Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II acts on cultured rat aortic vascular smooth muscle cells to stimulate phospholipase C-mediated hydrolysis of membrane phosphoinositides and subsequent formation of diacylglycerol and inositol phosphates. In intact cells, angiotensin II induces a dose-dependent increase in diglyceride which is detectable after 5 s and sustained for at least 20 min. Angiotensin II (100 nM)-stimulated diglyceride formation is biphasic, peaking at 15 s (227 +/- 19% control) and at 5 min (303 +/- 23% control). Simultaneous analysis of labeled inositol phospholipids shows that at 15 s phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 4-phosphate (PIP) decline to 52 +/- 6% control and 63 +/- 5% control, respectively, while phosphatidylinositol (PI) remains unchanged. In contrast, at 5 min, PIP2 and PIP have returned toward control levels (92 +/- 2 and 82 +/- 4% control, respectively), while PI has decreased substantially (81 +/- 2% control). The calcium ionophore ionomycin (15 microM) stimulates diglyceride accumulation but does not cause PI hydrolysis. 4 beta-Phorbol 12-myristate 13-acetate, an activator of protein kinase C, inhibits early PIP and PIP2 breakdown and diglyceride formation, without inhibiting late-phase diglyceride accumulation. Thus, angiotensin II induces rapid transient breakdown of PIP and PIP2 and delayed hydrolysis of PI. The rapid attenuation of polyphosphoinositide breakdown is likely caused by a protein kinase C-mediated inhibition of PIP and PIP2 hydrolysis. While in vascular smooth muscle stimulated with angiotensin II inositol 1,4,5-trisphosphate formation is transient, diglyceride production is biphasic, suggesting that initial and sustained diglyceride formation from the phosphoinositides results from different biochemical and/or cellular processes.
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PMID:Sustained diacylglycerol formation from inositol phospholipids in angiotensin II-stimulated vascular smooth muscle cells. 308 74

Angiotensin II stimulates prostaglandin (PG) E2 formation in mesangial cells cultured from rat renal glomeruli. The interactions between angiotensin II and PGE2 are important in modulating glomerular function. We examined the mechanism for stimulation of PGE2 production in mesangial cells using the putative diacylglycerol-lipase inhibitor RHC 80267 and trifluoperazine (TFP), an agent interfering with Ca2+-CaM-mediated processes. Although RHC 80267 inhibited diacylglycerol-lipase activity in mesangial cells, it did not influence PGE2 production in response to either angiotensin II or A23187. In contrast, TFP (50 microM) inhibited basal PGE2 production and stimulation by angiotensin II and A23187. TFP also decreased 14C release in response to angiotensin from cells prelabeled with [14C]arachidonic acid, which was associated with inhibition of 14C loss from phosphatidylinositol. In cells prelabeled with 32P, orthophosphate angiotensin II caused a rapid hydrolysis of phosphatidylinositol 4,5-bisphospate. TFP enhanced 32P labeling of phosphatidylinositides, but did not prevent the loss of phosphatidylinositol 4,5-bisphosphate in response to angiotensin. This was verified in cells prelabeled with myo-[3H]inositol where angiotensin stimulated formation of [3H]inositol trisphosphate. TFP enhanced formation of [3H]inositol trisphosphate both under basal- and angiotensin II-stimulated conditions. Thus TFP did not inhibit phospholipase C activation by angiotensin. Angiotensin II caused marked increases in [32P]lysophospholipids, indicating activation of also phospholipase A2. This process was inhibited by TFP. Taken together, these results are consistent with stimulation of both phospholipase C and A2 by angiotensin, the latter step responsible for the release of arachidonic acid and PGE2 formation. The activation of phospholipase A2, but not that of phospholipase C, is inhibited by TFP, perhaps by interference with calmodulin-dependent steps.
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PMID:Angiotensin II stimulates phospholipases C and A2 in cultured rat mesangial cells. 311 Dec 71

Angiotensin II increased PGE2 release from superfused glomeruli, and stimulated labeled inositol phosphate production. 12-O-Tetradecanoyl phorbol -13-acetate (TPA, 10(-7) M), which stimulates protein kinase C activity in soluble fractions of glomerular homogenates, suppressed angiotensin II actions on inositol phosphate production and PGE2. By contrast, 4a phorbol 12,13 di-decanoate and phorbol had no effect on protein kinase C activity or angiotensin II induced increases in inositol phosphate or PGE2. 1-(5-Isoquinolinyl)-2-methylpiperazine (H-7), which inhibits protein kinase C activity in soluble fractions of glomerular homogenates, prevented TPA induced suppression of angiotensin II actions on inositol phosphate production and PGE2. Moreover H-7 prolonged the time course of angiotensin II induced inositol phosphate production and enhanced angiotensin II actions on glomerular PGE2 production. The results support a role for inositol phospholipid hydrolysis through the phospholipase C pathway in the mediation of angiotensin II actions on PGE2 in glomeruli and are consistent with negative modulation of these actions by protein kinase C.
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PMID:Role for protein kinase C in the modulation of glomerular PGE2 production by angiotensin II. 316 21

The stimulation of phosphoinositide metabolism by angiotensin II (Ang II) was studied in [3H]inositol-labelled bovine adrenal glomerulosa cells. After separation of the phosphoinositols by ion-exchange high-performance liquid chromatography, it was shown that the formation of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) and inositol 1,3,4-trisphosphate (Ins(1,3,4)P3) followed distinct kinetics. The first compound to increase upon stimulation with 10(-7) M Ang II was Ins(1,4,5)P3, which reached a maximum (250% of basal level) within 10 s. At lower concentrations of Ang II, this response was slower. The formation of Ins(1,4,5)P3 depended upon the concentration of Ang II, with an EC50 of 2.4 +/- 1.5 X 10(-9) M Ang II. The potency of Ang II in stimulating the turnover of phosphoinositides and in increasing the biosynthesis of aldosterone was very similar, whereas the peptide was ten times more potent in its ability to mobilize Ca2+. Ang II was also able to stimulate the production of Ins(1,4,5)P3 in permeabilized glomerulosa cells. This effect was mimicked by a non-hydrolysable analog of GTP (GTP gamma S), suggesting that a GTP binding protein is involved in the mechanism coupling the Ang II membrane receptor to phospholipase C. These results strengthen the view that Ins(1,4,5)P3 plays a key role as second messenger in the steroidogenic response to Ang II in adrenal glomerulosa cells.
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PMID:Inositol trisphosphate isomers in angiotensin II-stimulated adrenal glomerulosa cells. 326 Dec 66

Angiotensin II (AII) interacts with specific receptors in the adrenal glomerulosa cell and stimulates the hydrolysis of plasma membrane phosphoinositides by phospholipase C, with production of inositol 1,4,5-trisphosphate (Ins-1,4,5-P3) and subsequent mobilization of intracellular Ca2+. In electrically permeabilized, [3H]inositol-labeled glomerulosa cells, AII stimulated Ins-1,4,5-P3 production within 15 s with half-maximal potency of 10(-9) M. The nonhydrolyzable GTP analog, guanosine 5'-O-thiotriphosphate (GTP gamma S), stimulated Ins-1,4,5-P3 formation in a dose-dependent manner with half-maximal effect at 10(-7) M. AII-activated Ins-1,4,5-P3 production was further increased by guanine nucleotides. The rate at which GTP gamma S-stimulated inositol polyphosphate production was consistently slower than that of AII. In adrenal membrane preparations, GTP gamma S-stimulated polyphosphoinositide hydrolysis was enhanced by Ca2+, with half-maximal activity at 300 nM free Ca2+. Ins-1,4,5-P3 formation was also increased by NaF, further indicating the involvement of a guanine nucleotide regulatory protein. In addition to Ins-1,4,5-P3 and its metabolites formed during degradation via the 4-monophosphate pathway, AII and GTP gamma S stimulated the formation of the phosphorylated metabolite inositol 1,3,4,5-tetrakisphosphate and inositol 1,3,4-trisphosphate in permeabilized cells. The absence of a significant rise in inositol 1-monophosphate indicated that phosphatidylinositol hydrolysis was not stimulated by AII or GTP gamma S. Pretreatment of glomerulosa cells with pertussis toxin for 12 h before permeabilization did not inhibit AII- or GTP gamma S-stimulated inositol polyphosphate formation. However, treatment with cholera toxin, forskolin, or 8-Br-cAMP for 12 h enhanced both basal and ligand-stimulated Ins-1,4,5-P3 production. These observations suggest that agonist binding to the AII receptor activates a polyphosphoinositide-specific phospholipase C in the adrenal glomerulosa cell, and that a distinctive guanine regulatory protein is involved in this mechanism.
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PMID:Angiotensin II and guanine nucleotides stimulate formation of inositol 1,4,5-trisphosphate and its metabolites in permeabilized adrenal glomerulosa cells. 328 18

Angiotensin II (ANG II) binds with high affinity to specific renal receptors and exerts major influences on hemodynamics and tubular transport. Glomerular and tubular epithelial receptors are well characterized in contrast to pre- and postglomerular and medullary vasculature. Therefore, the scope of this review is limited to an indepth comparison of ANG II receptor kinetics, analogue specificity, and mechanisms of receptor regulation and signal transduction in glomeruli and epithelial cells. Despite the fact that these receptors are in close proximity anatomically, there is evidence from a number of laboratories that permits classification into two distinct receptor subtypes. The receptor of the glomerular mesangium, classified herein as "type A," is characterized by high affinity for ANG II and the heptapeptide, des-Asp1-Ang II (ANG III), "downregulation" with high ambient concentrations of ANG II and signal transduction mediated by phospholipase C-induced Ca2+ transients. The tubular epithelial ANG II receptor, "type B," is of lower affinity for ANG II and ANG III, "upregulated" by high levels of ANG II and mediates inhibition of adenylate cyclase following coupling to an inhibitory GTP binding protein. Both receptors possess secondary mechanisms of signal transduction that may also participate in regulation of cellular function(s). These findings support the hypothesis that at least two distinct classes of ANG II receptors are present in the kidney cortex.
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PMID:Angiotensin receptor subtypes of the kidney cortex. 330 Mar 68

It was the aim of the present study to find out if a common mechanism exists by which the vasoconstrictive hormones angiotension II, noradrenaline and 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (AGEPC) increase prostaglandin E2 (PGE2) synthesis in cultures of rat renal mesangial cells. Angiotension II, noradrenaline and AGEPC stimulated PGE2 synthesis and uptake of 45Ca2+ in cultured mesangial cells. Both of these effects could be completely suppressed by the calcium channel blocker verapamil. Angiotensin II, noradrenaline and AGEPC caused a rapid breakdown of phosphatidylinositol 4,5-bisphosphate with a concomitant increase of 1,2-diacylglycerol and inositol trisphosphate, indicating an activation of phospholipase C by these hormones. Addition of verapamil had no effect on the hormone-induced stimulation of phospholipase C. The synthetic analogue of diacylglycerol, 1-oleoyl-2-acetylglycerol, and the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), both of which are known to stimulate protein kinase C, enhanced PGE2 synthesis. Chelation of extracellular calcium with EDTA or addition of verapamil abolished the effect of 1-oleoyl-2-acetylglycerol and phorbol ester on PGE2 synthesis. 1-Oleoyl-2-acetylglycerol and phorbol ester increased the uptake of 45Ca2+ by the cells in a dose-dependent manner and this effect could be blocked by verapamil. The entirety of these data leads us to suggest that vasoconstrictor-evoked synthesis of PGE2 in rat mesangial cells is mediated by the subsequent activation of phospholipase C and protein kinase C. The activation of protein kinase C by diacylglycerol is likely to be involved in the increase of the calcium permeability of the plasma membrane which is a prerequisite for PGE2 synthesis induced by vasoconstrictive hormones.
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PMID:Role of phospholipase C and protein kinase C in vasoconstrictor-induced prostaglandin synthesis in cultured rat renal mesangial cells. 345 63

Smooth muscle cells were cultured from rat thoracic aorta and labeled to a stable specific activity with 45Ca2+, myo-[2-3H]inositol, or 32Pi. The efflux of 45Ca2+ was monitored over 10-sec intervals. Angiotensin II (AII) increased the amount of 45Ca2+ lost by 5-fold in the first 10-sec interval after the addition of AII and by 10-fold in the second 10-sec interval. AII-stimulated 45Ca2+ release was blocked by the angiotensin antagonist [1-sarcosine, 8-leucine]AII and by La3+. The removal of external Ca2+ had no effect on AII-stimulated 45Ca2+ release. Depolarization with high external K+ only slightly increased 45Ca2+ efflux and had no effect on AII-induced 45Ca2+ release. AII had no effect on the initial rate of 45Ca2+ influx. These results indicate that the rapid 45Ca2+ efflux evoked by AII is probably due to the release of 45Ca2+ sequestered intracellularly rather than to an increase in the Ca2+ permeability of the plasma membrane. AII provoked rapid increases in the levels of phosphatidic acid and phosphoinositides in the cells. These increases in phospholipids were associated with increases in phospholipase C-generated inositol phosphates (tri-, di-, and mono-). It appears that AII simultaneously increases phosphoinositide hydrolysis and synthesis in vascular smooth muscle, and both phospholipid effects may contribute to inositol triphosphate generation, which was sufficiently rapid to have a role in intracellular Ca2+ mobilization.
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PMID:Angiotensin II rapidly increases phosphatidate-phosphoinositide synthesis and phosphoinositide hydrolysis and mobilizes intracellular calcium in cultured arterial muscle cells. 609 58

In cultured vascular smooth muscle cells (VSMC), inflammatory cytokines such as interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha stimulated nitric oxide (NO) production via the expression of an inducible type of NO synthase (iNOS). A potent vasoconstrictor, angiotensin II (Ang II), which causes a rapid phospholipase C-mediated phosphoinositide hydrolysis via the Ang II type 1 (AT1) receptor in VSMC, by itself did not stimulate the production of nitrite, a stable metabolite of NO, but dose dependently inhibited the IL-1 beta-induced nitrite production. This inhibitory effect of Ang II was blocked by an AT1 receptor antagonist, CV-11974, but not by an Ang II type 2 receptor antagonist, PD 123319. The presence of Ang II during the early induction phase of iNOS was required for this inhibition. Consistently, Ang II suppressed IL-1 beta-induced increases in iNOS mRNA and protein levels. Ang II also inhibited increases in nitrite production and iNOS mRNA and protein levels caused by tumor necrosis factor alpha. A protein kinase C-activating phorbol ester, phorbol 12-myristate 13-acetate, and a membrane-permeable diacylglycerol, 1,2-dioctanoyl-glycerol, similarly inhibited the IL-1 beta-induced nitrite production and iNOS mRNA and protein expression, although repetitive additions were needed in the case of diacylglycerol. These results indicate that Ang II negatively modulates cytokine-induced NO production by blocking iNOS expression via the AT1 receptor in VSMC and suggest that protein kinase C could be involved in this process.
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PMID:Angiotensin II inhibits cytokine-stimulated inducible nitric oxide synthase expression in vascular smooth muscle cells. 751 70

Angiotensin II AT1 receptor signal transduction has recently been shown to function through the phospholipase C isozyme, PLC-gamma. Since PLC-gamma is known to interact with phosphotyrosine containing proteins through SH2 domains, we examined the phosphorylation state of the AT1 receptor. Immunoprecipitation of the [32P] labeled AT1 receptor from rat aortic smooth muscle cells followed by alkali hydrolysis demonstrated the presence of tyrosine phosphorylation. Phosphoamino acid analysis of the excised bands demonstrated the presence of phosphoserine and phosphotyrosine residues. A fusion protein comprising the intracellular tail of the AT1 receptor was used to screen for candidate kinases, and the src kinase family displayed high activity. In summary, this study shows that the AT1 receptor is serine and tyrosine phosphorylated in vivo and suggests that a soluble kinase related to the src family may be responsible for the tyrosine phosphorylation.
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PMID:The angiotensin II AT1 receptor is tyrosine and serine phosphorylated and can serve as a substrate for the src family of tyrosine kinases. 751 59


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