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)

The relationship between angiotensin II-induced activation of G proteins and receptor internalization was analyzed by transiently expressing mutant and wild type cDNAs for the rat AT1a receptor in COS-7 cells. Pertussis toxin-sensitive G proteins did not appear to play a role in endocytosis since the receptor showed normal internalization kinetics in pertussis toxin-treated cells. Three deletion mutants of the third cytoplasmic loop revealed that the N-terminal part of this region is important for both receptor endocytosis and intracellular signaling. Three point mutations of Asp74, which has been implicated in signal transduction by the AT1a receptor, caused impaired G protein coupling and inositol phosphate responses. However, each of these mutants (D74N, D74H, and D74Y) showed markedly different internalization kinetics. The D74Y mutant showed the greatest impairment of internalization but retained the highest degree of inositol phosphate stimulation. In contrast, the D74N mutant, which showed the most impaired G protein coupling and inositol phosphate responses, had similar internalization kinetics to the wild type receptor. The combined mutant receptor containing the D74N substitution and deletion of residues 221-226 from the third cytoplasmic loop showed no G protein coupling or inositol phosphate response but was internalized about 60% as rapidly as the wild type receptor. These data demonstrate that endocytosis of the AT1 receptor is independent of agonist-activated signal transduction and indicate that receptor internalization and activation of phospholipase C have different structural requirements.
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PMID:Independence of type I angiotensin II receptor endocytosis from G protein coupling and signal transduction. 792 58

Angiotensin II (Ang II) is an important regulator of aldosterone production by bovine adrenal glomerulosa (BAG) cells. Ang II interacts with a specific receptor coupled to a guanyl nucleotide-binding protein (G protein) that controls the activity of phospholipase C. A primary culture of BAG cells was used to study short-term desensitization of the Ang II receptor. After short exposures to Ang II, BAG cells lost some [125I]Ang II binding capacity. This loss was dependent on the duration of the pretreatment and on the concentration of Ang II used. A maximal loss of [125I]Ang II binding of 55 +/- 10% was observed after a pretreatment of 30 min with 30 nM Ang II. The EC50 was 1.3 +/- 0.6 nM (mean +/- SD of three experiments). The desensitization was readily reversible, since most of the binding capacity (higher than 90%) was recovered after a 60-min incubation, at 37 C, in the absence of Ang II. Scatchard studies revealed that the Ang II receptor of BAG cells exists under two affinity states with one dissociation constant of 0.2 nM and another dissociation constant of 1.5 nM. After a 30-min exposure of BAG cells to 10 nM Ang II, an important decrease of high affinity binding sites was observed. The maximal amount of binding sites was similar on control and desensitized cells (around 52,000 receptors per cell). GTP gamma S, a potent activator of G proteins, decreased [125I]Ang II binding to permeabilized BAG cells. This GTP gamma S effect was not observed on permeabilized BAG cells that had previously been desensitized with 10 nM Ang II. These results suggested that, similarly to GTP gamma S, short exposure to 10 nM Ang II caused the uncoupling of Ang II receptor from its G protein. DuP-753 (a selective AT1 angiotensin II type 1 receptor antagonist) markedly unhibited, whereas PD-123319 (a selective AT2 angioten II type 2 receptor antagonist) had no effect on Ang II receptor desensitization, indicating that the AT1 receptor subtype was responsible for the observed phenomenon. Pretreatment of BAG cells with staurosporine (a protein kinase C inhibitor) and R24571 (a calmodulin inhibitor) did not modify Ang II-induced desensitization of AT1 receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Short-term desensitization of the angiotensin II receptor of bovine adrenal glomerulosa cells corresponds to a shift from a high to a low affinity state. 795 36

We tested the hypothesis that mineralocorticoids potentiate angiotensin II-stimulated phospholipase C activation through an increased number of angiotensin II receptors in cultured rat aortic vascular smooth muscle cells. Exposure of cells to aldosterone for 24 h resulted in concentration-dependent increases in angiotensin II receptor binding. Via studies of angiotensin II displacement by non-peptide receptor antagonists, both basal and upregulated angiotensin II receptors were found to be of the AT1 subtype. Incubation with 1 microM aldosterone resulted in 50-100% enhancement of angiotensin II (100 nM)-stimulated diacylglycerol formation and intracellular calcium mobilization. Exposure to 100 nM 1,25-(OH)2VitD3, which did not upregulate angiotensin II receptors, did not potentiate stimulated inositol phosphate formation. Incubation with aldosterone resulted in potentiation of inositol phosphate formation upon receptor occupation (100 nM angiotensin II) but not upon post-receptor stimulation (25 mM NaF/10 microM AlCl3). Aldosterone did not increase basal phospholipase C activity or content of the inositol trisphosphate precursor phosphatidylinositol-4,5-bisphosphate. These data are consistent with the hypothesis that aldosterone potentiates angiotensin II-stimulated, phospholipase C-dependent intracellular signals solely by coupling to an increased number of angiotensin II receptors. This mechanism may contribute to the sensitized vascular responses to angiotensin II observed in states of mineralocorticoid excess.
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PMID:Mechanisms of enhanced angiotensin II-stimulated signal transduction in vascular smooth muscle by aldosterone. 796 4

Vascular tone is maintained by both angiotensin II (Ang II) and glucocorticoids, but the effect of glucocorticoids on Ang II function in vascular smooth muscle cells (VSMC) is unclear. To determine the direct influence of glucocorticoids on VSMC Ang II receptor function, the effects of dexamethasone on Ang II receptor binding, Ang II-induced phospholipase C (PLC) activation, and Ang II-dependent cell growth were studied in cultured rat VSMC. Dexamethasone caused concentration- and time-dependent increases in Ang II binding which were prevented by glucocorticoid receptor inhibition with RU 38486. Dexamethasone-induced enhancement of Ang II binding resulted from increased AT1 receptors, as indicated by Northern blot analysis and competitive binding assays. Despite causing increased Ang II receptor number, dexamethasone preincubation prevented Ang II-induced PLC activation, as indicated by phosphatidylinositol 4,5-bisphosphate degradation and inositol trisphosphate formation. When PLC activity was directly measured in VSMC soluble and membrane fractions, Ang II receptor activation caused decreased soluble and increased membrane PLC activity, consistent with the interpretation that Ang II caused cytosol-to-membrane PLC translocation. The effect of Ang II on PLC translocation was prevented by dexamethasone preincubation. Finally, prolonged incubation with dexamethasone and Ang II had additive effects on VSMC hypertrophy. In conclusion, glucocorticoids directly altered Ang II function in VSMC by causing increased Ang II receptor number, Ang II receptor/PLC uncoupling, and enhanced Ang II-dependent hypertrophy.
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PMID:Glucocorticoid uncoupling of antiogensin II-dependent phospholipase C activation in rat vascular smooth muscle cells. 799 88

We previously showed that angiotensin II (Ang II) and angiotensin-(2-8)-peptide [Ang-(2-8)] activate a phosphoinositide-specific phospholipase C (PLC) and cause calcium mobilization in rat aortic vascular smooth-muscle cells (VSMC), while Ang II and Ang-(1-7) produce prostaglandins. To define further the signal-transduction mechanisms activated by angiotensin peptides in smooth-muscle cells, we measured diacylglycerol (DAG) accumulation in response to different angiotensin peptides and its inhibition by subtype-selective receptor antagonists. Both an initial (10 s) and secondary (10 min) phase of DAG production in response to 100 nM Ang II were inhibited by 1 microM losartan (DuP 753), an AT1 antagonist, while 1 microM PD 123177, an AT2 antagonist, was ineffective. In contrast, the heptapeptide Ang-(1-7) did not produce DAG in VSMC. Ang II also caused the hydrolysis of phosphatidylinositol and phosphatidylcholine, the formation of phosphatidic acid and the formation of phosphatidylethanol (PEt) in the presence of ethanol, through activation of a PLD and a PLD-induced transphosphatidylation reaction. A similar concentration of Ang-(2-8) also activated PLD; in contrast, Ang-(1-7) was ineffective. PEt production by 100 nM Ang II was significantly attenuated by the AT1 antagonists losartan, its metabolite EXP 3174 or L-158,809 (all at 1 microM), whereas a similar concentration of the AT2 antagonists CGP 42112A or PD 123177 was ineffective. The production of PEt by Ang II was also partially attenuated by the removal of extracellular calcium and potentiated by increasing calcium concentrations, indicating that PLD activity is partially dependent on extracellular calcium. Thus VSMC PLD is coupled to an AT1 receptor and occurs in response to Ang II or Ang-(2-8), but not Ang-(1-7). Since AT1 receptors in VSMC are also coupled to activation of PLC, both PLC and PLD may be coupled to the same or a different AT1 receptor. Alternatively, PLD may be sequentially activated in response to Ang II activation of PLC and a subsequent increase in calcium concentration.
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PMID:Vascular smooth-muscle cells contain AT1 angiotensin receptors coupled to phospholipase D activation. 799 90

An essential role of the conserved Asp74 in the coupling of the type 1 angiotensin II (AII) receptor (AT1) to phospholipase C has already been reported (Bihoreau, C., Monnot, C., Davies, E., Teutsch, B., Bernstein, K. B., Corvol, P., and Clauser, E. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 5133-5137). Moreover, preliminary modeling studies have shown that a spatial proximity exists between Asp74, located in transmembrane domain II, and Tyr292, located in transmembrane domain VII and conserved in many, but not all, G protein-coupled receptors. We mutated Tyr292 into Phe and evaluated the pharmacological and activation characteristics of the mutated receptor (Y292F) stably expressed in Chinese hamster ovary cells. This receptor possessed unchanged binding properties for agonist or antagonist peptide ligands compared to the wild-type receptor, while its coupling to phospholipase C was severely impaired. Interestingly, competition binding experiments, using 125I-[Sar1]AII as a tracer ligand, showed that the Y292F receptor displayed an increased Ki value for DuP 753, an AT1-specific nonpeptide antagonist and a greatly decreased Ki value for the AT2-specific ligand CGP 42112A. These pharmacological changes are similar to those observed for the previously reported mutation of Asp74 into Asn. This apparently symmetrical role of Asp74 and Tyr292 is consistent with the hypothesis that an interaction between these two amino acids could be a key event in the molecular processes linking AII recognition and AT1 receptor activation.
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PMID:Tyr292 in the seventh transmembrane domain of the AT1A angiotensin II receptor is essential for its coupling to phospholipase C. 806 94

Angiotensin II (ANG II) receptors were investigated in primary cultured rat aortic smooth muscle cells (SMC) that expressed either a proliferative phenotype (during the growth phase) or a contractile phenotype (at postconfluence). For each phenotype, alpha-smooth muscle actin expression, 125I-labeled ANG II specific binding, D-myo-inositol 1,4,5-triphosphate [Ins(1,4,5)P3] production, and ANG II-mediated increases in intracellular calcium (Cai2+) were studied. In both phenotypes, 1) ANG II-specific high-affinity binding (KD 0.5 +/- 0.1 nM and Bmax 196 +/- 106 pmol/mg protein in proliferative state, KD 1.5 +/- 0.3 nM and Bmax 560 +/- 299 pmol/mg protein in postconfluent state) was entirely inhibited by the selective AT1-antagonist losartan as well as by [Sar1,Ala8]ANG II and ANG III; 2) the AT2-antagonist CGP 42112A was ineffective, except at very high concentrations (> or = 10 microM); 3) the specific binding of ANG II was inhibited by guanosine 5'-[gamma-thio]triphosphate; and 4) ANG II induced a losartan-sensitive increase in Ins(1,4,5)P3. In postconfluent cultures, ANG II elicited a rapid biphasic elevation in Cai2+, which was abolished by losartan, whereas in growing cultures, this response was either absent or greatly attenuated. It is concluded that AT1-receptors coupled to phospholipase C via a G protein are expressed in the proliferative as well as in the contractile SMC phenotype and that their coupling to Cai2+ release is impaired in the proliferative phenotype. No evidence for AT2-receptor expression during phenotypic modulation of SMC was found.
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PMID:ANG II receptor expression and function during phenotypic modulation of rat aortic smooth muscle cells. 814 64

Angiotensin II has been shown to act prejunctionally to facilitate sympathetic neutrotransmission in various tissues including the iris-ciliary body. In the present study, we characterized the prejunctional angiotensin II receptor subtype and its signal transduction pathway in the rabbit iris-ciliary body. Angiotensin II caused concentration-dependent facilitation of electrically evoked [3H]-norepinephrine overflow from the isolated, superfused rabbit iris-ciliary body without affecting basal tritium efflux. Responses to angiotensin II were antagonized by saralasin and DuP753 but not by PD123177 indicating that prejunctional angiotensin II receptors of the AT1-subtype mediate the facilitation of evoked [3H]-norepinephrine release. The non-selective cyclic nucleotide phosphodiesterase inhibitor, isobutylmethyl xanthine enhanced the angiotensin II response whereas the cAMP-specific phosphodiesterase inhibitor, RO-20-1724 had no effect. In the presence of 8-bromo-cGMP, responses elicited by angiotensin II were significantly (P < 0.01) greater than that caused in the absence of 8-bromo-cGMP. In contrast, 8-bromo-cAMP had no effect on the angiotensin II-induced response. Guanylate cyclase inhibitors, methylene blue and LY83583 abolished angiotensin II-induced enhancement of [3H]-norepinephrine overflow without affecting basal tritium efflux. Taken together, these results suggest that cGMP could be involved in the angiotensin II response. Neither phospholipase C inhibitors (neomycin, 2-nitro-4-carboxyphenyl-N,N-diphenyl carbamate and phenylmethylsulfonyl fluoride) nor an inhibitor of protein kinase C (staurosporine) had any significant effect on the angiotensin II response, indicating that metabolites of inositol phospholipid metabolism or activation of protein kinase C are not involved in the response to this peptide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Prejunctional receptors and second messengers for angiotensin II in the rabbit iris-ciliary body. 828 27

Recent studies revealed that angiotensin II (Ang II) interacts with two pharmacologically different subtypes of cell surface receptors. Type I Ang II (AT1) receptor is characterized by signal transduction mediated through G protein and phospholipase C. In this study, the micro-localization of mRNAs coding for AT1 receptor and angiotensinogen was carried out in the rat kidney, using an assay of reverse transcription and polymerase chain reaction (RT-PCR) in individual microdissected renal tubule segments along the nephron, glomeruli, vasa recta bundle, and arcuate arteries. Large signals for AT1 receptor were detected in the glomerulus, proximal convoluted tubule (PCT), proximal straight tubule (PST), cortical collecting duct, and vascular system. Small signals were also seen in medullary thick ascending limb, outer medullary collecting duct, and inner medullary collecting duct (IMCD). Angiotensinogen mRNA is expressed largely in PCT, PST, and a small amount in glomerulus and vasa recta. Our data demonstrate that Ang II could be produced locally in proximal tubule and vasa recta bundle, and that the AT1 receptor was widely distributed not only in the glomerulus and vessels but also in tubules from PCT to IMCD.
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PMID:PCR localization of angiotensin II receptor and angiotensinogen mRNAs in rat kidney. 831 39

The kidney is an important target organ for angiotensin II. The diverse biologic effects of angiotensin II in the kidney and periphery suggest that angiotensin II may be interacting with more than one receptor. Recently, the synthesis of highly selective nonpeptide angiotensin II receptor antagonists and the expression cloning of the angiotensin receptor have unequivocally demonstrated the existence of at least two angiotensin II receptor subtypes, designated AT1 and AT2. Autoradiography and ligand binding studies have shown that most tissues, including the kidney, have a mixture of both receptor subtypes. The AT1 receptor is coupled via G proteins to traditional signal transduction mechanisms such as stimulation of phospholipase C, Ca2+ mobilization, and inhibition of adenylate cyclase. The AT2 receptor does not appear to be coupled to G proteins, and the signal transduction pathway(s) associated with this receptor is not known but may involve cGMP. In the kidney, as in the periphery, all of the major physiologic actions of angiotensin II appear to be mediated by activation of the AT1 receptor. In this review, the general characteristics of the AT1 and AT2 receptors and their distribution and function in the kidney will be discussed.
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PMID:Angiotensin II receptor subtypes in the kidney. 831 80


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