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:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the effect of dopamine on Na+,K(+)-ATPase activity in cultured aortic smooth muscle cells. Na+,K(+)- ATPase activity was measured by a coupled enzyme assay. Our results demonstrate that dopamine and dopamine receptor agonists, SKF-38393 (a D1 receptor agonist) and quinpirole (a D2 receptor agonist) produced 62%, 50% and 49% inhibition of Na+,K(+)-ATPase activity in aortic smooth muscle cells, respectively. The combination of the two agonists produced inhibition similar to that of dopamine. Dopamine- and the agonist-induced Na+,K(+)-ATPase inhibition was blocked by selective receptor antagonists. The Na+,K(+)-ATPase inhibition by SKF-38393 but not by quinpirole was abolished by pertussis toxin. Na+,K(+)-ATPase inhibition was also achieved by guanosine triphosphate analog GTP-gamma-S. SKF-38393 but not quinpirole stimulated phosphoinositide hydrolysis rate in rat aortic slices. SKF-38393-induced phosphoinositide hydrolysis stimulation was reversed by SCH-23390, a dopamine D1 receptor antagonist, and attenuated by pertussis toxin. In conclusion, our observations indicate that dopamine and dopamine receptor agonists inhibit Na+,K(+)-ATPase activity through specific vascular receptors. Dopamine D1 receptors are linked to pertussis toxin sensitive-mechanism(s) and a GTP-binding protein appears to be coupled to the enzyme inhibition. Finally, the inhibition of Na+,K(+)-ATPase activity in response to dopamine D1 receptor activation may be mediated by the phospholipase C signaling pathway.
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PMID:Regulation of Na+,K(+)-ATPase activity by dopamine in cultured rat aortic smooth muscle cells. 881 57

To investigate whether expression of the renal angiotensinogen gene is regulated by dopaminergic receptors, we used opossum kidney (OK 27) cells with a fusion gene containing the 5'- flanking regulatory sequence of the rat angiotensinogen gene fused with a human growth hormone (hGH) gene as a reporter [pOGH, angiotensinogen nucleotide (N) -1498/+18], permanently integrated into their genomes. The level of expression of pOGH (angiotensinogen N-1498/+18) in OK 27 was evaluated by the amount of immunoreactive hGH (ir-hGH) secreted into the culture medium. In the absence of 3-isobutyl-1-methylxanthine (IBMX), addition of dopamine (10(-13) to 10(-5)M) had minimal effect on the expression of the pOGH (angiotensinogen N-1498/+18) in OK 27 cells. In the presence of IBMX, addition of low concentrations (10(-13) and 10(-7) M) of dopamine stimulated the expression of pOGH angiotensinogen N-1498/+18) in OK 27 cells in a dose-dependent manner, whereas high concentrations (i.e., > 10(-7) M) had minimal effect. The stimulatory effect of dopamine on the expression of pOGH (angiotensinogen N-1498/+18) was inhibited by the presence of SCH-23390 (D1-dopaminergic receptor antagonist) and spiperone (D2-dopaminergic receptor antagonist), but not by ketanserin (5 HT2/5HT1c-serotonergic receptor antagonist). Moreover, the stimulatory effect of dopamine was inhibited by the presence of U-73122 (an inhibitor of phospholipase C and phospholipase A2) or staurosporine (an inhibitor of protein kinase C) or (R)-p-adenosine 3',5'-cyclic monophosphorothioate (Rp-cAMP[S]; an inhibitor of cAMP-dependent protein kinase AI and II). Addition of low concentrations (10(-13) to 10(-9)M) of SKF-82958 (D1-dopaminergic receptor agonist) or PPHT (D2-dopaminergic receptor agonist) also stimulated the expression of pOGH (angiotensinogen N-1498/+18). The stimulatory effect of SKF-82958 was inhibited by the presence of SCH-23390 or Rp-cAMP[S], whereas the effect of PPHT was inhibited by the presence of spiperone or staurosporine. These studies demonstrate that the expression of pOGH (angiotensinogen N-1498/+18) in OK 27 cells is modulated by dopaminergic receptor agonists.
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PMID:Dopaminergic receptors and angiotensinogen gene expression in opossum kidney cells. 885 71

Dopamine-induced natriuretic response which results from the activation of tubular dopamine1 (DA1) receptors is diminished in spontaneously hypertensive rats (SHR). This may be a result of alterations occurring at the receptor level and within the cellular signaling pathway which ultimately causes inhibition of Na+, K(+)-ATPase. There have been reports showing that DA1 receptor induced inhibition of Na+, K(+)-ATPase is abolished in SHR which is due to a decreased activation of PLC and PKC by dopamine. Of the mechanisms, adenylyl cyclase and phospholipase C are two known enzymes linked to DA1 receptors via G proteins. Furthermore, the involvement of phospholipase A2 (PLA2) has also been reported in this process. However, the site of defect in DA1 receptor signaling pathway in SHR is still not well understood. This report will (i) review the coupling of DA1 receptor with G proteins and their levels in Wistar Kyoto (WKY) rats and SHR and (ii) discuss studies dealing with the role of PLA2 in dopamine-induced inhibition of Na+, K(+)-ATPase in WKY rat and SHR kidneys. Fenoldopam, DA1 receptor selective agonist stimulated [35S]GTP gamma S binding in a concentration (10(-9)-10(-4) M)-dependent manner in WKY rats which was attenuated in SHR. Fenoldopam (10 microM)-induced stimulation of [35S]GTP gamma S binding was significantly reduced by a DA1 receptor selective antagonist, SCH 23390 suggesting the involvement of DA1 receptor. Furthermore, the specific antipeptides Gs alpha, and Gq/11 alpha significantly blocked fenoldopam-stimulation of [35S]GTP gamma S binding suggesting the coupling of DA1 receptor with both the G proteins. Western analysis revealed a significant decrease in Gq/11 alpha but no changes in Gs alpha in SHR compared to WKY rats. Dopamine inhibited Na+, K(+)-ATPase activity in a concentration (10(-9)-10(-5) M)-dependent manner in WKY rats while it failed to inhibit the enzyme activity in SHR. Dopamine (10 microM)-induced inhibition in Na+, K(+)-ATPase activity was significantly blocked by mepacrine (a PLA2 inhibitor) suggesting the involvement of PLA2 in dopamine-mediated inhibition of Na+, K(+)-ATPase. Arachidonic acid (AA), a PLA2 product, inhibited Na+, K(+)-ATPase in a concentration (1-100 microM)-dependent manner in WKY rats while the inhibition in SHR was significantly attenuated (IC50: 7.5 microM in WKY and 80 microM in SHR). Furthermore, lower concentration (1 microM) of AA stimulated the enzyme activity in SHR. This suggests a defect in the metabolism of AA in SHR. Proadifen (10 microM), an inhibitor of cytochrome P-450 monoxygenase (an arachidonic acid metabolizing enzyme) significantly blocked the inhibition produced by arachidonic acid in WKY rats and abolished the difference in arachidonic acid inhibition of Na+, K(+)-ATPase between WKY rats and SHR. These data suggest that (i) the reduced activation of G proteins following DA1 receptor stimulation, (ii) reduced amount of Gq/11 alpha and (iii) a defect in the AA metabolism may be responsible for the reduced dopaminergic inhibition of sodium pump activity and a diminished natriuretic response to dopamine in SHR.
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PMID:Dopamine-1 receptor G-protein coupling and the involvement of phospholipase A2 in dopamine-1 receptor mediated cellular signaling mechanisms in the proximal tubules of SHR. 902 41

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

The effects of dopamine D1 receptor agonists are often presumed to result from an activation of adenylyl cyclase, but dopamine D1 receptors may also be linked to other signal transduction cascades and the relative importance of these various pathways is currently unclear. SKF 83959 is an agonist at dopamine D1 receptors linked to phospholipase C, but has been reported to be an antagonist at receptors linked to adenylyl cyclase. The current report demonstrates that SKF 83959 induces pronounced, nonpatchy, expression of the immediate-early gene product Fos in the striatum of intact rats which can be converted to a patchy pattern by pretreatment with the dopamine D2-like receptor agonist quinpirole. In rats with unilateral 6-hydroxydopamine lesions SKF 83959 induces strong behavioral rotation and a greatly potentiated Fos response. All of the responses to SKF 83959, in both intact and dopamine-depleted animals, can be blocked by pretreatment with the dopamine D1 receptor antagonist SCH-23390. In intact subjects, SKF 83959 induced Fos expression less potently than the standard dopamine D1 receptor agonist SKF 82958, but the two drugs were approximately equipotent in deinnervated animals. These results demonstrate for the first time that possession of full efficacy at dopamine D1 receptors linked to adenylyl cyclase is not a necessary requirement for the induction of striatal Fos expression in intact animals and suggest that alternative signal transduction pathways may play a role in dopamine agonist induced Fos expression, especially in dopamine-depleted subjects.
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PMID:The atypical dopamine D1 receptor agonist SKF 83959 induces striatal Fos expression in rats. 1632 97

Though orofacial movements are fundamental motor patterns that are known to be regulated critically by D1-like dopamine receptors, these processes remain poorly understood. This uncertainty is heightened by evidence for putative D1-like receptors that are linked not only to adenylyl cyclase (AC) but also to phospholipase C (PLC). Using a new method, we have characterised four topographies of orofacial movement in the mouse using the novel D1-like agonist SKF 83822, which stimulates AC but not PLC. These were compared with responses to SKF 83959, which stimulates PLC but not AC. Also, effects were characterised using the D1-like antagonist SCH 23390 and the D2-like antagonist YM 09151-2. SKF 83822 induced vertical jaw movements with incisor chattering but inhibited horizontal jaw movements; there was little effect on tongue protrusions. Vertical jaw movements induced by SKF 83822 were inhibited by SCH 23390 but uninfluenced by YM 09151-2, while YM 09151-2 released horizontal jaw movements; thus, D1-like agonist-induced, AC-mediated vertical jaw movements constitute a 'pure' D1-like-dependent process that does not involve D1-like:D2-like interactions, while horizontal jaw movements involve oppositional interactions. Orofacial movements in mice appear to consist of at least four phenomenologically dissociable topographies that are mechanistically distinct. They are regulated differentially by AC- and/or PLC-dependent processes and these processes involve distinct D1-like:D2-like interactions.
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PMID:Differential involvement of cyclase- versus non-cyclase-coupled D1-like dopamine receptors in orofacial movement topography in mice: studies with SKF 83822. 1723 42

Classical agonists of the dopamine D1 receptor activate both adenylyl cyclase and phospholipase C (PLC) signaling pathways. As a result, the extent to which these two pathways are essentially involved in various effects produced by D1 receptor agonists is currently uncertain. In the present report we examined the effects of SKF 83822, a dopamine D1 agonist which has been reported to activate adenylyl cyclase, but not PLC, on behavior and immediate early gene (IEG) expression in rats with unilateral 6-hydroxydopamine lesions. SKF 83822 (25-100 microg/kg) induced dose dependent contralateral rotation in these subjects, and, additionally, stimulated strong expression of the IEG products c-Fos, Fra2, Zif/268 and Arc in the deinnervated striatum. All of these effects could be antagonized by pretreatment with the selective D1 dopamine antagonist SCH 23390 (0.5 mg/kg). Although PLC may be involved in many effects mediated through dopamine D1 receptors, these results suggest that direct activation of PLC is not necessary for the induction of either rotation or IEG expression in dopamine depleted rats.
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PMID:Rotation and immediate-early gene expression in rats treated with the atypical D1 dopamine agonist SKF 83822. 1730 71

Although adenosine exerts cardio-and vasculoprotective effects, the roles and signaling mechanisms of different adenosine receptors in mediating skeletal muscle protection are not well understood. We used a mouse hindlimb ischemia-reperfusion model to delineate the function of three adenosine receptor subtypes. Adenosine A(3) receptor-selective agonist 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IBMECA; 0.07 mg/kg ip) reduced skeletal muscle injury with a significant decrease in both Evans blue dye staining (5.4 +/- 2.6%, n = 8 mice vs. vehicle-treated 28 +/- 6%, n = 7 mice, P < 0.05) and serum creatine kinase level (1,840 +/- 910 U/l, n = 13 vs. vehicle-treated 12,600 +/- 3,300 U/l, n = 14, P < 0.05), an effect that was selectively blocked by an A(3) receptor antagonist 3-ethyl-5-benzyl-2-methyl-6-phenyl-4-phenylethynyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS-1191; 0.05 mg/kg). The adenosine A(1) receptor agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA; 0.05 mg/kg) also exerted a cytoprotective effect, which was selectively blocked by the A(1) antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.2 mg/kg). The adenosine A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680; 0.07 mg/kg)-induced decrease in skeletal muscle injury was selectively blocked by the A(2A) antagonist 2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e] [1,2,4]triazolo[1,5-C]pyrimidin-5-amine (SCH-442416; 0.017 mg/kg). The protection induced by the A(3) receptor was abrogated in phospholipase C-beta2/beta3 null mice, but the protection mediated by the A(1) or A(2A) receptor remained unaffected in these animals. The adenosine A(3) receptor is a novel cytoprotective receptor that signals selectively via phospholipase C-beta and represents a new target for ameliorating skeletal muscle injury.
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PMID:Protective roles of adenosine A1, A2A, and A3 receptors in skeletal muscle ischemia and reperfusion injury. 1792 28

Nicotinic mechanisms acting on the hippocampus influence attention, learning, and memory and constitute a significant therapeutic target for many neurodegenerative, neurological, and psychiatric disorders. Here, we report that brain-derived neurotrophic factor (BDNF) (1-100 ng/ml), a member of the neurotrophin gene family, rapidly decreases alpha7 nicotinic acetylcholine receptor responses in interneurons of the hippocampal CA1 stratum radiatum. Such effect is dependent on the activation of the TrkB receptor and involves the actin cytoskeleton; noteworthy, it is compromised when the extracellular levels of the endogenous neuromodulator adenosine are reduced with adenosine deaminase (1 U/ml) or when adenosine A(2A) receptors are blocked with SCH 58261 (2-(2-furanyl)-7-(2-phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine) (100 nm). The intracellular application of U73122 (1-[6[[(17beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione) (5 mum), a broad-spectrum inhibitor of phospholipase C, or GF 109203X (bisindolylmaleimide I) (2 mum), a general inhibitor of protein kinase C isoforms, blocks BDNF-induced inhibition of alpha7 nicotinic acetylcholine receptor function. Moreover, in conditions of simultaneous intracellular dialysis of the fast Ca(2+) chelator BAPTA (10 mm) and removal of extracellular Ca(2+) ions, the inhibitory action of BDNF is further prevented. The present findings disclose a novel target for rapid actions of BDNF that might play important roles on synaptic transmission and plasticity in the brain.
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PMID:Postsynaptic action of brain-derived neurotrophic factor attenuates alpha7 nicotinic acetylcholine receptor-mediated responses in hippocampal interneurons. 1849 95

Activity-induced elevation of extracellular purines and pyrimidines has been associated with autocrine and paracrine signaling in many tissues. Here we investigate the effect of purinergic signaling for the excitability and contractility of depolarized skeletal muscle. Muscle excitability was experimentally depressed by elevating the extracellular K(+) from 4 to 10 mM, which reduced the tetanic force to 24 +/- 2% of the force at 4 mM K(+). Upon addition of 1 mM ATP, however, the force recovered to 65 +/- 8% of the control force (P < 0.001, n = 5). A similar recovery was seen with ADP, but not with UTP or adenosine. The ATP-induced force recovery could be inhibited by P2Y(1) receptor antagonists (3 muM SCH-202676 or 1 muM MRS-2500). A fourfold increase in M-wave area demonstrated that the ATP-induced force recovery was associated with restoration of muscle excitability (P < 0.05, n = 4). Experiments using (86)Rb(+) as a tracer for K(+) showed that ATP also induced a twofold increase in the activity of muscle Na(+)-K(+) pumps. The force recovery and the stimulation of the Na(+)-K(+) pump activity by ATP were inhibited by 50 muM of the phospholipase C inhibitor U-73122. It is concluded that purinergic signaling can increase the Na(+)-K(+) pump activity and improve force and excitability of depolarized skeletal muscles. This novel purinergic regulation may be important for the maintenance of muscle excitability during intense exercise, where the extracellular K(+) can increase substantially.
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PMID:Effect of purinergic receptor activation on Na+-K+ pump activity, excitability, and function in depolarized skeletal muscle. 2045 38


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