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)

The effects of maternal ethanol exposure on neurotransmission and second messenger systems were examined in rats using histochemistry and in vitro autoradiography. Thirty % ethanol was administered to pregnant rats from gestational day 7 to the day of delivery. Quantitative autoradiography was used to map muscarinic cholinergic, dopamine D2, adenosine A1, and inositol 1,4,5-trisphosphate binding sites, as well as to localize adenylate cyclase and protein kinase C. We found no difference in the patterns of staining with acetylcholinesterase and Timm's stain between control and prenatally ethanol-exposed rats on postnatal day (PN) 30. In the ethanol-exposed rats, [3H]forskolin binding sites were increased during early development in the CA1 subfield of the hippocampus and the occipital cortex; [3H]phorbol ester binding sites were increased in the cortex, striatum, and hippocampus; hippocampal muscarinic cholinergic sites were increased on PN4 and 30; adenosine A1 binding was reduced on PN10 in most regions examined, but was increased in the CA1 subfield on PN30; dopamine D2 receptor levels were significantly reduced on PN30 in the striatum; and IP3 receptors were decreased in most regions studied, but particularly in the cerebellum. Thus, some of these changes were transient and others were long-lasting. Although histopathological abnormalities were minimal, the alterations of binding sites in the cerebellum (the coordination center) and in the hippocampus (related to memory and learning) that were detected may contribute to the behavioral and mental deterioration seen in the fetal alcohol syndrome.
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PMID:The effects of maternal ethanol exposure on neurotransmission and second messenger systems: a quantitative autoradiographic study in the rat brain. 166 22

The effect of purified protein kinase C (PKC) on dopamine D2 receptor binding was studied. Saturation binding with [3H]spiperone was not affected. In competition experiments using agonists PKC-treated membranes showed a significant reduction in the proportion of high affinity sites, and the influence of GTP gamma S was abolished. These results suggest that PKC-dependent mechanisms can regulate the coupling between the dopamine D2 receptor and its G-protein.
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PMID:Phosphorylation by protein kinase C modulates agonist binding to striatal dopamine D2 receptors. 198 73

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

The interaction of a ligand with its cognate receptor not only activates signal transduction pathways but also determines adaptive responses affecting key elements in these pathways, in particular the cell surface receptor. Such is the case for G protein-linked receptors, the expression and functional status of which are highly regulated. The regulatory mechanisms involved can be divided according to two distinct time frames, acute and chronic. In the short-term, posttranslational mechanisms alter the functional status of the elements without changing steady-state levels or gene expression. Protein phosphorylation plays a prominent role in these acute adaptive responses. Thus agonists promote phosphorylation and the desensitization of several G protein-linked receptors. And we have shown in the case of the dopamine D2 receptor that protein kinase C modulates receptor coupling to its G-protein. Longer-term regulation involves transcriptional (gene expression), posttranslational (mRNA stability), and posttranslational (protein phosphorylation) regulation of the turnover of the elements in the information transduction pathway. In the case of G protein-linked receptors, long-term regulation is often reflected in changes in steady-state levels of mRNA (which can be quantified by techniques such as northern blot analysis, solution hybridization or in-situ hybridization). For dopamine D2 receptors, prolonged administration of neuroleptic drugs induces an up-regulation of receptor mRNA in various brain regions, probably through an increase in gene transcription. Receptor-transduced extracellular stimuli are converted into long-term changes in gene expression through specific nuclear transcription factors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Regulation of the dopamine D2 receptor gene and the early genes in the CNS by neuroleptics]. 827 5

1. Phorbol 12-myristate-13-acetate (PMA), a protein kinase C activator, elevated cyclic AMP accumulation in EBV-transformed human B-lymphocytes, and potentiated isoproterenol-, prostaglandin- (PGE1), cholera toxin-, and forskolin-stimulated cyclic AMP accumulation. 2. The dopamine D1 receptor agonist, SKF38393 (10(-7) to 10(-5) MH, had no effect on cyclic AMP accumulation in transformed human B-lymphocytes. 3. The dopamine D2 receptor agonist, quinpirole (10(-7) to 10(-5) MH did not inhibit cyclic AMP accumulation even when cyclic AMP accumulation was maximized by the addition of PMA and forskolin. 4. These data suggest that dopamine D1- and D2-receptor coupling to a cyclic AMP generating system is not present at detectable levels in transformed human B-lymphocytes.
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PMID:Evaluation of cyclic AMP accumulation in EBV-transformed human B-lymphocytes: effects of dopamine agonists, isoproterenol, prostaglandin E1, cholera toxin, forskolin, and phorbol 12-myristate-13 acetate. 886 Nov 80

Tachykinin immunoreactivity is found in a ventromedial spinal plexus in the lamprey. Neurons in this plexus project bilaterally and are thus in a position to modulate locomotor networks on both sides of the spinal cord. We have examined the effects of the tachykinin substance P on NMDA-evoked locomotor activity. Brief (10 min) application of tachykinin neuropeptides results in a prolonged concentration-dependent (>24 hr) modulation of locomotor activity, shown by the increased burst frequency and more regular burst activity. These effects are blocked by the tachykinin antagonist spantide II. There are at least two phases to the burst frequency modulation. An initial phase (approximately 2 hr) is associated with the protein kinase C-dependent potentiation of cellular responses to NMDA. The long-lasting phase (>2 hr) appears to be protein synthesis-dependent, with protein synthesis inhibitors causing the increased burst frequency to recover after washing for 2-3 hr. The modulation of the burst regularity is caused by a separate effect of tachykinins, because unlike the burst frequency modulation it does not require the modulation of NMDA receptors for its induction and is blocked by H8, an inhibitor of cAMP- and cGMP-dependent protein kinases. The effects of substance P were mimicked by the dopamine D2 receptor antagonist eticlopride. The effects of eticlopride were blocked by the tachykinin antagonist spantide II, suggesting that eticlopride may endogenously release tachykinins. Because locomotor activity in vitro corresponds to that during swimming in intact animals, we suggest that endogenously released tachykinins will result in prolonged modulation of locomotor behavior.
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PMID:Substance P modulates NMDA responses and causes long-term protein synthesis-dependent modulation of the lamprey locomotor network. 961 53

Two isoforms of dopamine D2 receptor, D2L (long) and D2S (short), differ by the insertion of 29 amino acids specific to D2L within the putative third intracellular loop of the receptor, which appears to be important in selectivity for G-protein coupling. We have generated D2L- and D2S-expressing Chinese hamster ovary (CHO) cells, and regulation of the mitogen-activated protein kinase (MAPK) pathway was examined in these cells. Both D2L and D2S mediated a rapid and transient activation of MAPK with dominant activation of p42-kDa MAPK. Pertussis toxin treatment completely abrogated stimulation of MAPK mediated by D2L and D2S, demonstrating that both receptors couple to pertussis toxin-sensitive G proteins in this signaling. Stimulation of MAPK mediated by both D2L and D2S receptor was markedly attenuated by coexpression of the C-terminus of beta-adrenergic receptor kinase (betaARKct), which selectively inhibits Gbetagamma-mediated signal transduction. Further analysis of D2L- and D2S-mediated MAPK activation demonstrated that D2L-mediated MAPK activation was not significantly affected by PKC depletion or partially affected by genistein. In contrast, D2S-mediated MAPK activation was potentially inhibited by PKC depletion and genistein was capable of completely inhibiting D2S-mediated MAPK activation. Together, these results suggest that D2L- and D2S-mediated MAPK activation is predominantly Gbetagamma subunit-mediated signaling and that protein kinase C and tyrosine phosphorylations are involved in these signaling pathways.
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PMID:G protein-mediated mitogen-activated protein kinase activation by two dopamine D2 receptors. 1006 18

Ethanol and other drugs of abuse increase synaptic dopamine levels; however, little is known about how ethanol alters dopaminergic signaling. We have reported that ethanol induces translocation of delta and epsilon protein kinase C (PKC) in neural cells in culture. Using NG108-15 and Chinese hamster ovary cell lines that express the dopamine D2 receptor (D2R), we show here that the D2R agonist R(-)-2,10,11-trihydroxy-N-propyl-noraporphine hydrobromide (NPA) also causes translocation of delta and epsilon PKC to the same sites as ethanol-induced translocation. D2R agonist and ethanol-induced translocation of delta and epsilon PKC share a common pathway that is blocked by pertussis toxin and requires phospholipase C (PLC) activity. These data suggest that both D2R agonists and ethanol activate PLC via a trimeric G protein leading to production of diacylglycerol with subsequent activation and translocation of delta and epsilon PKC. Moreover, ethanol and NPA, when present together at low concentrations that alone are ineffective, act synergistically to cause translocation of delta and epsilon PKC. Our data suggest that ethanol causes translocation of delta and epsilon PKC but cells expressing the D2R, such as neurons in the nucleus accumbens, may be particularly sensitive to low concentrations of ethanol.
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PMID:Ethanol acts synergistically with a D2 dopamine agonist to cause translocation of protein kinase C. 1112 36

To determine the effect of dopamine on the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in pyramidal cells of layers V-VI of the prelimbic cortex, whole-cell patch-clamp recordings were made from 92 pyramidal cells of layers V-VI of the rat prelimbic cortex. In normal buffer, dopamine 100 microM apparently increased the frequency of spontaneous EPSCs. Decreasing the concentration of dopamine from 100 to 50 microM was accompanied by a decreased effect of dopamine. Further decreasing the dopamine concentration to 10 and 1 microM had no effects on the frequency of spontaneous EPSCs. In the presence of tetrodotoxin or cadmium, the increasing effect of dopamine was eliminated. The increasing effect of dopamine was blocked by the dopamine D1 receptor antagonist SCH23390, but not by the dopamine D2 receptor antagonist sulpiride. The D1 receptor agonist SKF38393 partially mimicked the increasing effect, but the D2 receptor agonist quinpirole did not. The alpha(1)-adrenoceptor antagonist prazosin could not block the increasing effect of dopamine on the frequency of spontaneous EPSCs in most cells tested. The protein kinase A inhibitor H-89 and the protein kinase C inhibitor chelerythrine could antagonize the effect of dopamine. The protein kinase A activator forskolin and the protein kinase C activator phorbol 12,13-dibutyrate could mimic the effect of dopamine. These results indicate that dopamine, presynaptically acting on dopamine D1 receptors, increases the frequency of spontaneous EPSCs via intracellular protein kinase A and protein kinase C signaling pathways in pyramidal cells of layers V-VI of the prelimbic cortex.
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PMID:Activation of presynaptic D1 dopamine receptors by dopamine increases the frequency of spontaneous excitatory postsynaptic currents through protein kinase A and protein kinase C in pyramidal cells of rat prelimbic cortex. 1207 93

In the striatum, stimulation of dopamine D2 receptors results in attenuation of glutamate responses. This effect is exerted in large part via negative regulation of AMPA glutamate receptors. Phosphorylation of the GluR1 subunit of the AMPA receptor has been proposed to play a critical role in the modulation of glutamate transmission, in striatal medium spiny neurons. Here, we have examined the effects of blockade of dopamine D2-like receptors on the phosphorylation of GluR1 at the cAMP-dependent protein kinase (PKA) site, Ser845, and at the protein kinase C and calcium/calmodulin-dependent protein kinase II site, Ser831. Administration of haloperidol, an antipsychotic drug with dopamine D2 receptor antagonistic properties, increases the phosphorylation of GluR1 at Ser845, without affecting phosphorylation at Ser831. The same effect is observed using eticlopride, a selective dopamine D2 receptor antagonist. In contrast, administration of the dopamine D2-like agonist, quinpirole, decreases GluR1 phosphorylation at Ser845. The increase in Ser845 phosphorylation produced by haloperidol is abolished in dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) knockout mice, or in mice in which the PKA phosphorylation site on DARPP-32 (i.e. Thr34) has been mutated (Thr34-->Ala mutant mice), and requires tonic activation of adenosine A2A receptors. These results demonstrate that dopamine D2 antagonists increase GluR1 phosphorylation at Ser845 by removing the inhibitory tone exerted by dopamine D2 receptors on the PKA/DARPP-32 cascade.
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PMID:Regulation of phosphorylation of the GluR1 AMPA receptor by dopamine D2 receptors. 1633 34


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