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)

In superfused rat hypothalamic slices prelabeled with [3H]-5-hydroxytryptamine [( 3H]-5-HT), the 5-HT autoreceptor agonists 5-methoxytryptamine and RU 24969 inhibited in a concentration-dependent manner the electrically evoked release of [3H]-5-HT. Exposure to phorbol-12,13-dibutyrate increased in a concentration-dependent manner the stimulation-evoked overflow of [3H]-5-HT and shifted to the right the 5-methoxytryptamine inhibition curve. Exposure to forskolin, a potent activator of adenylate cyclase, increased the stimulation-evoked [3H]-5-HT overflow and shifted to the left the 5-methoxytryptamine or RU 24969 inhibitory curves on transmitter release. A similar interaction was observed in the presence of 1-isobutyl,3-methylxanthine (IBMX), a phosphodiesterase inhibitor, or 8-bromo-cyclic AMP and the serotonin autoreceptor agonist 5-methoxytryptamine. In the presence of phorbol-12,13-dibutyrate or forskolin, the enhancing effect of the 5-HT autoreceptor antagonist methiothepin on the stimulation-evoked [3H]-5-HT overflow was significantly less pronounced than in the absence of these compounds. These results indicate that the presynaptic 5-HT autoreceptors that modulate the release of [3H]-5-HT in rat hypothalamic slices may be coupled to the phosphoinositide cycle and protein kinase C-dependent mechanisms. In addition, the increase in intracellular level of cyclic AMP by forskolin, IBMX, and 8-bromo-cyclic AMP potentiates the inhibitory effects of the autoreceptor agonist 5-methoxytryptamine on [3H]-5-HT release, although the mechanism of the interaction remains to be elucidated.
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PMID:Phorbol-12,13-dibutyrate antagonizes while forskolin potentiates the presynaptic autoreceptor-mediated inhibition of [3H]-5-hydroxytryptamine release in rat hypothalamic slices. 247 Jan 60

Oocytes of the frog Xenopus laevis express various exogenous neurotransmitter receptors and ion channels when injected with RNA from excitable tissues. The oocytes serve as a convenient model system in which modulation of neurotransmitter responses can be studied. We examined the effects of activators and an inhibitor of protein kinase C (PKC) on responses to serotonin (5-HT), acetylcholine (ACh), kainate, and gamma-aminobutyric acid (GABA) in oocytes injected with RNA from rat brain. The PKC activators beta-phorbol esters 4 beta-phorbol-12-myristate-13-acetate (PMA) and 4 beta-phorbol-12,13-dibutyrate (PDBu), as well as the synthetic diacylglycerol, 1-oleyl-2-acetylglycerol (OAG), significantly inhibited the responses to 5-HT and ACh (both known to be mediated by mobilization of intracellular Ca2+); the first (transient) phase of these responses was affected stronger than the second, slow phase. PKC activators also reduced the response to GABA. The effect of PDBu on the response to kainate was dual; either inhibition or potentiation were observed at different concentrations of PDBu. The inactive analogue of PMA, the alpha-PMA, was without effect on the responses to 5-HT and GABA. The PKC inhibitor 1,5-isoquinolinesulfonyl-2-methylpiperazine (H7) suppressed the inhibitory effect of PDBu on 5-HT response. Amiloride, a blocker of the Na+/H+ exchange (which is known to be activated by PKC in some tissues), did not suppress the effects of PDBu. We concluded that activation of PKC down-regulates the responses to 5-HT, ACh and GABA, and has a dual effect on response to kainate. Possible mechanisms of these effects are discussed.
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PMID:Protein kinase C modulates neurotransmitter responses in Xenopus oocytes injected with rat brain RNA. 247 Oct 32

Important findings on the molecular and regulatory properties of neurotransmitter receptors, GTP-proteins, ion channels and protein kinases were briefly reviewed. On the basis of recent advances in the theme mentioned above, we investigated the transmembrane signalling mechanism of serotonin (5-HT)-evoked inward current responses under the voltage clamp condition (holding at -60mV) in Xenopus oocytes injected with rat brain poly (A)+ mRNA, suggesting that 5-HT evokes a Cl- current via such a mechanism as follows: 1) activation of 5-HT1c subtype of receptors, 2) activation of pertussis toxin-sensitive Gi/G0, 3) phospholipase C activation, 4) inositol 1,4,5-trisphosphate (IP3) formation, 5) an increase of [Ca2+]i liberated by IP3, and 6) gating of Cl channels stimulated perhaps by Ca2+-calmodulin. On the other hand, protein kinase C (C-kinase) activation by diacylglycerol and Ca2+ seems to cause a feedback inhibition to the 5-HT responses by phosphorylation of certain proteins. Voltage-operated Ca channels of the N-type reconstituted in oocytes injected with brain mRNA seem to be modulated by C-kinase as well as by cAMP-dependent protein kinase. Significances of oocytes using as a model system to analyze the molecular mechanism of neuronal signalling in the brain were stressed and reviewed.
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PMID:[Recent advances in molecular pharmacology of cellular signalling mechanism]. 247 36

Both 5-HT and the 9 amino acid neuropeptide SCPb modulate 3 ionic currents in B15, enhancing a voltage-dependent inward sodium current, decreasing an outward potassium current and increasing an inward rectifying potassium current. In contrast, FMRFamide decreases a voltage-dependent inward sodium current and increases an outward potassium current. We have also investigated the roles of several second-messenger systems that may be mediating the effects of these modulators. Bath application of membrane permeable analogs of cAMP enhance the voltage-dependent inward sodium current and both 5-HT and SCPb increase cAMP levels in B15, suggesting that cAMP may be mediating part of the observed effects of these transmitters on B15. Experiments with phorbol ester, a protein kinase inhibitor, and a phospholipase inhibitor suggest that the phospholipase C/protein kinase C cascade may decrease an outward potassium current. Thus, 5-HT and SCPb may activate multiple second-messenger systems to modulate 3 ionic currents in B15. Additional studies suggest that a cascade involving arachidonic acid may be involved in mediating part of the FMRFamide responses in B15. These studies are beginning to define molecular mechanisms whereby a neuron differentially modulates multiple ionic currents in response to distinct chemical messengers.
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PMID:Modulation of ionic currents in Aplysia motor neuron B15 by serotonin, neuropeptides, and second messengers. 247 12

The effects of age on the activity and translocation of protein kinase C (PKC) and on the facilitation of 5-hydroxytryptamine (5-HT, serotonin) release induced by PKC activation with the phorbol ester phorbol 12-myristate 13-acetate were investigated. The activities of cortical PKC and its translocation in response to K+ depolarization and phorbol ester stimulation were reduced during aging in Fischer-344 rats. Parietal cortical brain slices from 6-, 12-, and 24-month-old animals were preloaded with [3H]5-HT and release was evoked by 65 mM K+ or the calcium ionophore A23187. 5-HT release induced by either K+ or A23187 was found to be reduced in 12- and 24-month-old as compared to 6-month-old animals. This decrease was not reversed by high extracellular Ca2+. Activation of PKC resulted in a facilitated transmitter release in tissue from 6- and 12-month-old animals but reduced [3H]5-HT release in slices from 24-month-old animals. These responses were prevented by the putative PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), but not by increasing extracellular or intracellular Ca2+. The results demonstrate an age-related change (1) in brain PKC activity and translocation and (2) in a physiological response to PKC stimulation. These results may have implications for other PKC-mediated functions that are altered during senescence.
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PMID:Effect of age on brain cortical protein kinase C and its mediation of 5-hydroxytryptamine release. 249 57

The effect of lithium on protein kinase C (PKC) stimulation-induced serotonin and norepinephrine release facilitation was examined in [3H]5-HT and [3H]NE preloaded superfused rat brain slices. The facilitation of K+-evoked [3H]5-HT release elicited by the active phorbol esters PMA and PDBu was inhibited by 4 mM but not by 1 mM in vitro lithium. In experiments performed in cortical, hippocampal and hypothalamic slices obtained from animals treated for 3 weeks with lithium-containing diet, PMA-induced facilitation of K+-elicited [3H]5-HT release was found to be inhibited by the treatment (serum lithium less than 1 mEq/l). Basal [3H]5-HT efflux, which was enhanced by PMA in control animals, was also inhibited by lithium treatment. In parietal cortical slices, PMA elicited increase in K+-evoked [3H]NE release was prevented in slices taken from lithium-treated (3 weeks) animals. Lithium treatment did not affect the activity and distribution of protein kinase C in cortical tissue. However, 3 weeks of treatment reduced the PMA-induced translocation of the enzyme. These results suggest that lithium treatment interferes with serotonin and norepinephrine release facilitation which results from the stimulation of PKC by phorbol esters. These actions of the ion may be mediated by its ability to inhibit PMA induced PKC translocation.
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PMID:Lithium inhibition of protein kinase C activation-induced serotonin release. 250 56

To identify proteins that may be involved in the induction of long-term changes in the nervous system, we investigated whether specific proteins in pleural sensory neurons of Aplysia were affected by procedures that mimic those used to produce long-term sensitization. Using two-dimensional PAGE, we found that exposure to serotonin (5-hydroxytryptamine, 5-HT) for 2 or 3 hr appeared to increase incorporation of labeled amino acids into one protein (P9) and decrease incorporation into two other proteins (P19 and P20). These effects of 5-HT were observed whether the labeled amino acid was leucine or methionine. The same proteins that were affected by 5-HT were also altered by the adenylate cyclase activator forskolin and by the 8-bromo and 8-benzylthio analogs of cAMP. Addition of Co2+ to 5-HT did not seem to affect the action of 5-HT on P9 and P20, but it did seem to block the effect of 5-HT on P19. However, the effect of analogs of cAMP on P9, P19, and P20 was not altered by inclusion of Co2+. A phorbol ester that activates protein kinase C did not appear to affect the proteins that were modified by 5-HT, but phorbol ester did appear to increase the amount of labeled amino acids incorporated into another protein (P24). To investigate the specificity of these effects for pleural ganglion neurons, we examined the effect of 3- and 6-hr treatments of 5-HT on proteins in the abdominal ganglion. 5-HT affected at least nine proteins in the abdominal ganglion. One of these proteins (P9) appeared to be the same as one altered by 5-HT in the pleural sensory neurons. However, the occurrence of some proteins and some effects of 5-HT were specific for one ganglion or the other. The identified proteins that were affected by both 5-HT and changes in cAMP may be involved in the induction of long-term changes in the nervous system of Aplysia.
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PMID:Information storage in the nervous system of Aplysia: specific proteins affected by serotonin and cAMP. 253 42

The role of serotonin (5-HT) and protein kinases in the regulation of the beta-receptor induced by typical and atypical antidepressants was investigated. Treatment with either mianserin or maprotiline for seven days produced a significant decrease in the beta-receptor density measured 6h after the last dose. The reduction in beta-receptors disappeared within 24h. However, combined treatment of mianserin or maprotiline with either fluoxetine or 5-hydroxytryptophan significantly decreased beta-receptors even 24h after the last dose. Following treatment with p-chlorophenylalanine the reduction in beta-receptors induced by desipramine was reversible within 24h. These results demonstrate that an increase in the synaptic 5-HT availability may contribute to the prolongation of the beta-receptor down-regulation by antidepressants. The intraventricular infusion of 12-0-tetradecanoyl-phorbol-13-acetate (TPA), a potent protein kinase C (PK-C) activator for seven days caused a significant decrease in beta-receptors, while forskolin or dibutyryl cyclic adenosine monophosphate had no influence on the receptor. The TPA-induced and desipramine-induced decreases in beta-receptors were not additive, suggesting that a similar mechanism is involved. The infusion of the PK-C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) caused an inhibition of the desipramine-induced decrease in beta-receptors. It is suggested that the beta-receptor down-regulation by antidepressants might be also regulated by PK-C through 5-HT-Ca2+-inositol-phospholipid systems.
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PMID:Involvement of protein kinase in the regulation of beta-adrenergic receptors by antidepressants. 254 Oct 90

A vasoactive inflammatory amine, serotonin, stimulates DNA synthesis in rat glomerular mesangial cells in a dose-dependent manner and acts synergistically with either insulin or epidermal growth factor (EGF). The combined effects of 10(-6) M serotonin and these peptide hormones are nearly equal to those induced by 10% fetal bovine serum. Serotonin stimulates the turnover of polyphosphoinositols resulting in a transient rise in intracellular free Ca2+ concentration, as measured either with the photoprotein aequorin, or with fura-2. This is accompanied by a transient increase in 45Ca2+ efflux from prelabeled cells. Serotonin also induces a prompt and sustained threefold increase in Ca2+ influx rate across the plasma membrane and a rapid and sustained twofold increase in cellular 1,2-diacylglycerol content. In addition, there is an increase in the extent of phosphorylation of an acidic 80-kDa protein, a putative substrate for protein kinase C. Activators of protein kinase C (including phorbol 12-myristate 13-acetate or 1,2-dioctanoylglycerol) mimic the mitogenic effect of serotonin. The effect of serotonin on cell proliferation is partially inhibited in a reversible manner by LiCl. Treatment of mesangial cells with insulin plus EGF for 60 min leads to a small but consistent increase in the content of inositol phosphates and 1,2-diacylglycerol. Their effects are additive to those of serotonin. Moreover, insulin and EGF significantly stimulate the phosphorylation of the 80-kDa protein, and potentiate the serotonin-induced phosphorylation of this protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Studies of the mitogenic effect of serotonin in rat renal mesangial cells. 255 Nov 88

Regulation of phosphate uptake was studied in HeLa cell lines after transfection with DNA encoding the human 5-HT1A receptor. Phosphate uptake was saturable and greater than 90% sodium-dependent, with Vmax approximately 30-35% without changing Km. Treatment with 5-HT or the 5-HT1A-specific agonist 8-OH-2-(di-n-propylamino)1,2,3,4-tetrahydronaphthalene increased Vmax approximately 40% without affecting Km. This effect was blocked by pretreatment with the 5-HT1 antagonists, methiothepine and spiperone, or pertussis toxin. Surprisingly, the stimulation was not secondary to an inhibition of adenylyl cyclase because 5-HT stimulated phosphate uptake approximately 20% in the presence of 1 mM 8-Br-cAMP. Rather, the primary pathway linked to the stimulation of phosphate uptake involved activation of protein kinase C because (i) 5-HT measurably activated protein kinase C in these cells, (ii) activators of protein kinase C (phorbol esters and diacylglycerol analogues) stimulated phosphate uptake in these cells (iii) the half-maximal doses for 5-HT-induced phosphatidylinositol hydrolysis and stimulation of phosphate uptake were virtually equivalent, and both effects were equally sensitive to pertussis toxin, and (iv) the stimulation was markedly attenuated in cells made deficient in protein kinase C. These results demonstrate that the stimulation of phosphatidylinositol hydrolysis by the 5-HT1A receptor can generate physiologically measurable effects on cellular transport and suggest that such accessory pathways may play a prominent role in signal transduction.
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PMID:The human 5-HT1A receptor expressed in HeLa cells stimulates sodium-dependent phosphate uptake via protein kinase C. 255 47


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