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)

Tonometric measurements of colonic and gastric mucosa pH are used as indirect determinants of splanchnic perfusion in shocked patients or those undergoing aortic cross-clamp. Mucosal acidification in response to splanchnic vasodilators such as dopamine has been assumed to signify ischemia. However, cellular acidification may occur independent of oxygenation and the direct effects of dopamine on mucosal acid-base are unknown. We examined the effects of dopamine on cellular pH (independent of oxygenation) of intestinal mucosa in vitro. Crypts isolated from the distal colon of Sprague-Dawley rats were loaded with a pH-sensitive fluorescent probe, perfused with a Hepes-buffered Ringers solution, and imaged with confocal laser scanning microscopy. In separate experiments, crypts were loaded with a calcium-sensitive probe (Fura-2) and concentrations of free cytosolic calcium were measured with fluorescence imaging. Dopamine perfusion produced a reversible cytosolic acidification of crypts which was not significantly affected by (i) the nominal absence of bicarbonate, (ii) alpha- and beta-adrenergic receptor blockade, or (iii) protein kinase C inhibition. Dopamine did not significantly affect intracellular calcium concentrations. However, dopamine-induced acidification was inhibited by (a) blocking sodium-hydrogen exchange with amiloride, (b) prior exposure to adenosine 3', 5'-cyclic monophosphate (cAMP), or (c) protein kinase A blockade (all P < 0.01). Dopamine directly acidifies mucosal crypt cells in a mechanism that involves a cAMP-mediated inhibition of sodium-hydrogen exchange. This finding accounts for the acidification of intestinal mucosa during low-dose dopamine infusion despite a demonstrable improvement in splanchnic perfusion. Direct mucosal effects of pharmacological agents must be considered in the evaluation of perfusion parameters based on tonometric data.
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PMID:Direct effects of dopamine on colonic mucosal pH: implications for tonometry. 1021 Jun 44

Dopamine, acting at a D1-like receptor, depresses the release of glutamate in the nucleus accumbens (NAcc) in brain slices, thereby reducing the amplitude of the excitatory postsynaptic current (EPSC). This effect depends upon an inhibitory feedback action of adenosine, liberated following facilitation of postsynaptic NMDA receptors by D1 receptor activation, an action independent of adenylyl cyclase stimulation or cyclic AMP-dependent protein kinase (PKA; Harvey, J., Lacey, M.G., 1997. J. Neurosci. 17, 5271). Using whole-cell recording from NAcc neurones, the dopamine depression of the EPSC was blocked by pre-treatment of brain slices with the selective protein kinase C (PKC) inhibitor Ro 32-0432, but only minimally attenuated by intracellular dialysis of single cells with Ro 32-0432 in the recording pipette. With synaptic transmission blocked by tetrodotoxin, inward currents caused by application of NMDA were enhanced by the D1 receptor agonist SKF 81297A in half the cells tested. In a separate population of cells dialysed intracellularly with Ro 32-0432, SKF 81297A was without effect on NMDA current amplitude. These findings indicate a functional role for phospholipase C-coupled D1-like receptors in both modulating synaptic transmission in NAcc and potentiating NMDA receptors on a subset of NAcc neurones, via PKC activation.
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PMID:Modulation by dopamine D1-like receptors of synaptic transmission and NMDA receptors in rat nucleus accumbens is attenuated by the protein kinase C inhibitor Ro 32-0432. 1021 63

Dopamine and the neuropeptides Ala-Pro-Gly-Trp-NH2 (APGWamide or APGWa) and Phe-Met-Arg-Phe-NH2 (FMRFamide or FMRFa) all activate an S-like potassium channel in the light green cells of the mollusc Lymnaea stagnalis, neuroendocrine cells that release insulin-related peptides. We studied the signaling pathways underlying the responses, the role of the G-protein betagamma subunit, and the interference by phosphorylation pathways. All responses are blocked by an inhibitor of arachidonic acid (AA) release, 4-bromophenacylbromide, and by inhibitors of lipoxygenases (nordihydroguaiaretic acid and AA-861) but not by indomethacin, a cyclooxygenase inhibitor. AA and phospholipase A2 (PLA2) induced currents with similar I-V characteristics and potassium selectivity as dopamine, APGWa, and FMRFa. PLA2 occluded the response to FMRFa. We conclude that convergence of the actions of dopamine, APGWa, and FMRFa onto the S-like channel occurs at or upstream of the level of AA and that formation of lipoxygenase metabolites of AA is necessary to activate the channel. Injection of a synthetic peptide, which interferes with G-protein betagamma subunits, inhibited the agonist-induced potassium current. This suggests that betagamma subunits mediate the response, possibly by directly coupling to a phospholipase. Finally, the responses to dopamine, APGWa, and FMRFa were inhibited by activation of PKA and PKC, suggesting that the responses are counteracted by PKA- and PKC-dependent phosphorylation. The PLA2-activated potassium current was inhibited by 8-chlorophenylthio-cAMP but not by 12-O-tetradecanoylphorbol 13-acetate (TPA). However, TPA did inhibit the potassium current induced by irreversible activation of the G-protein using GTP-gamma-S. Thus, it appears that PKA targets a site downstream of AA formation, e.g., the potassium channel, whereas PKC acts at the active G-protein or the phospholipase.
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PMID:Roles of G-protein beta gamma, arachidonic acid, and phosphorylation inconvergent activation of an S-like potassium conductance by dopamine, Ala-Pro-Gly-Trp-NH2, and Phe-Met-Arg-Phe-NH2. 1023 6

After cessation of repeated, intermittent amphetamine, we detected an emergent Ca2+-dependent component of amphetamine-induced dopamine release and an increase in calmodulin and Ca2+- and calmodulin-dependent protein kinase activity in rat striatum. This study examined the involvement of calmodulin-dependent protein kinase II (CaM kinase II) and synaptic vesicles in the enhanced Ca2+-dependent dopamine release in response to amphetamine or K+ in rat striatum. Rats were pretreated for 5 d with 2.5 mg/kg amphetamine or saline and withdrawn from drug for 10 d. The selective CaM kinase II inhibitor KN-93 (1 microM), but not the inactive analog KN-92, attenuated the Ca2+-dependent amphetamine-mediated dopamine release from amphetamine-pretreated rats but had no effect in saline-pretreated controls. [3H]Dopamine uptake was unaltered by repeated amphetamine or KN-93 and was Ca2+ independent. Striatal dopamine release stimulated by 50 mM KCl was enhanced twofold after repeated amphetamine compared with that in saline controls but was unaffected by KN-93. To examine the requirement for dopaminergic vesicles in the Ca2+-dependent dopamine release, we administered reserpine to saline- and amphetamine-pretreated rats 1 d before killing. Reserpine pretreatment did not affect amphetamine-mediated dopamine release from either pretreatment group but completely ablated K+-mediated dopamine release. Reserpine did not disrupt the ability of 1 microM KN-93 to block the Ca2+-dependent amphetamine-mediated dopamine release from amphetamine-pretreated rats. The results indicate that the enhanced dopamine release elicited by amphetamine from chronically treated rats is dependent on Ca2+- and calmodulin-dependent phosphorylation and is independent of vesicular dopamine storage. On the contrary, the enhanced depolarization-mediated vesicular dopamine release is independent of Ca2+- and calmodulin-dependent phosphorylation.
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PMID:Enhanced amphetamine- and K+-mediated dopamine release in rat striatum after repeated amphetamine: differential requirements for Ca2+- and calmodulin-dependent phosphorylation and synaptic vesicles. 1023 12

Dopamine, by activating D(1)- and D(2)-class receptors, plays a significant role in regulating gene expression. Although much is known about D(1) receptor-regulated gene expression, there has been far less information on gene regulation mediated by D(2) receptors. In this study, we show that D(2) receptors can activate the mitogen-activated protein kinase (MAPK) and the cAMP response element-binding protein (CREB) in neurons. Treatment of brain slices with the D(2) receptor agonist quinpirole induced rapid phosphorylation of MAPK and CREB. The neuroleptic drug eticlopride, a highly selective D(2) receptor antagonist, blocked the quinpirole-induced phosphorylation of MAPK and CREB. D(2) receptor-induced MAPK phosphorylation depended on intracellular Ca(2+) elevation, protein kinase C activation, and MAPK kinase activation, but not on the protein tyrosine kinase Pyk2, even though quinpirole stimulated Pyk2 phosphorylation. D(2) receptor-induced CREB phosphorylation was mediated by activation of protein kinase C and Ca(2+)/calmodulin-dependent protein kinase, but not MAPK. The dopamine and cAMP-regulated phosphoprotein DARPP-32 also was required for the regulation of MAPK and CREB phosphorylation by D(2) receptors. Our results suggest that MAPK and CREB signaling cascades are involved in the regulation of gene expression and other long-term effects of D(2) receptor activation.
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PMID:D(2) dopamine receptors induce mitogen-activated protein kinase and cAMP response element-binding protein phosphorylation in neurons. 1050 Feb 24

Our previous studies showed that dopamine inhibits Na+,K+-ATPase activity in acutely dissociated neurons from striatum. In the present study, we have found that in this preparation, dopamine inhibited significantly (by approximately 25%) the activity of the alpha3 and/or alpha2 isoforms, but not the alpha1 isoform, of Na+,K+-ATPase. Dopamine, via D1 receptors, activates cyclic AMP-dependent protein kinase (PKA) in striatal neurons. Dopamine is also known to activate the calcium- and phospholipid-dependent protein kinase (PKC) in a number of different cell types. The PKC activator phorbol 12,13-dibutyrate reduced the activity of Na+,K+-ATPase alpha3 and/or alpha2 isoforms (by approximately 30%) as well as the alpha1 isoform (by approximately 15%). However, dopamine-mediated inhibition of Na+,K+-ATPase activity was unaffected by calphostin C, a PKC inhibitor. Dopamine did not affect the phosphorylation of Na+,K+-ATPase isoforms at the PKA-dependent phosphorylation site. Phorbol ester treatment did not alter the phosphorylation of alpha2 or alpha3 isoforms of Na+,K+-ATPase in neostriatal neurons but did increase the phosphorylation of the alpha1 isoform. Thus, in rat neostriatal neurons, treatment with either dopamine or PKC activators results in inhibition of the activity of specific (alpha3 and/or alpha2) isoforms of Na+,K+-ATPase, but this is not apparently mediated through direct phosphorylation of the enzyme. In addition, PKC is unlikely to mediate inhibition of rat Na+,K+-ATPase activity by dopamine in neostriatal neurons.
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PMID:Regulation of Na+, K+-ATPase isoforms in rat neostriatum by dopamine and protein kinase C. 1050 Nov 94

Phototransduction in Drosophila is mediated by a G-protein-coupled phospholipase C transduction cascade in which each absorbed photon generates a discrete electrical event, the quantum bump. In whole-cell voltage-clamp recordings, cAMP, as well as its nonhydrolyzable and membrane-permeant analogs 8-bromo-cAMP (8-Br-cAMP) and dibutyryl-cAMP, slowed down the macroscopic light response by increasing quantum bump latency, without changes in bump amplitude or duration. In contrast, cGMP or 8-Br-cGMP had no effect on light response amplitude or kinetics. None of the cyclic nucleotides activated any channels in the plasma membrane. The effects of cAMP were mimicked by application of the non-specific phosphodiesterase inhibitor IBMX and the adenylyl cyclase activator forskolin; zaprinast, a specific cGMP-phosphodiesterase inhibitor, was ineffective. Bump latency was also increased by targeted expression of either an activated G(s) alpha subunit, which increased endogenous adenylyl cyclase activity, or an activated catalytic protein kinase A (PKA) subunit. The action of IBMX was blocked by pretreatment with the PKA inhibitor H-89. The effects of cAMP were abolished in mutants of the ninaC gene, suggesting this nonconventional myosin as a possible target for PKA-mediated phosphorylation. Dopamine (10 microM) and octopamine (100 microM) mimicked the effects of cAMP. These results indicate the existence of a G-protein-coupled adenylyl cyclase pathway in Drosophila photoreceptors, which modulates the phospholipase C-based phototransduction cascade.
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PMID:Modulation of the light response by cAMP in Drosophila photoreceptors. 1051 99

Dopamine dilates the coronary, renal and other vascular beds; however, the signaling pathway underlying this effect is unclear. In this study the signal-transduction process mediating dopamine-induced relaxation of porcine coronary arteries was investigated in isolated vessels and single arterial myocytes. Dopamine-induced relaxation of arteries was mediated through the DA- receptor and involved K+ efflux, and subsequent patch-clamp studies demonstrated that either dopamine or fenoldopam, a selective DA-1 agonist, increased the opening probability of the large-conductance, calcium- and voltage-activated K+ (BKCa) channel in coronary myocytes. Moreover, blockade of this channel by iberiotoxin prevented dopamine-induced coronary relaxation. Dopamine stimulation of BKCa channels was completely prevented by a DA-1-receptor antagonist, but was unaffected by propranolol. Furthermore, inhibiting adenylyl cyclase activity prevented stimulation of BKCa channel activity, whereas chlorophenylthio (CPT)-cyclic adenosine monophosphate (AMP), a membrane-permeable analog of cyclic AMP, mimicked the effects of dopamine. Interestingly, inhibiting the cyclic AMP-dependent protein kinase (PKA) did not affect the response to dopamine, whereas dopamine-induced channel activity was completely blocked by inhibiting the activity of the cyclic guanosine monophosphate (GMP)-dependent protein kinase (PKG). These findings demonstrate that activation of DA-1 receptors causes stimulation of BKCa channel activity by a mechanism involving cyclic AMP-dependent stimulation of PKG, but not PKA, and further suggest that this cross-reactivity mediates dopamine-induced coronary vasodilation.
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PMID:A novel transduction mechanism mediating dopamine-induced vascular relaxation: opening of BKCa channels by cyclic AMP-induced stimulation of the cyclic GMP-dependent protein kinase. 1054 76

Dopamine receptor activation regulates cyclic AMP levels and is critically involved in modulating neurotransmission in the striatum. Others have shown that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-type glutamate receptor-mediated current is potentiated by cyclic AMP-dependent protein kinase (PKA) activation. We made whole-cell patch clamp recordings from cultured striatal neurons and tested whether D1-type dopamine receptor activation affected AMPA receptor-mediated currents. After a 5-min exposure to the D1 agonist SKF 81297 (1 microM), kainate-evoked current amplitude was enhanced in approximately 75% of cells to 121+/-2.5% of that recorded prior to addition of drug. This response was inhibited by the D1 antagonist SCH 23390 and mimicked by activators of PKA. Moreover, by western blot analysis using an antibody specific for the phosphorylated PKA site Ser845 of GluR1, we observed a marked increase in phosphorylated GluR1 following a 10-min exposure of striatal neurons to 1 microM SKF 81297. Our data demonstrate that activation of D1-type dopamine receptors on striatal neurons promotes phosphorylation of AMPA receptors by PKA as well as potentiation of current amplitude. These results elucidate one mechanism by which dopamine can modulate neurotransmission in the striatum.
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PMID:D1 dopamine receptor-induced cyclic AMP-dependent protein kinase phosphorylation and potentiation of striatal glutamate receptors. 1058 4

In addition to its cofactor activities for aromatic L-amino acid hydroxylases and nitric oxide synthase (NOS), 6R-tetrahydrobiopterin (6R-BH(4)) shows diverse actions on neurons. Dopamine release from the rat striatum or PC12 cells was stimulated by 6R-BH(4). The action of 6R-BH(4) was independent of its cofactor activities and stereospecific. Ca(2+) channels in rat brain and PC12 cells were activated by 6R-BH(4) via cAMP-protein kinase A pathway. Membrane potential of PC12 cells was deplorized by 6R-BH(4). Thus, it is assumed that 6R-BH(4) acts on its specific action site (possibly outside of the cell membrane) to stimulate dopamine release by activating Ca(2+) channels. Apoptosis induced by depletion of serum and nerve growth factor in PC12 cells was prevented by 6R-BH(4). The cell surviving effect of 6R-BH(4) was also mediated by activation of Ca(2+) channels and cAMP-protein kinase A pathway. However, since 6R-BH(4) did not activate mitogen activated protein kinase, it did not support neuronal differentiation. Nitric oxide (NO)-induced cell death was prevented by 6R-BH(4) in PC12 cells. NOS activity was not changed by exogenous 6R-BH(4), but NO metabolites in culture medium were decreased by 6R-BH(4). When endogenous 6R-BH(4) was reduced by inhibition of biosynthesis, cell death was induced in PC12 cells. Superoxide is observed to be generated during autoxidation of 6R-BH(4). Superoxide producing system mimicked the cell protective action of 6R-BH(4) against NO toxicity. Thus, it is considered that 6R-BH(4) protects PC12 cells against NO toxicity by generating superoxide during its autoxidation. These results raised the possibility that 6R-BH(4) is a self-protective factor against NO toxicity in NO producing neurons. Our findings indicate that 6R-BH(4) regulates neuronal activities in the brain and that 6R-BH(4) can be a promising drug for neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease.
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PMID:The role of 6R-tetrahydrobiopterin in the nervous system. 1072 82


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