporine (10 nM), an inhibitor of protein kinase C completely inhibited contractile response to PDA as well as potentiating effects of N(G)-Nitro-L-arginine and methylene blue. Removal of the endothelium abolished contractile responses to both N(G)-Nitro-L-arginine and methylene blue in the presence of PDA. Removal of extracellular Ca2+ suppressed contractile responses to both PDA and N(G)-Nitro-L-arginine. On the other hand, N(G)-Nitro-L-arginine (100 microM) did not induce contractions of the rat aorta pre-treated with 4-alpha-phorbol 12-myristate 13-acetate, an inactive form of phorbol ester. Acetylcholine concentration-dependently induced reduction of tension induced by PDA (0.3 microM) in rat aorta. N(G)-Nitro-L-arginine or removal of endothelium prevented the effect of the acetylcholine-induced relaxation. Indomethacin (1 microM), glibenclamide (3 microM) and charybdotoxin (100 nM) did not affect the PDA response in rat aorta. These results indicate that in rat aorta, the basal release of nitric oxide could modulate the PDA-induced contraction, which is likely to accounts for the smaller contractile response induced by PDA in arteries with intact endothelium compared to much larger contractions seen in arteries without endothelium.
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PMID:Influence of endothelium in contraction induced by phorbol ester in isolated rat aortic rings. 915 Apr 14


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