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 (AII) receptors are known to interact with two distinct guanine nucleotide binding proteins, Gq/11 and Gi, in rat adrenal glomerulosa cells to activate phospholipase C and to inhibit adenylate cyclase, respectively. However, in cultured bovine glomerulosa cells AII potentiates rather than inhibits the stimulatory effect of adrenocorticotropin (ACTH) on cAMP levels. This effect of AII was partially mimicked by phorbol 12-myristate 13-acetate (PMA) and was partially inhibited by staurosporine or depletion of protein kinase C but was unaffected by pertussis toxin treatment. No potentiation was detectable in disrupted cells or in membrane preparations. In intact glomerulosa cells, treatment with cyclosporin A or FK506 completely inhibited AII- or PMA-induced potentiation of cAMP production without affecting the response to ACTH. In COS-7 cells transfected with the rat AT1 receptor, AII caused 2-3-fold enhancement of the ACTH-induced cAMP response, an effect that was partially reproduced by PMA. These potentiating actions of AII and PMA were prevented by preincubation with cyclosporin A or FK506, and the latter effect was abolished by rapamycin. These results implicate the Ca2+- and calmodulin-dependent protein phosphatase, calcineurin, in AII-induced enhancement of adenylate cyclase activity in both adrenal glomerulosa and transfected COS-7 cells. The finding that AII enhances ACTH-stimulated production of cAMP by a second messenger-mediated mechanism that involves the participation of calcineurin reveals an additional mode of cross-talk between pathways activated by Ca(2+)-mobilizing and cAMP-generating receptors.
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PMID:Evidence for participation of calcineurin in potentiation of agonist-stimulated cyclic AMP formation by the calcium-mobilizing hormone, angiotensin II. 792 24

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

Angiotensin II (ANG II) stimulates proximal tubule sodium transport by decreasing adenylyl cyclase activity. The role of ANG II-dependent phospholipase C is less certain. To determine the contribution of phospholipase C and adenylyl cyclase to apical (AP) ANG II-dependent sodium transport, unidirectional (AP to basolateral) 22Na flux was measured in rat proximal tubule cells cultured on permeable supports. AP ANG II (100 nM)-dependent sodium flux was prevented by preincubation with concentrations of the phospholipase C inhibitor U-73122 (1 microM) that blocked ANG II-dependent inositol phosphate formation. AP ANG II-dependent sodium flux was also abolished by preincubation with the intracellular calcium mobilization inhibitor 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8), further suggesting that ANG II-dependent sodium transport was mediated by inositol phosphates. Neither U-73122 nor TMB-8 prevented ANG II-dependent adenosine 3',5'-cyclic monophosphate (cAMP) decreases. Incubation with dibutyryl cAMP (10 microM) or forskolin (10 microM) prevented ANG II-dependent sodium flux as well as ANG II-dependent inositol phosphate formation. In conclusion, ANG II-dependent proximal tubule sodium transport in cultured cells was transduced by phospholipase C and adenylyl cyclase. The adenylyl cyclase effect on ANG II-dependent sodium transport was mediated by phospholipase C.
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PMID:Angiotensin II-dependent proximal tubule sodium transport is mediated by cAMP modulation of phospholipase C. 797 87

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

We examined the effects of endothelin-1 (ET-1) on [Ca2+]i and intracellular pH in cultured bovine trabecular meshwork cells and compared the effects of ET-1 with those of angiotensin II (another phospholipase C activating peptide). [Ca2+]i was measured with the Ca2+ fluorescent dye indo-1. Intracellular pH was measured using the pH sensitive fluorescent dye BCECF. Exposure to ET-1 (10 nM) produced a transient increase in [Ca2+]i (from 77.3 +/- 17.3 nM to 503.0 +/- 64.8 nM, p < 0.05, n = 12). Intracellular pH was also increased during exposure to 10 nM ET-1 (+0.081 unit, p < 0.05, n = 6). In the presence of 10 microM EIPA, ET-1 (10 nM) did not change intracellular pH. Angiotensin II did not significantly change [Ca2+]i or intracellular pH. These results suggest that ET-1 may be involved in the regulation of aqueous humor dynamics by changing [Ca2+]i and intracellular pH in trabecular meshwork cells.
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PMID:Effects of endothelin-1 on [Ca2+]i and pHi in trabecular meshwork cells. 819 67

Angiotensin II (ANG II) in mesangial cells (MC) promotes phosphatidylinositol (PI) hydrolysis resulting in diacylglycerol (DAG)-mediated increases in protein kinase C (PKC) activity. The paucity of MC inositol lipid prompted us to consider whether phosphatidylcholine (PC) could sustain DAG formation. ANG II released choline and increased phosphatidylethanol (PEt) via PC-phospholipase D (PC-PLD). ANG II also stimulated phosphorylcholine consequent to PC-phospholipase C (PC-PLC) activation. ANG II-mediated PC hydrolysis augmented DAG for 30 min. PC breakdown was influenced by extracellular Ca2+, because Ni2+ partially inhibited ANG II-induced PEt and obliterated agonist-mediated DAG formation. The consequence of Ca2+ modulation of PC metabolism was investigated by measuring PKC activity. Ni2+ had no effect on early (PI-associated) activation by ANG II at 90 s but obviated translocation from cytosol to the membrane at 10 min. The pathway responsible for PC-associated DAG was studied in PKC downregulated cells. Whereas downregulation prevented PLD-mediated PEt elevation, ANG II-stimulated DAG formation in myristate-labeled cells was unaltered, indicating PC-PLC activation. In summary, ANG II stimulates PC-PLD and PC-PLC in MC. PC-PLD is tightly regulated by PKC, whereas PC-PLC is stringently controlled by extracellular Ca2+. ANG II mediated PC breakdown principally via PC-PLC provides a mechanism for maintaining elevated DAG levels and PKC activation.
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PMID:Angiotensin-mediated phosphatidylcholine hydrolysis and protein kinase C activation in mesangial cells. 823

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

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

Early signals elicited after membrane receptor binding of agonists, the transmembrane signaling pathway of which involves activation of phosphoinositide-specific phospholipase C, were compared in fetal (22 days gestation) and adult rat hepatocytes. Free cytosolic calcium changes varied depending on the agonist and type of stimulated cells. Angiotensin II and ATP elicited the maximal responses in both types of cells, whereas the maximal Ca2+ increase produced by vasopressin was twice as much in adult than in fetal hepatocytes. The opposite response was observed for bombesin- or gastrin-releasing peptide-stimulated cells. Triggering of fetal and adult hepatocytes with substances that maximally promote endoplasmic reticulum calcium release or phosphoinositide-specific phospholipase C activation revealed that at least for the actions mediated through the angiotensin II and P2 purinergic receptor, the agonist stimulation was near the maximal response capacity of the signaling pathway. Agreement was observed between the relative number of membrane receptors and the biological responses.
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PMID:Differential calcium mobilization by vasopressin, angiotensin II, gastrin-releasing peptide, and adenosine triphosphate in adult and fetal hepatocytes. Relevance for the activation of calcium-dependent enzymes. 838 Mar 81

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


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