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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the role of the cAMP-dependent protein kinase (PKA) in the desensitization and down-regulation of the D(1) dopamine receptor, we stably expressed the rat cDNA for this receptor in mutant Chinese hamster ovary (CHO) cell lines deficient in PKA activity. The 10260 mutant CHO cell line has been characterized as expressing less than 10% of type I and type II PKA activities relative to the parental 10001 CHO cell line. The 10248 mutant CHO line lacks type II PKA activity and expresses a defective type I PKA. The transfected parental and mutant cell lines were found to express approximately 1 pmol/mg D(1) receptor binding activity (B(max)) as determined using [(3)H]SCH-23390 binding assays. All three cell lines demonstrated similar levels of dopamine-stimulated adenylyl cyclase activity. Pretreatment of all three CHO cells with dopamine resulted in desensitization of the adenylyl cyclase response, although the maximum desensitization was attenuated by 20 and 40% in the 10260 and 10248 cell lines, respectively. Dopamine also promoted, in a time- and dose-dependent fashion, a >90% down-regulation of D(1) receptors in the parental cell line but only a 50 and 30% decrease in the 10260 and 10248 cells, respectively. Similarly, treatment of the cells with the membrane-permeable cAMP analog 8-(4-chlorophenylthio)-cAMP induced functional desensitization and down-regulation of the D(1) receptor, although it was not as great as that observed with agonist pretreatment. As with the agonist pretreatments, the 8-(4-chlorophenylthio)-induced responses were attenuated in the mutant cells with the 10248 line exhibiting the least desensitization/down-regulation. Our results suggest that PKA significantly contributes to the desensitization and down-regulation of D(1) receptors in CHO cells and that type II PKA may be the more relevant isoform with respect to regulating D(1) receptor function.
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PMID:Altered regulation of the D(1) dopamine receptor in mutant Chinese hamster ovary cells deficient in cyclic AMP-dependent protein kinase activity. 1077 12

The mechanism(s) by which dopamine inhibits Na+-K+-ATPase activity in the renal proximal tubule is still controversial. We studied the short-term effects of dopamine on the sodium pump in rat renal proximal tubule suspensions with the 86Rb uptake method. Dopamine and the D1-like agonist, SKF81297, initially stimulated Na+-K+-ATPase activity at 5 min and subsequently inhibited it at 10 min and 20 min; the inhibition by 10 microM dopamine at 20 min was 21.3 +/- 4.5%. The inhibitory effect of dopamine on Na+-K+-ATPase activity was mimicked by thymeleatoxin (a classical protein kinase C [PKC] agonist) while Sp-8-CPT-cAMPS (a protein kinase A [PKA] agonist) had no effect. However, the combination of the PKC and PKA agonists mimicked the biphasic effects of dopamine and SKF81297. Rp-8-CPT-cAMPS (a PKA inhibitor), U-73122 (a phospholipase C inhibitor), or calphostin C (a PKC inhibitor), blocked the dopamine-mediated biphasic effects on Na+-K+-ATPase activity. It is suggested that the biphasic effects of dopamine on Na+-K+-ATPase activity (an initial stimulation and a subsequent inhibition) are transduced by activating both PKA and PKC through a D1-like receptor.
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PMID:Biphasic effects of dopamine on 86rubidium uptake in rat renal proximal tubules. 1080 34

Dopamine is a critical determinant of neostriatal function, but its impact on intrastriatal GABAergic signaling is poorly understood. The role of D(1) dopamine receptors in the regulation of postsynaptic GABA(A) receptors was characterized using whole cell voltage-clamp recordings in acutely isolated, rat neostriatal medium spiny neurons. Exogenous application of GABA evoked a rapidly desensitizing current that was blocked by bicuculline. Application of the D(1) dopamine receptor agonist SKF 81297 reduced GABA-evoked currents in most medium spiny neurons. The D(1) dopamine receptor antagonist SCH 23390 blocked the effect of SKF 81297. Membrane-permeant cAMP analogues mimicked the effect of D(1) dopamine receptor stimulation, whereas an inhibitor of protein kinase A (PKA; Rp-8-chloroadenosine 3',5' cyclic monophosphothioate) attenuated the response to D(1) dopamine receptor stimulation or cAMP analogues. Inhibitors of protein phosphatase 1/2A potentiated the modulation by cAMP analogues. Single-cell RT-PCR profiling revealed consistent expression of mRNA for the beta1 subunit of the GABA(A) receptor-a known substrate of PKA-in medium spiny neurons. Immunoprecipitation assays of radiolabeled proteins revealed that D(1) dopamine receptor stimulation increased phosphorylation of GABA(A) receptor beta1/beta3 subunits. The D(1) dopamine receptor-induced phosphorylation of beta1/beta3 subunits was attenuated significantly in neostriata from DARPP-32 mutants. Voltage-clamp recordings corroborated these results, revealing that the efficacy of the D(1) dopamine receptor modulation of GABA(A) currents was reduced in DARPP-32-deficient medium spiny neurons. These results argue that D(1) dopamine receptor stimulation in neostriatal medium spiny neurons reduces postsynaptic GABA(A) receptor currents by activating a PKA/DARPP-32/protein phosphatase 1 signaling cascade targeting GABA(A) receptor beta1 subunits.
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PMID:D(1) dopamine receptor activation reduces GABA(A) receptor currents in neostriatal neurons through a PKA/DARPP-32/PP1 signaling cascade. 1080 95

Dopamine causes natriuresis and diuresis via activation of D1-like receptors located in the renal proximal tubules. It is reported that this response to dopamine results from the inhibition of Na,H-exchanger and Na,K-ATPase. Earlier studies have suggested a role of protein kinase A (PKA) in the inhibition of Na,H-exchanger, however, the effect of dopamine or the dopamine receptor subtype responsible for the stimulation of PKA has not been reported. Present study was designed to examine the effect of dopamine and D1-like receptor agonist, SKF 38393, on the stimulation of PKA activity in rat renal proximal tubules. Dopamine and SKF 38393 (1 nM - 1 microM) caused stimulation of PKA activity, an effect which was antagonized by a D1-like receptor antagonist, SCH 23390 (10 microM). Stimulation of PKA activity was also seen with forskolin and di-butyryl cAMP. We also observed that dopamine and SKF 38393 inhibited Na,H-exchanger activity in the proximal tubules. This response was blocked by SCH 23390 and Rp-cAMPS triethylamine, a selective inhibitor of PKA. Similarly, forskolin and di-butyryl cAMP inhibited Na,H-exchanger activity. The data provide direct evidence showing that dopamine, through the activation of D1-like receptors stimulates PKA activity which in turn inhibits Na,H-exchanger in the proximal tubules.
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PMID:Dopamine inhibits na,h-exchanger via D1-like receptor-mediated stimulation of protein kinase a in renal proximal tubules. 1097 67

Dopamine (DA) promotes the morphological differentiation of striatal GABAergic neurons through D(1) receptor activation and cAMP/PKA signaling. In this study, we investigated the developmental role of DA on the expression of the two GAD(65/67) genes and the alternative splicing of GAD(67) transcripts in the rat striatum. In vivo, embryonic and adult GAD(67) splice variants and GAD(65) transcripts increased until E17 and E19, respectively. Thereafter, the embryonic GAD(67) isoform disappeared, whereas GAD(65) mRNA levels remained unchanged postnatally. The hypothesis that the prenatal ingrowth and functional maturation of nigrostriatal afferents may be responsible for these developmental events through DA-dependent signaling pathways was tested in E17 rat striatal cultures. Treatment with DA and D(1) but not D(2) agonists decreased the ratio of embryonic to adult GAD(67) mRNAs and increased GAD(65) mRNA levels as well as GABA synthesis rates. Our findings demonstrate a distinct developmental switch in the regulation of GAD(65) expression and GAD(67) splicing in the rat striatum which clearly depends upon D(1) receptor but not D(2) signaling. The dopaminergic input thus appears to control the functional differentiation of GABAergic neurons not only by upregulation of expression of the two GAD genes but also by regulating GAD(67) splicing.
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PMID:Developmental regulation of glutamic acid decarboxylase mRNA expression and splicing in the rat striatum by dopamine. 1100 Apr 75

Synaptic transmission from vertebrate photoreceptors involves activation of L-type calcium currents (ICa). Dopamine is an important circadian neuromodulator in the retina and photoreceptors possess D2 dopamine receptors. We examined modulation of ICa by dopamine and cAMP in retinal slices and isolated cells of larval tiger salamander. Results show that dopamine and a D2 agonist, quinpirole, enhanced ICa in rods and red-, blue- and UV-sensitive small single cones but inhibited ICa in red-sensitive large single cones. A D1 agonist, SKF-38393, was without effect. Quinpirole effects were blocked by pertussis toxin (PTx) pretreatment indicating involvement of PTx-sensitive G-proteins. Like dopamine, inhibition of cAMP-dependent protein kinase (PKA) by Rp-cAMPS enhanced ICa in rods and small single cones, but inhibited ICa in large single cones. In contrast, forskolin and Sp-cAMPS, which stimulate PKA, inhibited ICa in rods and small single cones but enhanced ICa in large single cones. Sp-cAMPS also occluded effects of quinpirole. These results suggest that D2 receptors modulate ICa via inhibition of cAMP. Differences among the responses of photoreceptors to cAMP are consistent with the possibility that small single cones and rods may possess different Ca2+ channel subtypes than large single cones. The results with dopamine and quinpirole showing inhibition of ICa in large single cones and enhancement of rod ICa were unexpected because previous studies have shown that dopamine suppresses rod inputs and enhances cone inputs into second-order neurons. The present results therefore indicate that the dopaminergic enhancement of cone inputs does not arise from modulation of photoreceptor ICa.
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PMID:Differential modulation of rod and cone calcium currents in tiger salamander retina by D2 dopamine receptors and cAMP. 1102 23

Dopamine and cAMP-regulated phosphoprotein of M(r) 32,000 (DARPP-32) plays an obligatory role in most of the actions of dopamine. In resting neostriatal slices, cyclin-dependent kinase 5 (Cdk5) phosphorylates DARPP-32 at Thr-75, thereby reducing the efficacy of dopaminergic signaling. We report here that dopamine, in slices, and acute cocaine, in whole animals, decreases the state of phosphorylation of striatal DARPP-32 at Thr-75 and thereby removes this inhibitory constraint. This effect of dopamine is achieved through dopamine D1 receptor-mediated activation of cAMP-dependent protein kinase (PKA). The activated PKA, by decreasing the state of phosphorylation of DARPP-32-Thr-75, de-inhibits itself. Dopamine D2 receptor stimulation has the opposite effect. The ability of activated PKA to reduce the state of phosphorylation of DARPP-32-Thr-75 is apparently attributable to increased protein phosphatase-2A activity, with Cdk5 being unaffected. Together, these results indicate that via positive feedback mechanisms, Cdk5 signaling and PKA signaling are mutually antagonistic.
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PMID:Amplification of dopaminergic signaling by a positive feedback loop. 1105 Jan 61

It is pointed out that Ca(2+)-dependent modification rules for NMDA-dependent (NMDA-independent) synaptic plasticity in the striatum are similar to those in the neocortex and hippocampus (cerebellum). A unitary postsynaptic mechanism of synaptic modification is proposed. It is based on the assumption that, in diverse central nervous system structures, long-term potentiation/depression (LTP/LTD) of excitatory transmission (depression/potentiation of inhibitory transmission, LTDi/LTPi) is the result of an increasing/decreasing the number of phosphorylated AMPA and NMDA (GABA(A)) receptors. According to the suggested mechanism, Ca(2+)/calmodulin-dependent protein kinase II and protein kinase C, whose activity is positively correlated with Ca(2+) enlargement, together with cAMP-dependent protein kinase A (cGMP-dependent protein kinase G, whose activity is negatively correlated with Ca(2+) rise) mainly phosphorylate ionotropic striatal receptors, if NMDA channels are opened (closed). Therefore, the positive/negative post-tetanic Ca(2+) shift in relation to a previous Ca(2+) rise must cause NMDA-dependent LTP+LTDi/LTD+LTPi or NMDA-independent LTD+LTPi/LTP+LTDi. Dopamine D(1)/D(2) or adenosine A(2A)/A(1) receptor activation must facilitate LTP+LTDi/LTD+LTPi due to an augmenting/lowering PKA activity. Activation of muscarinic M(1)/M(4) receptors must enhance LTP+LTDi/LTD+LTPi as a consequence of an increase/decrease in the activity of protein kinase C/A. The proposed mechanism is in agreement with known experimental data.
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PMID:The cortico-basal ganglia-thalamocortical circuit with synaptic plasticity. I. Modification rules for excitatory and inhibitory synapses in the striatum. 1108 40

Pigmented (PE) and nonpigmented (NPE) ciliary epithelial cells comprise the ciliary epithelium, the site of aqueous humor formation in the eye. In man, catecholamines increase the rate of aqueous humor formation, but the mechanism underlying these effects is not understood. Recent evidence suggests that Na-K-Cl cotransport plays a central role in blood-to-aqueous chloride transport across ciliary epithelium in cow and rabbit. We therefore investigated whether catecholamines stimulate Na-K-Cl cotransport in human PE cells. Na-K-Cl cotransporter protein was detected as a 170 kDa protein band on immunoblots. Immunofluorescence microscopy detected cotransporter on the basolateral membranes of the PE layer of ciliary epithelium from a human donor. Cotransporter immunofluorescence was also detected in cultured PE cells. Na-K-Cl cotransport activity measured as ouabain-insensitive bumetanide-sensitive(86)Rb uptake was stimulated by isoproterenol 1.6-fold, with an EC(50) = 28 n M and maximal stimulation at 1 microM. Other transport mechanisms involved in(86)Rb uptake were not affected. Stimulation by 1 microM isoproterenol was blocked by 10 n M ICI 118,551, a beta(2)-specific receptor antagonist, whereas the receptor subtype-specific antagonists yohimbine (alpha(2)), prazosin (alpha(1)) and atenolol (beta(1)) were ineffective. Norepinephrine stimulation (EC(50) = 280 n M) was also blocked by ICI 118,551. Dopamine stimulated Na-K-Cl cotransport 1.6-fold with an EC(50) = 14 microM. The dopamine effect could not be blocked by 10 microM SCH 23390, a D1-antagonist, but was abolished by ICI 118,551. Forskolin and CPT-cAMP stimulated Na-K-Cl cotransport 1.79- and 1.71-fold, respectively, whereas the inactive forskolin analogue 1,9-dideoxyforskolin had no effect. However, high concentrations of the PKA inhibitors PKI amide 14-22 and KT 5720 were needed to inhibit both PKA activity in cell lysates and isoproterenol stimulation of cotransport. This finding may indicate the presence of a novel PKA isoform in PE cells. Inhibitors of other protein kinases, including myosin light chain kinase, protein kinase G, calmodulin-dependent kinase and tyrosine kinase, were without effect on stimulated Na-K-Cl cotransport. When EC(50)s for catecholaminergic stimulations of Na-K-Cl cotransport in PE were compared to those in NPE, values within five-fold of one another were seen for isoproterenol and norepinephrine. In contrast, dopamine was 28-fold more potent in NPE than in PE. The data suggest that both PE and NPE possess beta(2)adrenergic receptors, but only NPE cells possess dopamine D1 receptors linked to Na-K-Cl cotransport.
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PMID:Catecholaminergic regulation of Na-K-Cl cotransport in pigmented ciliary epithelium: differences between PE and NPE. 1113 77

Dopamine causes inhibition of Na(+),K(+)-ATPase activity via activation of dopamine D(1)-like receptors. It is the phosphorylation of Serine(18) of the alpha(1)-subunit of Na(+),K(+)-ATPase which results in the inhibition of the enzyme activity; however, such a phosphorylation by dopamine D(1)-like receptor agonist has not been demonstrated in the proximal tubules. We show here by immunoprecipitation and detection with phosphoserine antibody that SKF 38393, a dopamine D(1)-like receptor agonist, causes phosphorylation of the alpha(1)-subunit of Na(+),K(+)-ATPase. The effect of (+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride, SKF 38393, is blocked by R(+)-7-choro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride, SCH 23390, a dopamine D(1)-like receptor antagonist, and staurosporin, a protein kinase C inhibitor. The phosphorylation is also increased by phorbol 12-13 dibutyrate ester. However, Rp-cAMP triethylamine, an inhibitor of protein kinase A, does not affect the SKF 38393-mediated phosphorylation of Na(+),K(+)-ATPase. Therefore, these results provide the evidence that dopamine D(1)-like receptor activation causes phosphorylation of the alpha(1)-subunit of Na(+),K(+)-ATPase in renal proximal tubules via protein kinase C pathway.
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PMID:Activation of dopamine D(1)-like receptor causes phosphorylation of alpha(1)-subunit of Na(+),K(+)-ATPase in rat renal proximal tubules. 1113 59


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