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)

Our previous in vitro microperfusion studies established that dopamine inhibits sodium chloride transport in the rat medullary thick ascending limb. The present study was designed to determine the intracellular signaling pathway mediating this response. The dopamine D1 receptor agonist fenoldopam (1 microM) inhibited sodium chloride transport in the thick ascending limb by 42+/-5%. The dopamine D1 receptor antagonist R-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-HCl (SCH-23390) completely blocked this effect of fenoldopam. Suppression of protein kinase A activity using either myristoylated protein kinase inhibitor (PKI) or N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl (H-89), as well as suppression of phospholipase C activity using 1-(6-((17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione (U-73122), had no effect on fenoldopam-dependent inhibition of transport. In contrast, inhibition of phospholipase A2 activity using E-6-(Bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (HELSS) significantly attenuated the effect of fenoldopam by 74%. The cytochrome P-450 monooxygenase inhibitor 17-octadecynoic acid (17-ODYA) and the protein kinase C inhibitor staurosporine both significantly attenuated the effects of fenoldopam by 67%. Exposure to 20-Hydroxy-(5Z, 8Z, 11Z, 14Z)-eicosatetraenoic acid (20-HETE) inhibited transport by 31+/-5%, and this effect was significantly attenuated by 66% in the presence of staurosporine. We propose a signaling pathway in which dopamine activates a calcium-independent phospholipase A2 in the medullary thick ascending limb. Released arachidonic acid is then metabolized to 20-HETE which subsequently increases protein kinase C activity that acts as a final transport effector.
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PMID:Dopamine D1 receptor-dependent inhibition of NaCl transport in the rat thick ascending limb: mechanism of action. 1289 37

Symptoms of Huntington's disease may be caused by a toxic insult triggered by the mutant human huntingtin (Htt) protein itself, by a maladaptive protective mechanism initiated in response to an insult, or by a combination of these. We observed a protection from N-methyl-d-aspartate (NMDA) receptor-induced excitotoxicity in striata of symptomatic N171-82Q mice, a new transgenic model of Huntington's disease. The goal of this study was to determine if NMDA receptor-mediated signalling pathways are altered in these mice. Multiple proteins of NMDA receptor and dopamine D1 receptor pathways are being regulated in ways predictive of the protection we observe. Although examining NMDA receptor subunit proteins showed no change in NR1, NR2A, or NR2B in the striata of the symptomatic mice, we observed a decrease in phosphorylation of NR1 at Ser897, previously reported to decrease NMDA receptor current. The dopamine D1 receptor, responsible for protein kinase A activation and subsequent phosphorylation of Ser897 of NR1, also showed an age-related decrease. Other proteins regulated in this disease were associated with PSD-95-like scaffolding proteins of the NMDA receptor. Specifically, we observed a decrease in membrane-associated neuronal nitric oxide synthase (nNOS), a decrease in PSD-95-like proteins, which link nNOS to the NMDA receptor complex, and a decrease in citron, a protein associated with dendritic spine formation. From these data, we conclude that the N171-82Q mice seem to be regulating, in a protective direction, many of the known effector pathways of NMDA receptor-induced excitotoxicity. These regulations, although seemingly effective in decreasing neuronal death, may in fact be causing some of the symptoms associated with the disease.
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PMID:Regulation of proteins affecting NMDA receptor-induced excitotoxicity in a Huntington's mouse model. 1466 21

Interactions between dopamine and N-methyl-D-aspartate receptors (NMDARs) in prefrontal cortex (PFC) and other brain regions are believed to play an important role in normal mental function and neuropsychiatric disorders. In this study, we examined the regulation of NMDAR currents by the dopamine D1 receptor in PFC pyramidal neurons. Application of the D1 receptor agonist SKF81297 caused a prominent increase of the steady-state NMDA-evoked current in acutely isolated PFC pyramidal neurons. The D1 effect on NMDARs was independent of protein kinase A or protein phosphatase 1, but was abolished by incubation of neurons in Ca2+-free medium. Intracellular application of the Ca2+ chelator, calmodulin, or calmodulin inhibitors largely prevented the D1 modulation of NMDAR currents. Moreover, inhibiting PKC activity or disrupting PKC association with its anchoring protein also significantly reduced the D1 effect on NMDAR currents. This upregulation of NMDAR activity by dopamine D1 receptors and the previous finding on up-regulation of dopamine D1 receptors by NMDAR activation provide a cellular mechanism for the reciprocal interactions between D1 and NMDARs. These interactions may play an important role in modulating synaptic plasticity and thus in cognitive and emotional processes.
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PMID:Potentiation of NMDA receptor currents by dopamine D1 receptors in prefrontal cortex. 1498 54

Phosphodiesterase (PDE) 7B, a cAMP-specific PDE which is dominantly expressed in striatum, is expected to be involved in dopaminergic signaling in striatal neurons. Here we show, for the first time, the involvement of the dopaminergic signaling pathway in transcriptional activation of rat PDE7B in primary striatal culture. RT-PCR analysis revealed that dopamine, D1 agonist, forskolin and 8-Br-cAMP stimulation potentiated PDE7B transcription in striatal neurons, while D2 agonist failed to activate the PDE7B transcription. Pre-treatment with D1 antagonist abolished the dopamine- or D1 agonist-induced transcriptional activation of PDE7B. The activation of PDE7B transcription by these stimulators was completely ablated by pre-treatment of the cells with a cAMP-dependent protein kinase inhibitor, H-89. RT-PCR using splice variant-specific primers revealed that transcription of PDE7B1, but not of other splice variants, was activated by D1 agonist. We determined the putative transcription start site of PDE7B1, a brain-specific splice variant of PDE7B, by 5'-RACE and identified a promoter region of PDE7B1. Sequence analysis of the PDE7B1 promoter revealed the presence of a canonical cAMP-response element at 166 bp upstream of the putative transcription start site. The cAMP-responsiveness of the PDE7B1 promoter was demonstrated by functional promoter analysis using the luciferase reporter system. Deletion and mutation of the cAMP-response element site in the PDE7B1 promoter abolished the forskolin-induced activation of the PDE7B1 promoter activity. Electrophoretic mobility shift assay showed the binding of cAMP-response element binding protein to the PDE7B1 promoter. These data demonstrate the dopamine D1 receptor-mediated transcriptional activation of PDE7B through the cAMP/cAMP-dependent protein kinase/cAMP-response element binding protein pathway in striatal neurons.
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PMID:Transcriptional activation of phosphodiesterase 7B1 by dopamine D1 receptor stimulation through the cyclic AMP/cyclic AMP-dependent protein kinase/cyclic AMP-response element binding protein pathway in primary striatal neurons. 1505 90

Previously, we demonstrated that dopamine D1 receptor (D1R) agonists inhibit epidermal growth factor (EGF)-induced passage of mouse fetal cerebral cortical precursor cells from the G1 phase to the S phase of the cell cycle. Here, we report that this action of D1R agonists may involve regulation of cyclin D, and P27, which respectively promote and suppress the G1 to S transition. Furthermore, regulation of Raf-1, a component of the receptor tyrosine kinase mitogen-activated protein kinase pathway engaged in the mitogenic activity of EGF, may also be involved. Specifically, levels of cyclin D and Raf-1 decrease, whereas those of P27 first increase and then decrease in a dose-dependent fashion in response to the D1R agonist, SKF38393. This agonist also promotes Raf-1 phosphorylation on serine 338 residue, suggesting increased activation of this protein. Only the latter effect can be blocked by adenylyl cyclase (AC) and cAMP-dependent protein kinase A (PKA) inhibitors, and mimicked by agonists of the cAMP signaling pathway. Another D1R agonist, SKF83959, which stimulates phospholipase Cbeta (PLCbeta) but not AC, reduces levels of Raf-1 and cyclin D similar to SKF38393. However, we detected only down-regulation of P27 by this agonist. Additionally, the concentration-dependent patterns of both SKF38393- and SKF83959-induced alterations in the levels of P27 closely resemble the effects of these ligands on the levels of the D1R-PLCbeta-associated second-messenger cascades linker, calcyon. These findings suggest that D1R-induced suppression of the cell cycle progression in EGF-supported fetal cortical precursor cells represents a net effect of competing cell cycle promoting and inhibiting molecular changes, which involve cyclin D, P27 and Raf-1. The data also show that cAMP second messenger cascade is not engaged in the D1R-induced regulation of the levels of these three proteins. Such regulation probably involves PLCbeta-associated pathways.
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PMID:D1 dopamine receptor regulation of the levels of the cell-cycle-controlling proteins, cyclin D, P27 and Raf-1, in cerebral cortical precursor cells is mediated through cAMP-independent pathways. 1523 44

This study reports some of the modifications in dopaminergic signalling that accompany cocaine and morphine behavioural sensitization. Cocaine-sensitized rats showed increased phosphorylation of dopamine- and cyclic AMP-regulated phosphoprotein Mr 32 kDa (DARPP-32) at threonine-75 (Thr75) and decreased DARPP-32 phosphorylation at Thr34, in the caudate-putamen (CPu) and nucleus accumbens (NAc) 7 days after sensitization assessment. Conversely, in morphine-sensitized rats, no apparent modifications in DARPP-32 phosphorylation pattern were observed. Morphine-sensitized rats have increased binding and coupling of micro -opioid receptors and increased dopaminergic transmission in striatal areas and, upon morphine challenge, exhibit dopamine D1 receptor-dependent stereotypies. Thus, the DARPP-32 phosphorylation pattern was studied in morphine-sensitized rats at different times after morphine challenge. Morphine challenge increased levels of phospho-Thr75 DARPP-32 and decreased levels of phospho-Thr34 DARPP-32 in a time-dependent manner in the CPu and NAc. In order to assess whether these modifications were related to modified cyclic AMP-dependent protein kinase (PKA) activity, the phosphorylation levels of two other PKA substrates were examined, the GluR1 and NR1 subunits of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate and NMDA receptors respectively. The phosphorylation levels of GluR1 and NR1 subunits decreased in parallel with those of phospho-Thr-34 DARPP-32, supporting the hypothesis that morphine challenge elicited a decrease in PKA activity in morphine-sensitized rats.
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PMID:Dopamine and cyclic AMP-regulated phosphoprotein-32 phosphorylation pattern in cocaine and morphine-sensitized rats. 1528 84

Nicotine, acting on nicotinic acetylcholine receptors (nAChRs) expressed at pre-synaptic dopaminergic terminals, has been shown to stimulate the release of dopamine in the neostriatum. However, the molecular consequences of pre-synaptic nAChR activation in post-synaptic neostriatal neurons are not clearly understood. Here, we investigated the effect of nAChR activation on dopaminergic signaling in medium spiny neurons by measuring phosphorylated DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa) at Thr34 (the PKA-site) in mouse neostriatal slices. Nicotine produced dose-dependent responses, with a low concentration (1 microm) causing a sustained decrease in DARPP-32 Thr34 phosphorylation and a high concentration (100 microm) causing a transient increase in DARPP-32 Thr34 phosphorylation. Depending on the concentration of nicotine, either dopamine D2 or D1 receptor signaling was predominantly activated. Nicotine at a low concentration (1 microm) activated dopamine D2 receptor signaling in striatopallidal/indirect pathway neurons, likely by activating alpha4beta2* nAChRs at dopaminergic terminals. Nicotine at a high concentration (100 microm) activated dopamine D1 receptor signaling in striatonigral/direct pathway neurons, likely by activating (i) alpha4beta2* nAChRs at dopaminergic terminals and (ii) alpha7 nAChRs at glutamatergic terminals, which, by stimulating the release of glutamate, activated NMDA/AMPA receptors at dopaminergic terminals. The differential effects of low and high nicotine concentrations on D2- and D1-dependent signaling pathways in striatal neurons may contribute to dose-dependent actions of this drug of abuse.
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PMID:Differential regulation of dopamine D1 and D2 signaling by nicotine in neostriatal neurons. 1531 65

Communication between dopaminergic and glutamatergic synapses is critical for several functions related to cognition and emotion. Here, we examined whether dopamine receptor activity regulates phosphorylation and trafficking of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit, GluR1. We find treatment with a dopamine D1 receptor agonist enhanced GluR1 phosphorylation at Ser845, the PKA phosphorylation site, in both striatal and prefrontal cortical neurons. Enhanced phosphorylation of GluR1 also correlated with increased amounts of GluR1 on the cell surface. These effects were disrupted by expression of mutant forms of the A-kinase anchoring protein (AKAP79/150) and the postsynaptic density protein, PSD-95, that fail to target synaptic sites. Similar enhancement of the phosphorylation of GluR1 was observed in the nucleus accumbens upon stimulation of dopamine release in vivo using electrical stimulation of dopamine cell bodies in the ventral tegmental area. These results suggest in vivo stimulation of dopamine release directly influences AMPA receptor phosphorylation and together with in vitro data indicate that coupling of the AMPA receptor to AKAP79/150 and PSD-95 modulate this process.
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PMID:Modulation of dopamine mediated phosphorylation of AMPA receptors by PSD-95 and AKAP79/150. 1545 48

Dopamine (DA) receptor-mediated signal transduction and gene expression play a central role in many brain disorders from schizophrenia to Parkinson's disease to addiction. While trying to evaluate the role of L-type Ca2+ channels in dopamine D1 receptor-mediated phosphorylation of the transcription factor cyclic AMP response element-binding protein (CREB), we found that activation of dopamine D1 receptors alters the properties of L-type Ca2+ channel inhibitors and turns them into facilitators of Ca2+ influx. In D1 receptor-stimulated neurons, L-type Ca2+ channel blockers promote cytosolic Ca2+ accumulation. This leads to the activation of a molecular signal transduction pathway and CREB phosphorylation. In the absence of dopamine receptor stimulation, L-type Ca2+ channel blockers inhibit CREB phosphorylation. The effect of dopamine on L-type Ca2+ channel blockers is dependent on protein kinase A (PKA), suggesting that protein phosphorylation plays a role in this phenomenon. Because of the adverse effect of activated dopamine receptors on L-type Ca2+ channel blocker action, the role of L-type Ca2+ channels in the dopamine D1 receptor signal transduction pathway cannot be assessed with pharmacological tools. However, with antisense technology, we demonstrate that L-type Ca2+ channels contribute to D1 receptor-mediated CREB phosphorylation. We conclude that the D1 receptor signal transduction pathway depends on L-type Ca2+ channels to mediate CREB phosphorylation.
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PMID:L-type Ca2+ channel blockers promote Ca2+ accumulation when dopamine receptors are activated in striatal neurons. 1553 Jun 53

Acute cocaine administration increases extraneuronal dopamine and Thr34 phosphorylation of dopamine- and cAMP-regulated phosphoprotein (M(r) 32 kDa; DARPP-32) in striatal and cortical areas. Novel palatable food consumption increases extraneuronal dopamine in the same areas. We examined the DARPP-32 phosphorylation pattern in food non-deprived rats at different times after vanilla sugar consumption. The phosphorylation state of DARPP-32 and two cAMP-dependent protein kinase (PKA) substrates, GluR1 and NR1, were detected by immunoblotting. Thirty to 45 min after vanilla sugar consumption, phospho-Thr34 DARPP-32, GluR1 and NR1 levels increased in the nucleus accumbens, and phospho-Thr75 DARPP-32 levels decreased. At 60 min, all parameters returned to baseline values. However, 2 and 3 h after vanilla sugar consumption, phospho-Thr34 DARPP-32 levels decreased, while phospho-Thr75 DARPP-32 levels increased. In contrast to the pattern observed in the NAcS, no delayed changes in DARPP-32 phosphorylation were observed in the mPFC. Both early and delayed DARPP-32, GluR1 and NR1 phosphorylation changes were prevented by a dopamine D1 receptor antagonist administration. The delayed modifications in nucleus accumbens DARPP-32 phosphorylation were prevented by an mGluR5 antagonist administration. The mesolimbic dopaminergic response to an unfamiliar taste is correlated to a gustatory memory trace development, and the observed changes in DARPP-32 phosphorylation may be part of this process.
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PMID:The mesolimbic dopaminergic response to novel palatable food consumption increases dopamine-D1 receptor-mediated signalling with complex modifications of the DARPP-32 phosphorylation pattern. 1568 89


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