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)

Dopamine and the D1 receptor agonist SKF 38393 activate the phospholipase C-mediated hydrolysis of phosphoinositides in brain slices. This action is selectively inhibited by SCH-23390, thus suggesting its mediation through the dopamine D1 receptor. To determine if the dopamine receptor that mediates phosphoinositide hydrolysis is the adenylyl cyclase-linked D1 receptor or a different subtype of the dopamine D1 receptor, 20 benzazepine compounds that were previously characterized as selective dopamine D1 receptor agonists were tested for stimulation of phosphoinositide hydrolysis in rat striatal slices and for activation of adenylyl cyclase in rat striatal membranes. The compounds displayed a range of potencies and efficacies in stimulating adenylyl cyclase or phosphoinositide hydrolysis. Compounds such as SKF 81427 and SKF 38393 were as efficacious as dopamine in stimulating phosphoinositide hydrolysis, whereas other compounds, including SKF 85174 and SKF 86284, although showing high efficacy in stimulating cyclic AMP, failed to stimulate inositol phosphate formation. There was no correlation between the potencies (r = 0.016; p > 0.95) or efficacies (r = -0.294; p > 0.24) of the tested compounds in stimulating cyclic AMP formation and phosphoinositide hydrolysis. These observations indicate that the D1-like dopamine receptor that mediates phosphoinositide hydrolysis is pharmacologically distinct from the classic D1 receptor that is coupled to stimulation of cyclic AMP formation.
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PMID:Evidence for a distinct D1-like dopamine receptor that couples to activation of phosphoinositide metabolism in brain. 790 49

Dopamine receptors of D2 type present on lactotroph cells are coupled to a large series of transduction mechanisms. Beside their negative coupling with adenylate cyclase, they are also coupled with potassium and calcium channels, leading to a decreased intracellular calcium concentration. In addition, D2 dopamine receptors also modulate phospholipase activities. Dopamine inhibits inositol phosphate production, through two distinct mechanisms. One of them could represent a direct negative coupling with phospholipase C. All these transduction mechanisms of the D2 dopamine receptors implicate G proteins sensitive to pertussis toxin. In contrast, these receptors are negatively coupled to phospholipase A2 through G proteins insensitive to this toxin. Both isoforms of the D2 dopamine receptor, generated by alternate splicing of a single gene are present in lactotroph cells. After transfection in CH4C1 cells the two isoforms are coupled with adenylate cyclase while only the shortest isoform appears negatively coupled to phospholipase C. Functional D2 dopamine receptors are present in human prolactinomas. Resistance to bromocriptine therapy is associated with a decrease density of these receptors in the tumor. In addition, the ratio of the two receptor isoforms (measured by PCR) is different in responsive and resistant tumors. Furthermore, the activity of Gi/Go proteins coupled to adenylate cyclase appears also affected in resistant tumors. Resistance to bromocriptine therapy appears thus to involve multiple changes at the different levels of the multiple mechanisms of action of dopamine on lactotroph cells.
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PMID:[Membrane receptors and coupling proteins in adenohypophyseal cells]. 824 19

In the present study, we examined the effects of dopamine and angiotensin II (ANG II) in renal brush-border membrane (BBM). With isolated BBM vesicles, dopamine (> 10(-4) M) directly inhibited BBM 22Na+ uptake and activated phospholipase C (PLC). These effects were mimicked by DA1 agonist but not DA2 agonist and were prevented by DA1 antagonist but not DA2 antagonist, indicating the involvement of DA1 receptors. In contrast to dopamine, ANG II directly stimulated BBM 22Na+ uptake and activated BBM phospholipase A2 (PLA2). Neither dopamine nor ANG II altered BBM adenosine 3',5'-cyclic monophosphate content. In the presence of dopamine, ANG II failed to stimulate BBM Na+ uptake and PLA2. However, both DA1 and DA2 agonists similarly abrogated the actions of ANG II, and both DA1 and DA2 antagonists were required to restore ANG II actions in the presence of dopamine, indicating the involvement of both DA1 and DA2 receptors in the antagonistic effect of dopamine. Dopamine, as well as DA1 or DA2 agonists, also lowered 125I-ANG II BBM binding. In summary, these results show that, in renal BBM, dopamine impedes ANG II receptor binding and antagonizes the stimulatory effects of ANG II on Na+ uptake and PLA2. This occurred through both DA1 and DA2 receptors and independent of DA1 effects on BBM Na+ uptake or PLC.
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PMID:Dopamine antagonizes the actions of angiotensin II in renal brush-border membrane. 838 74

We have previously reported that dopamine-1 receptor-mediated activation of phospholipase C is diminished in renal cortical slices of adult spontaneously hypertensive rats. To determine the potential consequences of this phenomenon, we performed the present studies in which renal proximal tubule suspensions obtained from spontaneously hypertensive and Wistar-Kyoto rats of 10-12 weeks of age were used. The tubule suspensions were incubated with dopamine in the presence or absence of dopamine receptor antagonists, and sodium, potassium adenosine trisphosphatase (sodium pump) activity was measured as the ouabain-sensitive adenosine trisphosphate hydrolysis. We found that dopamine produced a concentration-related inhibition of sodium pump activity in the normotensive rats but not in the hypertensive rats. Dopamine-induced inhibition of sodium pump activity in the normotensive rats was abolished by the phospholipase C inhibitor U-73122 or the protein kinase C inhibitor sphingosine, suggesting the involvement of a phospholipase C-coupled protein kinase C pathway in this response. Dopamine-induced inhibition in the normotensive rats was attenuated by the dopamine-1 receptor antagonist SCH 23390 but not by the dopamine-2 receptor antagonist domperidone. To identify possible sites of defect in dopamine-1 receptor-coupled signaling pathways in the hypertensive rats, we incubated the proximal tubules with phorbol 12,13-dibutyrate or the synthetic diacylglycerol analogue 1-oleoyl-2-acetyl-rac-glycerol. The results showed that both compounds inhibited sodium pump activity as effectively in the hypertensive as in the normotensive rats, suggesting that the protein kinase C-coupled sodium pump pathway was not defective in the hypertensive animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dopamine fails to inhibit renal tubular sodium pump in hypertensive rats. 838 2

Table I summarizes the properties of all of the dopamine receptors that have been cloned to date. Thus far, five different genes encoding pharmacologically distinct receptors have been identified and isolated. Based on their structural, pharmacological, and functional similarities, two of these, D1A and D1B (or D1 and D5), comprise the D1 subfamily. D2, D3, and D4 receptors represent a D2 subfamily whose members are also structurally and pharmacologically similar. In fact, given these considerations, it has been suggested that the D2, D3, and D4 receptors be termed the D2A, D2B, and D2C receptors, respectively, in recognition of their D2-like properties. Given the unexpected heterogeneity of the dopaminergic receptor system, it is logical to ask if there are other dopamine receptor subtypes remaining be identified. This seems probable, as the characteristics of the cloned subtypes do not match all of the properties of some dopamine receptors which have been previously investigated. For instance, there is extensive evidence that "D1-like" dopamine receptors exist which are linked to the activation of phospholipase C, phosphatidylinositol turnover, and Ca2+ mobilization. Dopamine, as well as several "D1-selective" agonists, has been shown to stimulate phosphatidylinositol turnover in both brain slices and kidney membranes (Felder et al., 1989; Undie and Friedman, 1990; Vyas et al., 1992), and injection of striatal mRNA into Xenopus oocytes leads to dopamine-stimulated phosphatidylinositol turnover and Ca2+ mobilization (Mahan et al., 1990). These dopamine receptors might be analogous to the alpha 1-adrenergic receptors which stimulate phospholipase C activity and might define a third distinct subfamily of dopamine receptors. There is also evidence for additional members of the D2 subfamily of receptors. Using gene transfer methods, a receptor with D2-like pharmacology has been identified and expressed but not yet sequenced (Todd et al., 1989). Also, a D2-related receptor has been characterized in kidney inner medulla membranes (Huo et al., 1991). It thus appears that there may be more dopamine receptor subtypes yet to be discovered.
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PMID:Molecular neurobiology of dopaminergic receptors. 846 63

Dopamine is an endogenous catecholamine which exerts its actions by occupancy of specific receptors. Dopamine receptors are classified into two main groups: the two cloned D1-like receptors (D1A and D1B in rats; D1B is also known as D5 in humans) are linked to stimulation of adenylyl cyclase, while the three cloned D2-like receptors (D2 or D2A, D3 or D2B, D4 or D2C) are linked to inhibition of adenylyl cyclase. All these dopamine receptors originally cloned from the brain are expressed in tissues outside the central nervous system including the kidney. Dopamine regulates many cellular activities, including transmembrane ion transport. Activation of D1-like receptor decreases sodium transport by cAMP dependent and cAMP independent mechanisms. Dopamine, via D1-like receptors, may inhibit Na+/H+ exchange activity in renal brush border membranes by a cAMP independent/Gs alpha-linked mechanism. Another cAMP independent pathway of sodium transport inhibition is mediated by phospholipase C, which has several isoforms (PLC beta, PLC gamma, and PLC delta with several members in each). Catecholamines stimulate expression and activity of phospholipase C isoforms in a concentration, time, and receptor-dependent as well as regional and subcellular compartmental-specific manner. In renal cortical membranes, intrarenal administration of norepinephrine for 3-4 h increases PLC beta expression and activity but has no effect on PLC gamma activity. In contrast, intrarenal administration of a D1 agonist for 3-4 h increases PLC beta 1 but decreases PLC gamma expression and activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dopamine D1 receptor regulation of phospholipase C. 852 72

Renal proximal tubular Na,K-ATPase plays an important role in the maintenance of sodium homeostasis and it is known that dopamine (DA) exerts an inhibitory effect on the activity of this enzyme. We have found that DA-induced inhibition of Na,K-ATPase is abolished in the spontaneously hypertensive rats (SHR) in comparison with age-matched Wistar-Kyoto (WKY) rats. Dopamine inhibits Na,K-ATPase via phospholipase C coupled protein kinase C pathway. The enzyme protein kinase C subsequently causes inhibition of Na,K-ATPase. In the SHR, DA-induced activation of phospholipase C is diminished, which in turn is responsible for the abolished inhibition of Na,K-ATPase. We have now shown that DA-induced activation of protein kinase C, which results from activation of DA-1 receptors is also abolished in the SHR which would account for the failure of DA to inhibit Na,K-ATPase in the hypertensive animals. Recently, we have examined the possibility that the failure of DA to inhibit Na,K-ATPase activity may be related to abnormal expression of DA receptors. In radioligand binding studies with [3H] SCH 23390 as a DA-1 receptor ligand and [3H] spiroperidol as a DA-2 receptor ligand we showed that both [3H] SCH 23390 and [3H] spiroperidol bindings are best fit to one site model in either WKY or SHR. Both Bmax and KD of either ligand binding to proximal tubule in the SHR were not statistically different from their WKY counterparts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dopaminergic modulation of Na,K-ATPase activity in the proximal tubules of normotensive and hypertensive rats. 852 73

We investigated the effect of dopamine on the vascular Na+-pump activity in isolated rat tail artery sections. Effect of dopamine on vascular tone was also assessed using a perfused tail artery preparation. Dopamine inhibited the Na+-pump activity in isolated rat tail arteries in a dose-dependent manner. Both SKF-38393 HCl, a selective dopamine D1 receptor agonist, and quinpirole HCl, a selective dopamine D2 receptor agonist inhibited the Na+-pump activity. The inhibition of the Na+-pump activity. The inhibition of the Na+-pump by dopamine was accompanied with a transient increase in the vascular tone. SKF-38393, but not quinpirole produced a sustained increase in the vascular tone. Tissues preincubated simultaneously with SCH-23390 HCl, a selective dopamine D1 receptor antagonist, and sulpiride, a selective dopamine D2 receptor antagonist, prevented the dopamine inhibition of the Na+-pump activity. Pertussis toxin blocked the Na+-pump inhibition produced by the dopamine D1 receptor agonist but not by the dopamine D2 agonist. Similarly, the dopamine D1 receptor but not dopamine D2 agonist increased the rate of phosphoinositide hydrolysis in rat tail artery sections. Our results indicate that dopamine inhibition of the Na+-pump is mediated by a pertussis toxin-sensitive mechanism and may be coupled to the activation of the phospholipase C system in rat tail arteries. The modulation of the Na+-pump by dopamine may contribute to the vascular tone.
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PMID:Regulation of Na(+)-pump activity by dopamine in rat tail arteries. 866 11

To evaluate further the signal transduction mechanisms involved in the short-term modulation of Na-K-ATPase activity in the mammalian kidney, we examined the role of phospholipase C-protein kinase C (PLC-PKC) pathway and of various eicosanoids in this process, using microdissected rat proximal convoluted tubules. Dopamine (DA) and parathyroid hormone (either synthetic PTH1-34 or PTH3-34) inhibited Na-K-ATPase activity in dose-dependent manner; this effect was reproduced by PKC530-558 fragment and blocked by the specific PKC inhibitor calphostin C, as well as by the PLC inhibitors neomycin and U-73122. Pump inhibition by DA, PTH, or arachidonic acid, and by PKC activators phorbol dibutyrate (PDBu) or dioctanoyl glycerol (DiC8) was abolished by ethoxyresorufin, an inhibitor of the cytochrome P450-dependent monooxygenase pathway, but was unaffected by indomethacin or nordihydroguaiaretic acid, inhibitors of the cyclooxygenase and lipoxygenase pathways of the arachidonic acid cascade, respectively. Furthermore, each of the three monooxygenase products tested (20-HETE, 12(R)-HETE, or 11,12-DHT) caused a dose-dependent inhibition of the pump. The effect of DA, PTH, PDBu or DiC8, as well as that of 20-HETE was not altered when sodium entry was blocked with the amiloride analog ethylisopropyl amiloride or increased with nystatin. We conclude that short-term regulation of proximal tubule Na-K-ATPase activity by dopamine and parathyroid hormone occurs via the PLC-PKC signal transduction pathway and is mediated by cytochrome P450-dependent monooxygenase products of arachidonic acid metabolism, which may interact with the pump rather than alter sodium access to it.
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PMID:Regulation of Na-K-ATPase activity in the proximal tubule: role of the protein kinase C pathway and of eicosanoids. 867 85

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


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