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 (Ang II) causes a rapid induction of immediate-early genes and hypertrophy in the cardiac myocyte. However, the signaling mechanism of Ang II-induced immediate-early gene expression in cardiac myocytes has not been characterized. Therefore, we examined signal transduction of Ang II in neonatal rat cardiac myocytes, using c-fos gene expression as a model system. Transient transfection of c-fos reporter gene constructs indicated that the serum response element is not only required but also sufficient for Ang II-induced activation of the c-fos promoter. Ang II is known to cause an increase in [Ca2+]i. We found that Ang II also causes a small increase in cAMP in cardiac myocytes. However, the Ca2+/cAMP response element of the c-fos gene was not sufficient to confer Ang II responsiveness to the c-fos promoter, and inhibitors of protein kinase A had no effects on Ang II-induced c-fos expression. On the other hand, chelating intracellular Ca2+ with BAPTA-AM inhibited Ang II-induced c-fos expression in a dose-dependent manner, suggesting that Ca2+ is required for Ang II-induced signaling. Measurements of phospholipid-derived second messengers revealed that Ang II increased production of inositol trisphosphate, diacylglycerol, phosphatidic acid, and arachidonic acids, resulting in a sustained increase in protein kinase C activity. This and other evidence suggest that Ang II activates phospholipase C, phospholipase D, and possibly phospholipase A2. All of these second-messenger systems are activated through the AT1 receptor. Pharmacological inhibition of phospholipase C or downregulation of protein kinase C significantly suppressed Ang II-induced c-fos expression. In conclusion, Ang II activates multiple phospholipid-derived second-messenger systems via the AT1 receptor in cardiac myocytes. Among these second-messenger systems, phospholipase C and protein kinase C seem essential for Ang II-induced c-fos gene expression, whereas Ca2+ may play a permissive role. Finally, the "Ang II response element" of the c-fos gene maps to the protein kinase C-dependent portion of the serum response element.
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PMID:Signal transduction pathways of angiotensin II--induced c-fos gene expression in cardiac myocytes in vitro. Roles of phospholipid-derived second messengers. 834 87

The vascular angiotensin (A) II receptor cDNA (AT1a) was transfected into Chinese hamster ovary (CHO) cells to generate the stable cell line CHO-AT1a. This cell line was used to investigate the binding and signal transduction properties of the cloned vascular AT1 receptor. Specific binding of sarcosine1(-)[125I]tyrosine4-isoleucine8-AII ([125I]SI-AII) to CHO-AT1a membranes reached equilibrium after 1 h at 25 degrees C and was consistently greater than 95% of total binding. Saturation binding analyses demonstrated [125I]SI-AII bound to a saturable population of sites on membranes with an equilibrium dissociation constant (KD) of 0.7 nM and a binding site maximum of 1.2 pmol/mg protein. [125I]SI-AII binding to CHO cells was inhibited by the following compounds with a rank order of potency of SI-AII > AII > losartan > AI >> PD 123,177. AII (1 microM) treatment of CHO-AT1a cells caused an increase in inositol phosphates and intracellular calcium relative to basal levels. These responses were blocked by losartan but not by PD 123,177. AII (1 microM) did not effect adenylate cyclase activity in CHO-AT1a cells, whereas the agonist inhibited adenylate cyclase activity in rat liver cell membranes. These effects were blocked by 10 microM losartan. These results indicate that CHO-AT1a cells express functional AT1a receptors which stimulate phospholipase C activity but not adenylate cyclase activity. CHO-AT1a cells should provide a useful model for studies of AT1a receptor domains which are critical to signaling pathways.
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PMID:Binding and signal transduction of the cloned vascular angiotensin II (AT1a) receptor cDNA stably expressed in Chinese hamster ovary cells. 846 68

Recent evidence suggests that there are two classes of receptors for angiotensin II (AngII), AT1 which is sensitive to losartan (DuP753) and is G-protein coupled, and AT2 which is sensitive to both PD123319 and CGP42112A, and is non-G-protein coupled. In rat mesangial cells two subtypes of AT1 receptor could be distinguished, AT1A subtype is more sensitive to losartan whereas AT1B subtype is more sensitive to PD123319, but insensitive to CGP42112A. The present studies were designed to ascertain which receptor subtype mediates three AngII-induced physiologic functions in rat mesangial cells namely intracellular Ca2+ mobilization, adenylyl cyclase inhibition and protein synthesis as monitored via [3H]leucine incorporation. The rank order of potency for inhibition of AngII-induced [Ca(2+)]i mobilization and adenylyl cyclase regulation was PD123319 > or = losartan > CGP42112A. By contrast, losartan was quite effective at inhibiting protein synthesis (IC50 = 8 nM) while PD123319 was without effect. These findings are consistent with AngII mediated signal transduction through AT1A and AT1B sites for phospholipase C mediated [Ca(2+)]i mobilization and inhibition of adenylyl cyclase. On the other hand, AT1A receptors appear to exclusively mediate AngII-induced protein synthesis. These observations underscore the complexity of AngII mediated signal transduction in glomerular mesangium.
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PMID:Signal transduction mediated by angiotensin II receptor subtypes expressed in rat renal mesangial cells. 846 70

The adequate biological function of the renin-angiotensin system in blood pressure regulation and volume control involves additional factors for a fully balanced response. This includes arachidonic acid-derived lipid mediators, the eicosanoids. Angiotensin II (Ang II) causes (AT1)-receptor mediated stimulation of phospholipase C, resulting in generation of IP3 (inositol triphosphate) and activation of protein kinase C, elevated cytosolic Ca+ and stimulation phospholipase A2. These processes culminate in the generation of cell-specific eicosanoids and their autocrine action on the generating cell or paracrine effects on cells in the vicinity. In vascular tissue, liberated arachidonic acid is mainly converted into vasodilator prostaglandins, i.e. prostacyclin (PGI2) and PGE2. These prostaglandins may attenuate any direct Ang II-induced vasoconstriction, lower systemic vascular resistance and stimulate renal sodium excretion. In some vessels, arachidonic acid released by Ang II may also be converted to vasoconstrictor eicosanoids, i.e. thromboxane A2, PGF2 alpha and 12-HETE. The biological significance of endogenous eicosanoid generation becomes evident if vasoactive eicosanoids become limiting factors for maintaining homoiostasis, i.e. in the fetal circulation, Bartter's syndrome and congestive heart failure where vasodilating eicosanoids (PGE2, PGI2) are involved in maintenance of low vascular resistance and reduced or absent vasoconstriction by Ang II. Vasoconstrictor eicosanoids (thromboxane A2, PGF2 alpha, 12-HETE) contribute to high blood pressure in (renovascular) hypertension and pregnancy-induced hypertension. Alternatively, generation of vasodilator prostaglandins may be reduced in these situations. The vascular renin-angiotensin system is subject to the action of a number of drugs and chemicals, most notably specific inhibitors of the angiotensin-converging enzyme and drugs affecting kidney function (furosemide) and/or vessel tone (propranolol).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prostaglandin-mediated actions of the renin-angiotensin system. 849 70

The relative contributions of Ca2+ influx and intracellular Ca2+ mobilization were examined for angiotensin II-stimulated [3H]phorbol 12,13-dibutyrate binding, which reflects the level of activated protein kinase C in bovine chromaffin cells. Angiotensin II receptors activate phospholipase C in chromaffin cells, leading to a short-lived mobilization of intracellular Ca2+. Angiotensin II-stimulated [3H]phorbol 12,13-dibutyrate binding was largely blocked in Ca(2+)-free buffer and by pretreatment with the Ca(2+)-channel blocker omega-conotoxin GVIA. The [3H]phorbol 12,13-dibutyrate binding response to [Sar1]angiotensin II also appeared to be voltage sensitive, as no additivity was observed with the response to the depolarizing agent 4-aminopyridine (3 mM). Threshold sensitivities of the extra- and intracellular Ca(2+)-mobilizing pathways to angiotensin II were similar, and all examined effects of angiotensin II in these cells were apparently mediated by losartan-sensitive (AT1-like) receptors. The dependence of angiotensin II-stimulated [3H]phorbol 12,13-dibutyrate binding on extracellular Ca2+ entry, in contrast to stimulation by other phospholipase C-linked receptor agonists (bradykinin and methacholine), suggests that angiotensin II preferentially stimulates protein kinase C translocation to the plasma membrane, rather than to internal membranes, in bovine adrenal medullary cells.
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PMID:Role of omega-conotoxin GVIA-sensitive Ca2+ entry in angiotensin II-stimulated [3H]phorbol 12,13-dibutyrate binding in bovine adrenal medullary cells. 851 89

Cardiac fibroblasts appear to be important in producing and maintaining the extracellular matrix (ECM) of the heart. The abnormal proliferation of cardiac fibroblasts and deposition of the ECM protein, collagen, associated with hypertension and myocardial infarction, may adversely affect the performance of the heart. Several groups of factors affect collagen gene expression and/or growth of cardiac fibroblasts. Angiotensin II, aldosterone and endothelins play a central role in the remodeling of the ECM in hypertension, and decrease collagenase activity and/or increase collagen synthesis in cultured cells. Regulatory peptides that are generally elevated at sites of injury, such as TGF-beta 1 and PDGF, increase collagen synthesis and/or stimulate mitogenesis. Mechanical stretch enhances collagen expression and cell proliferation, responses which could in part be due to integrin activation. Cytokines may stimulate or inhibit cell growth, the latter through prostaglandin formation. Angiotensin II is a principal determinant in vivo of cardiac fibroplasia and synthesis of the ECM proteins, collagen and fibronectin. Cardiac fibroblasts possess G-protein-coupled AT1 receptors for angiotensin II that couple to activation of multiple signalling pathways, including: phospholipase C-beta, with the subsequent release of Ca2+ from intracellular stores and activation of protein kinase C, mitogen-activated protein kinases, tyrosine kinases, phospholipase D, phosphatidic acid formation, and the STAT family of transcription factors. Cardiac fibroblasts respond to angiotensin II with hyperplastic/hypertrophic growth, and increased expression of collagen, fibronectin, and integrins. The mechanisms by which the AT1 receptor activates multiple signalling pathways are not known, although the receptor might interact at some level with both integrins and cytokine receptors. Different signalling pathways of the AT1 receptor may subserve different cellular responses, such as mitogenesis, ECM synthesis, or an inflammatory/stress response. Crosstalk among the signalling pathways of the AT1 receptor, and those of G-protein, cytokine, and growth-factor receptors, may determine the ultimate response of the cell.
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PMID:Molecular signalling mechanisms controlling growth and function of cardiac fibroblasts. 857 2

The peptide hormones angiotensin II and vasopressin play a major role in water and electrolyte homeostasis. These peptides act on membrane bound receptors, which all belong to the large family of G protein coupled receptors. The receptors for angiotensin II are divided into 2 groups: the AT1 receptors, which are responsible for transducing the majority if not all actions of angiotensin II. The primary structure of this receptor has been identified by molecular cloning of the cDNA in many species and is represented by two isoforms (AT1A and AT1B) in rodent. This receptor is specifically coupled to a G protein of the Gq family, which activates a phospholipase C producing two second messengers involved in protein phosphorylation and calcium mobilization. The sequences or amino-acids involved in the binding site of peptidic agonists or non peptidic antagonists and in receptor activation and G protein coupling have been identified; the AT2 receptor primary sequence has also been identified, but the physiological role and the signaling mechanisms of this receptor are still unknown. The vasopressin receptors can be divided in three classes depending on their pharmacological properties, their tissular distribution and their coupling mechanisms. The primary structure of all 3 types of receptors has been elucidated. The V1a receptor is ubiquitous and transduces the vasoconstrictive effect of vasopressin by activating a phospholipase C, like the AT1 receptors; the V2 receptor is involved in water reabsorption in the kidney and is coupled to a GS protein activating an adenylyl cyclase; the V3 or V1b receptor is expressed in the pituitary, where it regulates the ACTH secretion, via the activation of a phospholipase C. These two family of G protein coupled receptors illustrate the structural and functional diversity of the receptors for peptidic hormones.
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PMID:[Comparative study of the structure and molecular functions of angiotensin II and vasopressin receptors]. 859 Feb 17

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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