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)

Angiotensin II stimulates proximal tubule acidification by activating both the Na-H antiporter and the Na-HCO3 cotransporter. The mechanism whereby angiotensin II stimulates the Na-HCO3 cotransporter was investigated in renal cortical basolateral membrane vesicles of the rabbit by measuring 22Na uptake in the presence of HCO3 and gluconate. Na-HCO3 cotransporter activity (expressed in nanomoles per milligram of protein per 3 s) was taken as the difference in 22Na uptake in the presence of HCO3 and gluconate. Angiotensin II stimulated Na-HCO3 cotransporter activity significantly (control, 1.5 +/- 0.4; angiotensin II, 3.3 +/- 0.6; P < 0.05), and this stimulation was prevented by the angiotensin II receptor antagonist DuP 753. Angiotensin II has been shown to stimulate both pertussis toxin-sensitive Gi protein and pertussis toxin-insensitive Gq protein. In the presence of pertussis toxin, angiotensin II (10(-11) M) failed to stimulate the Na-HCO3 cotransporter, suggesting a role of Gi protein in mediating this effect. In the presence of a polyclonal antibody against Gi protein, angiotensin II failed to stimulate the Na-HCO3 cotransporter (control, 1.6 +/- 0.4; angiotensin II, 3.9 +/- 0.9; angiotensin II + Gi, 1.2 +/- 0.7). Angiotensin II stimulated inositol triphosphate release, and this effect could be blocked by the phospholipase C inhibitor U73122, suggesting a role of phospholipase C or A2 in this effect of angiotensin II. In the presence of the protein kinase C inhibitor calphostin C (50 nM), angiotensin II also failed to stimulate the Na-HCO3 cotransporter. These results demonstrate that angiotensin II stimulates the renal Na-HCO3 cotransporter by interacting with a specific angiotensin II receptor and that this stimulation is mediated by the activation of Gi and Gq proteins.
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PMID:Regulation of the renal Na-HCO3 cotransporter: IV. Mechanisms of the stimulatory effect of angiotensin II. 858 87

Angiotensin II is the major effector peptide of the renin-angiotensin system. In addition to its vasoconstrictor activity, angiotensin II stimulates smooth muscle cell growth in arterial hypertension and in models of vascular injury. The angiotensin II type 1 receptor is a seven-transmembrane receptor and is responsible for virtually all the physiological actions of angiotensin II. This class of receptor signals in part through its association with heterotrimeric G proteins. A newly developed concept for guanine nucleotide protein-coupled receptors is the activation of intracellular second-messenger proteins via tyrosine phosphorylation. For instance, angiotensin II stimulates the rapid tyrosine phosphorylation and activation of phospholipase C-gamma1. Also, angiotensin II stimulates the tyrosine phosphorylation of Janus kinases. In this review, we discuss early signaling events induced by angiotensin II with an emphasis on tyrosine phosphorylation. Understanding the importance of tyrosine phosphorylation in the signaling pathways of the angiotensin II type 1 receptor may lead to new treatment modalities for cardiovascular disease.
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PMID:Importance of tyrosine phosphorylation in angiotensin II type 1 receptor signaling. 861 89

Tyrosine kinases have been implicated in vascular smooth muscle cell proliferation and contraction. Underlying mechanisms may involve C(a2+) -dependent pathways. This study assesses relationships between angiotensin II (Ang II)-stimulated phospholipase C-mediated Ca2+ transients and tyrosine kinase-dependent pathways in vascular smooth muscle cells. Intracellular free Ca2+ concentration ([Ca2+]i) was measured in primary cultured unpassaged vascular smooth muscle cells derived from mesenteric resistance vessels of Wistar-Kyoto rats with the use of fura 2 methodology. [Ca2+]i effects of Ang II (1 nmol/L) were determined in vascular smooth muscle cells in which tyrosine kinase pathways were stimulated by insulin (70 muU/mL; 0.5 nmol/L), insulin-like growth factor-I (1 ng/mL; 0.13 nmol/L), or platelet-derived growth factor-BB (1 ng/mL; 0.04 nmol/L) and in cells in which tyrosine kinase was inhibited by specific inhibitors (1 mumol/L tyrphostin A-23 and genistein). Ang II elicited a rapid and transient [Ca2+]i response (from 94 +/- 8 to 239 +/- 5.8 nmol/L). Activation of the receptor tyrosine kinase by insulin, platelet-derived growth factor, and insulin-like growth factor-I significantly reduced (P < .01) Ang II-induced [Ca2+]i to 161 +/- 7, 189 +/- 3.7, and 183 +/- 5 nmol/L, respectively. In the presence of tyrphostin A-23 and genistein, Ang II-stimulated [Ca2+]i remained persistently elevated and failed to return to basal levels. Tyrphostin A-1, the inactive tyrphostin analogue, had not significant effect on Ang II-induced [Ca2+]i. This study demonstrates that activation of tyrosine kinase pathways reduces Ang II-elicited [Ca2+]i responses, whereas tyrosine kinase inhibition prevents [Ca2+]i recovery after agonist stimulation. Interaction between tyrosine kinase- and phospholipase C-dependent signaling pathways modulates vascular smooth muscle cell [Ca2+]i responses to Ang II.
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PMID:Tyrosine kinase signaling pathways modulate angiotensin II-induced calcium ([Ca2+]i) transients in vascular smooth muscle cells. 862 Dec 2

Results presented in this study demonstrate that, in rat glomerulosa cells, fluoroaluminate (AlF4-) alone stimulates both cAMP accumulation (maximal stimulation 10-fold, ED50, 24 mM) and total inositol phosphate accumulation (maximal stimulation 12-fold, ED50 14 mM). Despite a transient accumulation of Ins(1,4,5)P3 after AlF4- stimulation, no rapid and transient intracellular calcium mobilization was observed. In contrast to angiotensin II (Ang II) or vasopressin (AVP), AlF4- induces only a slow and sustained increase in intracellular Ca2+. We demonstrate that this increase results from a Ca2+ influx mediated by cAMP-protein kinase A (PKA) pathway since preincubation with H-89, a potent PKA inhibitor, inhibits this influx. Moreover, a short preincubation (15 min at 37 degrees C) of cells with AlF4- or ACTH prevents the initial release of Ca2+ from intracellular stores induced by Ang II, but does not affect the amount of InsPs accumulated under Ang II stimulation. This rapid inhibition of Ang II action is mediated by ACTH- or AlF4(-)-stimulated cAMP production since pretreatment with H-89 leads to a complete reversal. cAMP most likely acts at the level of Ins(1,4,5)P3 receptors since an increase in intracellular cAMP blunts the calcium response induced by addition of exogenous Ins(1,4,5)P3 to permeabilized cells. These results point out that, in rat glomerulosa cells, activation of the cAMP pathway can induce a rapid desensitization of the phospholipase C pathway by acting downstream of inositol phosphate accumulation.
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PMID:Dual effects of fluoroaluminate on activation of calcium influx and inhibition of agonist-induced calcium mobilization in rat glomerulosa cells. 865 54

In cultured rat vascular smooth muscle cells, angiotensin II (Ang II) induced a rapid increase in mitogen-activated protein kinase (MAPK) activity through the Ang II type 1 receptor, which was insensitive to pertussis toxin but was abolished by the phospholipase C inhibitor, U73122. The Ang II-induced MAPK activation was not affected by the protein kinase C inhibitor, GF109203X, and was only partially impaired by pretreatment with a phorbol ester, whereas both treatments completely prevented MAPK activation by the phorbol ester. Intracellular Ca2+ chelation by TMB-8, but not extracellular Ca2+ chelation or inhibition of Ca2+ influx, abolished Ang II-induced MAPK activation. The calmodulin inhibitor, calmidazolium, and the tyrosine kinase inhibitor, genistein, completely blocked MAPK activation by Ang II as well as by the Ca2+ ionophore A23187. Ang II caused a rapid increase in the binding of GTP to p21(ras), and this was inhibited by genistein, TMB-8, and calmidazolium but not by pertussis toxin or GF109203X. These data suggest that Ang II-induced MAPK activation through the Ang II type 1 receptor could be mediated by p21(ras)activation through a currently unidentified tyrosine kinase that lies downstream of Gq-coupled Ca2+/calmodulin signals.
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PMID:Identification of an essential signaling cascade for mitogen-activated protein kinase activation by angiotensin II in cultured rat vascular smooth muscle cells. Possible requirement of Gq-mediated p21ras activation coupled to a Ca2+/calmodulin-sensitive tyrosine kinase. 866 12

1. Angiotensin II (AngII)-induced, activation of phospholipase C (PLC) and Ca2+-dependent Cl- channels is an important signal transduction pathway for the regulation of vascular smooth muscle cell (VSMC) and glomerular mesangial cell contraction and growth. While AT receptors are traditionally thought to be G-protein coupled to the beta isoform of PLC, recent evidence suggests that in some tissues AT receptors may also activate the PLC-gamma isoform via tyrosine phosphorylation. 2. By western analysis, we identified PLC-gamma1 in the above cell types. We found that within 3 min of exposure to 10(-7) mol/L AngII, tyrosine phosphorylation of PLC-gamma1 was observed; however, peak response (>3-fold increase) occurred within 0.5 min. In addition, pre-incubation of these cells with the tyrosine kinase inhibitor genistein blocked the tyrosine phosphorylation of PLC-gamma1 by AngII. In contrast, preincubation with the tyrosine phosphatase inhibitor sodium vanadate increased the levels of tyrosine phosphorylation of PLC-gamma1. Similar results were found when intracellular levels of 1,4,5-IP3 were measured after AngII exposure. 3. By using patch clamp techniques on cultured rat mesangial cells exposed to AngII, we found that the release of 1,4,5-IP3-sensitive intracellular Ca2+ stores stimulated low conductance Cl- channels. Preincubation with genistein, abolished the usual 10-fold increase in Cl- channel activity observed with AngII. 4. Therefore, we conclude that in VSMC and glomerular mesangial cells (i) AngII transiently stimulates PLC activity via tyrosine phosphorylation of the gamma1 isoenzyme, (ii) tyrosine phosphorylation of PLC-gamma1 and production of 1,4,5-IP3 in response to AngII is dramatically inhibited by tyrosine kinase inhibition and stimulated by tyrosine phosphatase inhibition, (iii) activation of Ca2+-dependent Cl- channels by AngII-induced release of 1,4,5-IP3-dependent intracellular Ca2+ stores is also abolished by tyrosine kinase inhibition. In summary, this AngII-induced signal transduction cascade provides a possible mechanism for both the contractile and growth-stimulating effects of AngII on VSMC and glomerular mesangial cells.
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PMID:Angiotensin II-induced tyrosine phosphorylation in mesangial and vascular smooth muscle cells. 871 1

Angiotensin II stimulates DNA synthesis in aortic smooth muscle cells prepared from spontaneously hypertensive rats, with maximal levels detected 20 h after stimulation. Angiotensin II receptor antagonists inhibited the angiotensin II-induced DNA synthesis. In particular, the noncompetitive antagonist 2-ethoxy-1-[[2'(1 H-tetrazol-5-yl) biphenyl-4-yl]methyl]-1 H-benzimidazole-7-carboxylic acid (CV11974) was more effective than expected from its affinity for the angiotensin II receptor and its potency for inhibiting angiotensin II-induced increase in cytosolic free Ca2+ concentration 2-n-Butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1 H-tetrazol-5-yl)biphenyl-4-yl) methyl]imidazole, potassium salt (losartan), one of the antagonists, inhibited angiotensin II-induced DNA synthesis by 92% and 79%, even when added 2 and 4 h after angiotensin II stimulation, respectively. Angiotensin II also increases the mRNA of platelet-derived growth factor-A chain and basic fibroblast growth factor. The increase was observed within 4 h after angiotensin II stimulation. In this case, the addition of losartan at 4 h after angiotensin II stimulation hardly influenced the time course of the mRNA level of growth factors. Also, conditioned media of cells stimulated with angiotensin II did not influence DNA synthesis in the presence of CV11974. These results suggest that sustained receptor stimulation with angiotensin II is required for DNA synthesis in addition to the early intracellular signaling following phospholipase C activation in a manner independent of the induction of growth factors such as platelet-derived growth factor-AA and basic fibroblast growth factor.
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PMID:A long-term receptor stimulation is requisite for angiotensin II-dependent DNA synthesis in vascular smooth muscle cells from spontaneously hypertensive rats. 871 28

Angiotensin II receptors present in cardiomyocytes, nonmyocytes (predominantly fibroblasts), nerve terminals, and the heart vasculature mediate the multiple actions of angiotensin II (AII) in the heart, including modulation of normal and pathophysiological cardiac growth. Although the cellular processes that couple AII receptors (principally the AT1 subtype) to effector responses are not completely understood, recent studies have identified an array of signal transduction pathways activated by AII in cardiac cells. These include: the stimulation of phospholipase C which results in the activation of protein kinase C and the release of calcium from intracellular stores; an enhancement of phosphaditic acid formation; the coupling to soluble tyrosine kinase phosphorylation events; the initiation of the mitogen activated protein kinase (MAPK) cascade; and the induction of the STAT (Signal Transducers and Activators of Transcription) signaling pathway. It is tempting to speculate that these latter responses, which have been previously associated with growth factor signaling pathways, are involved in AII-induced cardiac growth. Interestingly, some of these novel pathways are apparently not under the same strict control imposed upon the more classical signaling pathways. Thus, while AII-induced calcium transients are rapidly (within minutes) desensitized following exposure to AII, the MAP kinase pathway is not, and activation of the STAT pathway requires hours of agonist exposure for maximal induction. These observations support an emerging picture in which the downstream signal transduction pathways of AII receptors are initiated and terminated with a distinct temporal arrangement. This organization allows appropriate rapid responses (e.g. vascular contraction) to transient AII exposure, some of which are rapidly terminated, perhaps for protective reasons, and others not. In contrast, additional responses (e.g. growth) probably require prolonged exposure to agonist.
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PMID:Cardiac effects of AII. AT1A receptor signaling, desensitization, and internalization. 872 86

1. Angiotensin II (AII) actions are mediated by two distinct types of receptors: AT1, which includes two subtypes, AT1A and AT1B, and AT2. AII produces vasoconstriction on the vascular wall acting directly on smooth muscle cells via AT1 receptors. AII receptors have recently been demonstrated on endothelial cells. But the pharmacological characteristics of these receptors and the intracellular signal pathways coupled to them remain unclear. 2. The aim of this work was to characterize the AII receptor subtypes in rat aortic endothelial cells (RAEC) in primary culture and to evaluate the signal pathways coupled to these receptors by measuring the activation of phospholipase C (PLC) and phospholipase A2 (PLA2). 3. Labelled AII bound to RAEC in a specific, saturable manner. Scatchard analysis showed a Kd of 1.87 +/- 0.49 nM and a Bmax of 50.2 +/- 10.9 x 10(3) sites per cell. AII was displaced by the AT1-specific antagonist, DuP753 with a Ki of 17.37 +/- 1.49 nM, but not by the AT2 receptor analogues CGP42771B or PD123177. These data were confirmed by the finding of AT1 mRNA in endothelial cells. Analysis of RNA expression by RT-PCR showed the presence of both subtypes, AT1A and AT1B in endothelial cells, whereas smooth muscle cells express only AT1A. 4. The activation of PLC and PLA2 in response to AII was evaluated by measuring inositol phosphate production and arachidonic acid release, respectively. Both were enhanced by AII in a dose-dependent manner, and inhibited by DuP753, but not by PD123177. 5. We conclude that AT1 receptors are expressed by endothelial cells in primary culture and that phospholipase C and phospholipase A2 activated via this receptor.
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PMID:Angiotensin II-elicited signal transduction via AT1 receptors in endothelial cells. 873 79

In the present study we investigated the regulation of tyrosine hydroxylase (TH) by angiotensin II (Ang II) in an attempt to provide cellular and molecular evidence that this hormone has increased neuromodulatory actions in the spontaneously hypertensive (SH) rat brain. Neuronal cells in primary culture from the hypothalamus-brain stem of both normotensive [Wistar-Kyoto (WKY)] and SH rats have been used. These cultures mimic in vivo situations. Ang II caused a time-dependent increase in TH activity in WKY rat brain neurons. A maximal increase of 2.5-fold was observed with 100 nM Ang II in an actinomycin- and cycloheximide-dependent process. In addition, Ang II caused a parallel increase in TH messenger RNA (mRNA) levels, with a maximal stimulation of 5-fold in 4 h by 100 nM Ang II in WKY rat brain neurons. The stimulation of TH mRNA was mediated by the AT1 receptor subtype, resulted from an increase in its transcription, and involved activation of phospholipase C and protein kinase C. Antisense oligonucleotide for c-fos attenuated Ang II stimulation of TH mRNA in a time- and dose-dependent fashion, indicating an involvement of c-fos as a putative third messenger in Ang II stimulation of TH. Ang II also caused stimulation of TH activity and its mRNA levels in neuronal cultures of SH rat brain by a mechanism similar to that observed for neuronal cultures of WKY rat brain, involving AT1 receptors, protein kinase C, and c-fos. However, the stimulation of TH activity and that of TH mRNA were approximately 30% and 80% higher, respectively, in the SH rat brain neurons than those in the WKY rat brain neurons. In vivo experiments have been carried out to validate the elevated response of TH gene expression to Ang II in SH rat brain neuronal cultures. Ang II stimulated both TH activity and TH mRNA levels in the hypothalami and brain stems of adult WKY and SH rats. The level of stimulation in the brain of the SH rat was significantly higher than that in the WKY rat. These observations are consistent with an increase in AT1, receptor gene expression and suggest that increased TH gene expression could be the cellular/molecular basis for the greater neuromodulatory action of Ang II in the SH rat brain.
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PMID:Angiotensin II regulation of tyrosine hydroxylase gene expression in the neuronal cultures of normotensive and spontaneously hypertensive rats. 875 88


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