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)

To examine whether the subpopulation of the rat type 1 angiotensin II (AII) receptor (AT1A) couples with a single or multiple signal transduction pathways, we constructed Chinese hamster ovary (CHO) cell lines producing the recombinant receptor. The expressed AT1A receptor exhibits typical pharmacological characteristics of the AT1 receptor, known to mediate the main physiological function of AII. Addition of AII to the CHO cells induced a rapid, transient increase in intracellular free Ca2+ concentrations ([Ca2+]i) followed by a lower, sustained phase. Nicardipine, a blocker of voltage-dependent L-type Ca2+ channels, attenuated the transient [Ca2+]i response and abolished the sustained phase. The transient phase was also reduced dose-dependently by the phospholipase C inhibitor neomycin. Furthermore, AII inhibited forskolin-evoked cAMP accumulation. These data suggest, although another subpopulation named AT1B is present, that the rat AT1A receptor can independently couple with all three signal transduction pathways known to be induced by AII: i.e., i) activation of phospholipase C resulting in InsP3 generation with a subsequent release of intracellularly stored Ca2+, ii) activation of dihydropyridine-sensitive voltage-dependent Ca2+ channels, and iii) inhibition of adenylate cyclase activity.
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PMID:The rat angiotensin II AT1A receptor couples with three different signal transduction pathways. 137 99

With the development of subtype specific angiotensin II (Ang II) receptor antagonists and their introduction into the treatment of heart failure and hypertension, the regulation of the Ang II receptor with its subtypes AT1 and Ang T2 gains clinical importance. In cell cultures, the number of surface AT1 is clearly down-regulated by Ang II exposure. Down-regulation can be due to reversible internalization, to phosphorylation and to reduced synthesis and involves protein kinase C and phospholipase C mediated pathways. In this respect, the AT1 behaves as a typical G-protein coupled receptor. Aldosterone, cAMP, norepinephrine and extracellular glucose concentrations can contribute to AT1 regulation. There are very few data regarding the regulation of the subtype AT2, indicating modulation by a number of growth factors and by Ang II. In whole animal models receptor regulation deviates partially from cell cultures. In the rat, the two subtypes AT1A and AT1B are differentially regulated and the expression of subtypes is organ specific. In most experiments, including our own experiences, the AT1, in the adrenals was up-regulated by Ang II infusion and down-regulated by angiotensin converting enzyme inhibitors (ACEI) or Ang II receptor antagonists. Differing effects were observed in other organs. In humans, a number of studies seeking an association between Ang II levels, Ang II receptor regulation and physiological events have been conducted in platelets. In pregnant women, a negative correlation between plasma Ang II levels and Ang II binding and an association between receptor regulation and pregnancy-induced hypertension has been described.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of the angiotensin receptor subtypes in cell cultures, animal models and human diseases. 771 21

Recent developments in angiotensin II receptor research are discussed in the context of our knowledge in preceding years. Cloning of non-mammalian angiotensin II receptors without high affinity for non-peptide antagonists has permitted a new approach to the delineation of ligand-binding domains. Cloning of the second major isoform of angiotensin II receptor, AT2, and identification as a seven transmembrane domain receptor with only 32% sequence homology with the first isoform, AT1, provide the first concrete step toward our understanding of the roles of AT2. The discovery of phospholipase C-mediated pathway for AT1 in vascular smooth muscle cell signaling introduces an entirely unexpected angle to future research. New aspects of AT1 gene regulation and receptor desensitization and internalization are evolving. Molecular mechanisms and physiological implications of the differential expression of AT1A and AT1B are being clarified. The recent discovery of human AT1B may make studies on animal models interesting and more meaningful. The first paper on the genetic role of the AT1 gene in human hypertension has just been published. A promising future is expected in the further development of angiotensin-receptor research in relation to cardiac, renal, and vascular function by employing techniques of molecular biology.
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PMID:Recent progress in molecular and cell biological studies of angiotensin receptors. 774 57

To identify the mechanisms of action of isoforms angiotensin II receptors (AT1A, AT1B, and AT2) and to overcome the difficulties encountered in attempts to purify the receptors, we have expression-cloned their cDNAs from bovine and rat sources and isolated human cDNA and rat and human genomic DNA. The AT1A and AT1B cDNAs were found to encode respective receptor proteins with 359 amino acid residues, whereas, AT2 encodes a 363 amino acid residue receptor protein. Both AT1 and AT2 were found to conform with the seven transmembrane receptor structural motif, but showed only 32% amino acid residue identity to each other. The AT1 receptor was shown to be coupled to, at least, three different G proteins activating phospholipase C, inhibiting adenylyl cyclase and opening an L-type Ca(2+)-channel, whereas, AT2 was found to inhibit a phosphotyrosine phosphatase activity without affecting guanylyl cyclase by a pertussis-toxin-sensitive, presumably G-protein-mediated mechanism.
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PMID:Angiotensin II receptors: cloning and expression. 774 65

ISOFORMS OF ANGIOTENSIN II RECEPTORS: So far, three isoforms of angiotensin II receptors have been identified by complementary DNA cloning, all with seven transmembrane domain structures. AT1A and AT1B are the most common isoforms. They are coupled to phospholipase C through Gq/G11 proteins and to a calcium channel, and negatively coupled to adenyl cyclase. AT2 is only remotely related to the AT1 family. KNOWN STRUCTURAL DETAILS OF ANGIOTENSIN II RECEPTORS: Ligand-binding domains are being defined in the space surrounded by transmembrane helices. Coupling to Gq seems to involve the second cytosolic loop. Receptor proteins undergo transition to a low-affinity form, which is desensitized and internalized. CHROMOSOME LOCATION: In the rat, AT1A, AT1B and AT2 are located on chromosomes 17, 2 and X, respectively. SIGNALING PATHWAY: Studies with receptors are revealing several different pathways of angiotensin signaling that modulate protein tyrosine phopsphorylation.
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PMID:Molecular biology of angiotensin II receptors: an overview. 776 96

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

A stable cell line expressing the angiotensin II (AII) receptor has been obtained by transfecting the human neuroblastoma SH-SY5Y with the plasmid pCEP4 containing the entire coding region of the rat angiotensin AII receptor AT1A. Angiotensin II (AII; 1-100 nM) evokes the release of [3H]noradrenaline ([3H]NA) in this cell line. Pretreatment with 100 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) enhances the AII-evoked release of [3H]NA approximately two-fold. Removal of extracellular Ca2+ ([Ca2+]o) decreases 100 nM AII-evoked release of [3H]NA by over 50% both in the presence and absence of TPA. AII increases intracellular Ca2+ ([Ca2+]i) in this cell line which is consistent with the AT1A receptor being coupled to phospholipase C. Pretreatment with 100 nM TPA for 8 min attenuated the effect of AII on [Ca2+]i. The effects of AT1A receptor stimulation are therefore regulated differently in this cell line by activation of protein kinase C (PKC). Thus a useful cell line has been obtained from the human neuroblastoma SH-SY5Y in which to study at the molecular level the mechanism(s) by which AII regulates NA release.
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PMID:The effect of the angiotensin II (AT1A) receptor stably transfected into human neuroblastoma SH-SY5Y cells on noradrenaline release and changes in intracellular calcium. 858 37

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

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

To evaluate and functionally compare the rat AT1A and AT1B receptor subtypes, stable Chinese hamster ovary (CHO) cell lines expressing either recombinant receptor in approximately equal numbers were generated. Radioligand binding data suggests that the recombinant AT1A receptor is pharmacologically similar to the recombinant AT1B receptor. Functional studies indicate that both receptor subtypes can independently activate the phospholipase C/IP3 and the dihydropyridine-sensitive voltage-dependent Ca2+ channel signal transduction pathways with equal efficiency, but are unable to modulate cAMP accumulation under our experimental conditions. Furthermore, both receptors can be directly involved in the cellular growth properties of AII. Slot-blot experiments clearly demonstrate that these receptors are expressed in a tissue-specific manner. A sequence comparison of the 5' flanking regions of these two genes shows that they have very little sequence homology (approximately 36%), suggesting that although the AT1A and AT1B receptors appear to be pharmacologically and functionally similar, the control of their expression seems to be governed by distinct transcription factors.
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PMID:A functional comparison of the rat type-1 angiotensin II receptors (AT1AR and AT1BR). 874 40


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