Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 effect of dopamine (DA) on the binding of [3H]phorbol 12,13-dibutyrate ([3H]PdBu) in cultured rat striatal cells was examined. DA maximally increased specific [3H]PdBu binding by 70 +/- 10%, an increase comparable to that observed with norepinephrine (NE). This finding suggests that DA activates protein kinase C in cultured striatal cells, because increases in [3H]PdBu binding reflect translocation of protein kinase C. Half-maximal stimulation was observed with 10(-6) M DA. The peak response was observed at 2-3 min after addition of 10(-4) M DA, but [3H]PdBu binding was still increased above basal at 30 min. DA was not acting via an adrenergic receptor. Prazosin (10(-6) M) blocked the response to NE, suggesting mediation by an alpha 1-adrenergic receptor, but had little effect on the response to DA. Conversely, the D1 receptor antagonist SCH-23390 (10(-6) M) blocked the response to DA, but only partially inhibited the response to NE. Morphine (10(-6) M) inhibited the response to DA by 46 +/- 14%, but did not affect significantly the response to NE. The DA effect on [3H]PdBu binding is apparently independent of the increase in cyclic AMP seen on D1 receptor activation. Forskolin, apomorphine, and the D1 agonist SKF-38393 all increased cyclic AMP in striatal cells, but were less effective than DA in stimulating [3H]PdBu binding. The D2 agonist quinpirole was ineffective in stimulating either cyclic AMP or [3H]PdBu binding.
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PMID:Dopamine stimulates [3H]phorbol 12,13-dibutyrate binding in cultured striatal cells. 131 74

Rats, injected with small doses of amphetamine (0.03-0.1 mg/kg, i.p.), showed an increase in the soluble and a decrease in the activity of the particulate protein kinase C (PKC) in the striatum, while large doses of amphetamine (0.3-1.0 mg/kg) had the opposite effect of decreasing the soluble and increasing the particulate activity of PKC. These effects were manifested as a change in the Km for calcium, without an alteration in the Vmax. They were attenuated by pretreatment with benztropine, a dopamine (DA) uptake blocker and by alpha-methyl-p-tyrosine (alpha-MT), a DA synthesis inhibitor. The effects of 0.1 mg/kg amphetamine were insensitive to pretreatment with reserpine but were attenuated by the DA antagonists, SCH 23390 or sulpiride. These results suggest that the changes in activity of PKC induced by a small dose of amphetamine were mediated by an activation of DA autoreceptors, through an increase in the biophase concentration of DA at the synapse. In contrast, the effects of 1.0 mg/kg amphetamine on activity of PKC were attenuated by reserpine and by the DA agonists, LY 171555 or SKF 38393. They were, furthermore, potentiated by simultaneous treatment with sulpiride, which indicates that the two drugs act by different mechanisms. These results suggest that larger doses of amphetamine altered the activity of PKC at the DA transport site.
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PMID:Protein kinase C and dopamine transport--1. Effects of amphetamine in vivo. 136 65

Significant proximal tubular responses to exogenous dopamine require 0.1 to 10 mumol/L concentrations but endogenous peritubular dopamine and DOPA concentrations are in the picomolar to nanomolar range. Dopamine concentration approaches micromolar levels within proximal tubular cells and their brush borders, as a result of DOPA decarboxylation and secretion, and in collecting duct fluid, as a result of tubular fluid absorption. Thus dopamine probably acts either within the proximal tubule cell or brush border or from the collecting tubular lumen. DOPA and Na+ uptake are coupled; dopamine uptake is linked to intracellular electrical potential and its secretion to H+ counter-transport; therefore alterations in proximal tubular Na+ and H+ transport influence dopamine excretion. Haloperidol and SCH 23390 block dopamine excretion, therefore dopamine antagonists may inhibit tubular dopamine responses by lowering intracellular dopamine concentration as well as by receptor blockade. Evidence for an intracellular site of dopamine action can be deduced from the inhibitory effect of DOPA on oxygen consumption and 86Rb uptake in proximal tubule cells. We have confirmed these findings in isolated proximal tubule cells but not in proximal tubule fragments. The discrepant responses may be due to the fact that isolated cells loose their polarity while tubule fragments remain polarized. Dopamine inhibition of proximal tubular Na+, K(+)-ATPase is not reproduced by single dopamine agonists or inhibited by dopamine antagonists. Dopamine effects which are not linked to known dopamine receptors may be the result of redox cycling. Micromolar dopamine oxidizes sulfhydryl groups which may modify enzyme structure and activate protein kinase C.
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PMID:Functional effects of proximal tubular dopamine production. 220 Apr 36

Dopamine causes a significant retraction of neurites of bull-head catfish horizontal cells maintained in culture. The effects of dopamine are blocked by haloperidol and SCH 23390, a D1 antagonist, but not by sulpiride, a D2 antagonist. The dopamine-induced morphological changes were mimicked by SKF 38393, a D1 agonist, but not by quinpirole, a D2 agonist. Kainate also caused process retraction, but other neuroactive substances tested including glutamate, 5-hydroxytryptamine, N-methyl-D-aspartate, gamma-aminobutyric acid, and glycine caused only minor changes in neurite length. Cyclic AMP analogues do not induce neurite retraction in horizontal cells, indicating that this effect of dopamine is not mediated by cyclic AMP. However, a protein kinase C activator (phorbol 12-myristate 13-acetate) and synthetic diacylglycerol analogs (1-oleoyl-2-acetyl-sn-glycerol and dioctanoglycerol) caused marked neurite retraction. Their effects, as well as the dopamine-induced changes, were blocked by staurosporine, a potent protein kinase antagonist. The results suggest that dopamine causes neurite retraction by the activation of protein kinase C via diacylglycerol.
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PMID:Dopamine induces neurite retraction in retinal horizontal cells via diacylglycerol and protein kinase C. 226 20

The hypothesis that protein kinase C (PKC) plays a role in the release of dopamine (DA) in the nigrostriatal pathway was examined. It was found that injections of apomorphine, SKF 38393 (D1 agonist), LY 171555 (D2 agonist) or gamma-butyrolactone (GBL) (which decreases impulse-induced release of DA) resulted in a decrease in particulate, and an increase in soluble, PKC activity. Injections of fluphenazine, haloperidol, SCH 23390 (D1 antagonist), sulpiride (D2 antagonist) or picrotoxin (gamma-aminobutyric acid antagonist which increases DA release transneuronally) had the opposite effect of increasing particulate and decreasing soluble PKC activity. The total activity was not changed. These effects were receptor mediated since the effect of each agonist could be reversed by its specific antagonist. These drugs influenced PKC in the striatum in a dose-dependent manner. In contrast, no effects were seen in the cerebellum, a region with sparse dopaminergic innervations. The change in PKC activity was mediated via a change in the Km for calcium, while the Vmax was unchanged. The phosphorylation of endogenous substrate proteins by PKC was also altered by injections of these drugs. Besides affecting PKC, these DA acting drugs also affected the calmodulin-dependent protein kinase activity, but the direction of change was opposite to that for PKC. In a synaptosomal preparation, PKC acting drugs also affected the depolarization-induced release of DA. Adriamycin and melittin decreased the potassium-induced release of DA, whereas tetradecanoyl-phorbol-13-acetate (TPA) enhanced this release. These results showed that there was a good correlation between the ability of drugs to alter the impulse-induced release of DA in vivo and their ability to affect changes in particulate and soluble PKC activity. They lend support to the hypothesis that PKC, together with calmodulin, plays a key role in the release of DA in the nigrostriatal pathway.
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PMID:Protein kinase C and dopamine release--II. Effect of dopamine acting drugs in vivo. 305 15

The effect of dopamine (DA) receptor stimulation on the distribution of gamma protein kinase C (gamma PKC) in hippocampal slices was assessed. Nanomolar concentrations of DA decreased cytosolic gamma PKC (56%) without altering membrane gamma PKC levels, resulting in decreased total gamma PKC immunoreactivity. The maximal decrease in cytosolic gamma PKC occurred at 20 min of incubation and was significantly blocked by the D1 DA antagonist SCH 23390 (10(-6) M) but not by the D2 antagonist sulpiride (10(-5) M). The D1 agonists SKF 38393 and A 77636 mimicked the effect of DA with similar responses produced at 10 microM and 1 nM, respectively. The D2 agonist quinpirole had no effect on gamma PKC immunoreactivity, thus indicating that this dopaminergic response is mediated through a D1-like receptor. DA had no effect on alpha, delta, or zeta PKC isozyme immunoreactivity in the same hippocampal preparations. The DA-induced decrease in cytosolic gamma PKC immunoreactivity was blocked by the Ca(2+)-dependent protease inhibitor N-acetyl-Leu-Leu-norleucinal (100 microM) and by the inorganic Ca2+ channel blocker Co2+. The data suggest that DA stimulates a D1-like DA receptor, which increases the influx of Ca2+ and activates the Ca(2+)-dependent proteolysis of gamma PKC.
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PMID:Dopamine receptor stimulation decreases cytosolic gamma protein kinase C immunoreactivity in rat hippocampal slices: evidence for increased Ca(2+)-dependent proteolysis. 756 57

Although it is suggested that in the renal proximal tubules, dopamine D1 receptor activation causes inhibition of Na+/K+ATPase via a phospholipase C and protein kinase C coupled pathway, the direct stimulation of protein kinase C by dopamine has not been reported. The present study was designed to examine the effects of dopamine and selective dopamine D1 receptor and dopamine D2 receptor agonists on protein kinase C activity. The renal proximal tubule suspensions were obtained from male Sprague-Dawley rats. The tubules were incubated separately with dopamine and fenoldopam in the presence or absence of dopamine D1 receptor antagonist, SCH 23390 ([(R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine]). The protein kinase C activity was measured by using a kinase target peptide, conjugated to a fluorescent molecule in water. The amino acid sequence of this peptide is, Proline-Leucine-Serine-Arginine-Threonine-Leucine-Serine-Valine-Alanine- Alanine-Lysine(PKSRTLSVAAK). We found that dopamine and fenoldopam [6-chloro-2,3,4,5-tetrahydro-1-(4-hydroxyphenyl)-1H-3-benzazepine-7,8-di ol] produced concentration-dependent increases in protein kinase C activity, which was blocked by SCH 23390. However, the dopamine D2 receptor agonist, bromocriptine [(5' alpha)-2-bromo-12'-hydroxy-2'-(1-methyl-ethyl)-5'-(2-methylpropyl)erg o- taman-3',6',18-trione] failed to stimulate protein kinase C activity at all the concentrations tested. These results provide direct evidence that dopamine stimulates protein kinase C activity via activation of dopamine D1 receptors.
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PMID:Dopamine causes stimulation of protein kinase C in rat renal proximal tubules by activating dopamine D1 receptors. 762 15

We have previously reported that dopamine-1 receptor-mediated activation of phospholipase C is diminished in renal cortical slices of spontaneously hypertensive rats. The present study was carried out to examine the effect of dopamine on protein kinase C (PKC), which is one of the enzymes involved in the signal-transduction pathway leading to dopamine-induced inhibition of Na+/K(+)-ATPase in the renal proximal tubule. Renal proximal tubule suspensions were obtained from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats of 10-12 weeks old. The tubules were incubated with dopamine in the presence or absence of DA-1 receptor antagonist SCH 23390. The PKC activity was measured by using a specific fluorescent peptide substrate (sequence, PKSRTLSVAAK). We found that dopamine produced a concentration-dependent increase in protein kinase C activity in the WKY rats, however, it failed to stimulate PKC activity in the SHR. Peak stimulation of 3.828 +/- 0.35 (ng/micrograms) protein in the WKY rats was observed at dopamine concentration of 1 microM, which was blocked in a concentration-dependent manner by SCH 23390 (0.25 microM). These results provide evidence that dopamine directly stimulates PKC activity via activation of DA-1 receptors in WKY rats. Furthermore, we discovered that dopamine fails to stimulate PKC activity in the SHR. This phenomenon may be responsible for the failure of dopamine to inhibit Na+/K(+)-ATPase activity in the hypertensive animals.
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PMID:Dopamine fails to stimulate protein kinase C activity in renal proximal tubules of spontaneously hypertensive rats. 765 51

The effects of D1 and D2 dopamine ligands on protein kinase C (PKC) activity were examined in synaptoneurosomes. Incubation with D1 agonists (SKF 38393, fenodopam), in the presence of calcium, decreased the soluble and increased the particulate PKC activity. These effects were reversed by SCH 23390, which by itself had the opposite effect of increasing the soluble and decreasing the particulate PKC activity. In contrast, incubation with the D2 agonists [LY 171555, (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine, RU 24213] increased the soluble and decreased the particulate PKC activity. These effects were reversed by sulpiride. (-)-3-(3-Hydroxyphenyl)-N-n-propylpiperidine had a D2 antagonist profile. Apomorphine showed a biphasic dose-response change; i.e., it decreased particulate PKC activity at the D2 receptor at low concentrations (0.1 microM) and increased it at the D1 receptor at higher concentrations (10 microM). Pretreatment with tetrodotoxin or omission of calcium in the incubation medium did not alter the responses of the D2 agonists, but it reversed the changes in PKC activity induced by the D1 agonists and converted the biphasic response of apomorphine to a monophasic inhibition. These results indicate that (1)D1 and D2 dopamine receptors are negatively coupled to PKC and (2) the increase in particulate PKC activity seen with the D1 drugs in the presence of calcium is mediated indirectly via a transneuronal effect.
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PMID:Activation of D1 and D2 dopamine receptors inhibits protein kinase C activity in striatal synaptoneurosomes. 791 8

1. In this study we investigated the effects of dopamine receptor agonists and antagonists on rat striatal synaptosomal aromatic L-amino acid decarboxylase (AADC) activity. 2. The results show that 10(-5)-10(-7) M cis-flupenthixol increased the striatal synaptosomal AADC activity (by 25% to 57%) in a time-dependent manner. SCH 23390 and remoxipride alone had little or no effect on striatal synaptosomal AADC activity, but in combination they increased AADC activity by 20%, suggesting that the increases in striatal synaptosomal AADC activity occurred only after blockade of both dopamine D1 and D2 receptors. 3. Treatment with (+)-amphetamine and (+/-)-2-(N-phenylethyl-N-propyl)amino-5- hydroxytetralin hydrochloride ((+/-)-PPHT) produced a reduction of striatal synaptosomal AADC activity in a concentration- and time-dependent manner. SKF 38393 and (-)-quinpirole, however, exhibited no effect on striatal synaptosomal AADC activity, suggesting that only the mixed dopamine receptor agonists can reduce the AADC activity. Incubation with apomorphine at a concentration of 10(-4) M inhibited the AADC activity by 74% and this inhibition cannot be antagonized by SCH 23390, remoxipride or cis-flupenthixol, suggesting that apomorphine-induced inhibition of striatal synaptosomal AADC activity was not mediated by dopamine receptors. 4. cis-Flupenthixol can reverse the reduction of AADC activity induced by (+)-amphetamine and (+/-)-PPHT. The inhibition of AADC activity elicited by (+/-)-PPHT also can be reversed by SCH 23390 and remoxipride. 5. The inhibition of striatal synaptosomal AADC activity induced by (+/-)-PPHT is calcium-dependent and protein kinase C may play a role in the regulation of striatal AADC activity. 6. These studies show that striatal synaptosomal AADC activity is regulated by dopamine receptors and indicate that in vitro dopamine DI and D2 receptors have a synergistic effect in this regulation.
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PMID:Regulation of aromatic L-amino acid decarboxylase in rat striatal synaptosomes: effects of dopamine receptor agonists and antagonists. 791 79


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