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)

Na(+)-Ca2+ exchange contributes to regulation of cytosolic free Ca2+ levels ([Ca2+]i) of cultured human mesangial cells following phospholipase C stimulation, as shown by larger responses to vasoconstrictors such as angiotensin II (ANG II) or endothelin 1 in Na(+)-free media. In turn, previous activation of phospholipase C by vasoconstrictors significantly enhances the amplitude of the [Ca2+]i elevation induced by Na+ withdrawal. We studied the mechanisms of upregulation in monolayer cultures loaded with the fluorescent Ca(2+)-sensitive probe fura-2. The exchanger was stimulated by insulin and inhibited by chronic exposure to serum. A rise of [Ca2+]i was not sufficient per se to enhance exchange activity, as prior elevation of [Ca2+]i with the ionophores ionomycin or 8-bromo-A23187 failed to augment the response to Na+ withdrawal. Protein kinase C (PKC) activation by phorbol 12-myristate-13-acetate (PMA), alone or in combination with a rise of [Ca2+]i, potently inhibited basal and vasoconstrictor-enhanced Na(+)-Ca2+ exchange. Suppression of the effects of ANG II was not due to frustrated phospholipase C activation by PMA, because addition of PMA after ANG II also inhibited Na(+)-Ca2+ exchange. PKC downregulation by 24-h pretreatment with PMA or inhibition with 1-(5-isoquinolinesulfonyl)-2-methylpiperazine or staurosporine did not prevent activation by ANG II. The exchanger was markedly potentiated by Na+ loading the cells with gramicidin D or reducing extracellular K+. ANG II failed to stimulate Na(+)-Ca2+ exchange when added in the absence of extracellular Na+. Therefore vasoconstrictors promote Na(+)-Ca2+ exchange by a mechanism independent of [Ca2+]i and PKC while presumably linked to Na+ influx.
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PMID:Regulation of Na(+)-Ca2+ exchange in cultured human mesangial cells. 171 60

In our previous report (Biochem. Biophys. Res. Commun. 165(3), 1221-1228, 1989), we have demonstrated the biphasic increase of intracellular free calcium concentration ([Ca++]i) induced by angiotensin II (ANG II) in isolated rat early proximal tubule (S1). The present study was undertaken to determine the effect of HgCl2 on ANG II-induced [Ca++]i increase using Fura-2. HgCl2 (10(-10) M2-10(-8) M) potentiated the [Ca++]i increase induced by ANG II (10(-11) M) in a dose-dependent manner. To determine the mechanism of stimulatory effect by HgCl2 on ANG II-induced [Ca++]i increase, nephron segments were pretreated with 10(-4) M propranolol, a phospholipase C inhibitor. The stimulatory effect by 10(-9) M HgCl2 in 10(-11) M ANG II-induced [Ca++]i increase was completely inhibited by propranolol. Moreover, 10(-4) M propranolol completely blocked the stimulatory effect of HgCl2 on ANG II-mediated IP3 production. This study suggests for the first time that HgCl2 stimulates the [Ca++]i increment induced by ANG II, possibly through an activation of phospholipase C.
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PMID:Mercury chloride as a possible phospholipase C activator: effect on angiotensin II-induced [Ca++]i transient in the rat early proximal tubule. 226 Sep 72

We evaluated the role of GTP-binding proteins in the activation of phospholipase C, release of arachidonic acid, and synthesis of prostaglandin (PG) E2 in response to platelet-activating factor (PAF) and angiotensin II (ANG II) in cultured rat mesangial cells. Pretreatment with pertussis toxin (PT) decreased PGE2 formation and arachidonic acid release in response to PAF and ANG II but not that to A 23187. PT pretreatment also inhibited formation of inositol trisphosphate (IP3) in response to ANG II or PAF but did not significantly alter the rise in intracellular calcium detected by fura-2. PT catalyzed ADP ribosylation of two proteins of molecular mass approximately 40 and 41 kDa. Further evidence for involvement of GTP-binding protein in phospholipase C activation was that GTP-gamma S stimulated IP3 generation. Immunoblots with antibodies directed against different inhibitory alpha subunits of GTP-binding proteins showed that the major 40-kDa PT substrate reacted with an antibody directed against a decapeptide of the G protein subunit alpha i2 that is also found in leukocytes. This was further confirmed by Northern blot that showed the existence of mRNA in mesangial cells that hybridized with a cDNA probe for G alpha i2. In addition lesser amounts of mRNA hybridized with a restriction fragment cDNA probe for G alpha i3, which corresponds to the 41-kDa substrate for PT ribosylation. These results show that phospholipase C activation by PAF and ANG II in mesangial cells involves a specific G protein, most likely G alpha i2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relationship of GTP-binding proteins, phospholipase C, and PGE2 synthesis in rat glomerular mesangial cells. 249 60

Angiotensin II (ANG II) and vasopressin (AVP) are two powerful vasoconstrictors, and atrial natriuretic peptide (ANP) is a potent vasorelaxant. The changes in the density or affinity of binding sites for these agents that may alter target organ responsiveness in hypertension are reviewed. ANG II binding in mesenteric arteries was unaltered in one-kidney, one-clip (1-K, 1-C) and in 2-K, 1-C hypertensive rats, while in deoxycorticosterone acetate (DOCA)-salt hypertensive rats ANG II binding to blood vessels was significantly increased. A role of mineralocorticoids to increase the number of vascular ANG II sites in some hypertensive models is suggested. In spontaneously hypertensive rats (SHR) ANG II receptors were increased in young rats in the prehypertensive stage with respect to Wistar-Kyoto (WKY) control rats, but normal in older rats. AVP binding in the vasculature of hypertensive rats was uniformly decreased in inverse correlation to plasma AVP levels, but vascular responsiveness to AVP was exaggerated. Inositol trisphosphate production by blood vessels of SHR in response to AVP showed that increased AVP receptor-coupled phospholipase C activity may mediate in part the exaggerated pressor response in spite of reduced or normal density of receptors for vasoconstrictor peptides. Vascular ANP sites in 2-K, 1-C, 1-K,1-C, and DOCA-salt hypertensive rats varied inversely with plasma concentrations of ANP. Normal densities of ANP receptors in saralasin-sensitive 2-K, 1-C hypertensive rats correlated with ANP sensitivity, while saralasin-insensitive 2-K, 1-C hypertensive rats, which did not respond to ANP, had significantly decreased density of ANP vascular receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vascular receptors for angiotensin, vasopressin, and atrial natriuretic peptide in experimental hypertension. 255 50

It was the aim of the present study to get insight into some of the intracellular mechanisms by which the vasoconstrictor hormones angiotensin II (ANG II), arginine vasopressin (AVP), and norepinephrine (NE) inhibit renin release from renal juxtaglomerular cells. To this end a primary cell culture from rat renal cortex was established that consisted of 50% juxtaglomerular cells. The cultured juxtaglomerular cells contained prominent renin granules closely resembling those in the intact kidney and responded to a number of stimuli of renin release. By using these cultures, we found that ANG II (10(-7) M), AVP (10(-6) M), and NE (10(-5) M) inhibited renin release and increased the calcium permeability of the plasma membrane of the cultured cells. Both the effects on renin release and on calcium permeability could be diminished or even be abolished by the calcium channel blocker verapamil (Vp) (10(-5) M). ANG II, AVP, and NE led to an increased formation of diacylglycerol (DAG), a well-known stimulator of protein kinase C (PKC). Moreover, a direct stimulation of PKC by 12-O-tetradecanoylphorbol-13-acetate (TPA) (10(-8)-10(-6) M) also inhibited renin release and increased the calcium permeability of the cell membrane. Similar to ANG II, AVP, and NE, the effects of TPA on calcium permeability and renin release could be diminished by Vp. In conclusion, these results point toward a common mechanism by which vasoconstrictors inhibit renin release from renal juxtaglomerular cells: ANG II, AVP, and NE activate a phospholipase C, which generates DAG.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of protein kinase C in inhibition of renin release caused by vasoconstrictors. 300 66

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

The effects of U-73122, a phospholipase C (PLC) inhibitor, on pressor responses to angiotensin II (ANG II), norepinephrine (NE), serotonin (5-HT), BAY K 8644, and the thromboxane A2 (TxA2) mimic, U-46619, were studied in the pulmonary vascular bed of the intact-chest cat. Under conditions of constant lobar blood flow, injections of ANG II, NE, 5-HT, U-46619, and the calcium channel opener, BAY K 8644, into the lobar arterial perfusion circuit caused dose-related increases in lobar arterial pressure, which were reproducible with respect to time. Infusion of U-73122, a PLC inhibitor, into the perfused lobar artery at 10-100 micrograms/kg for 10 min significantly reduced responses to ANG II, serotonin, and NE; however, U-73122 did not alter responses to BAY K 8644 or to U-46619. In a separate series of animals, the effects of the myosin light chain kinase inhibitor, KT-5926, were investigated, and after infusion of KT-5926 into the perfused lobar artery at 1-2 micrograms/kg for 10 min, responses to ANG II, NE, 5-HT, BAY K 8644, and U-46619 were reduced significantly. In a final series of experiments, the effects of the L-type calcium channel blocker, nicardipine, were investigated, and infusion of the L-type calcium channel blocker into the perfused lobar artery at 0.5-1 microgram/kg for 10 min reduced responses to ANG II, BAY K 8644, and NE. However, nicardipine did not alter pressor responses to 5-HT or the TxA2 mimic, U-46619.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Influence of PLC and MLCK inhibitors and the role of L-calcium channels in the cat pulmonary vascular bed. 748 23

A stable Chinese hamster ovary fibroblast line expressing the rat vascular type 1a angiotensin II (ANG II) receptor was used to study the lipid-derived signal transduction pathways elicited by type 1a ANG II receptor activation. ANG II caused a biphasic and dose-dependent increase in diacylglycerol (DAG) accumulation with an initial peak at 15 s (181 +/- 11% of control, P < 0.02) and a second sustained peak at 5-10 min (214 +/- 10% of control, P < 0.02). The late DAG peak was derived from phosphatidylcholine (PC), and the formation was blocked by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. ANG II also increased phosphatidic acid (PA) production nearly fourfold by 7.5 min. In the presence of ethanol, ANG II markedly increased phosphatidylethanol (PEt) formation, indicating activation of phospholipase D (PLD). ANG II was shown to increase the mass of three separate PA species, one of which apparently originated from DAG kinase action on PC-phospholipase C (PLC)-produced DAG, providing evidence for PC-PLC activity. ANG II also formed a third PA species, which originated neither from PLD nor from DAG kinase. These results demonstrate that multiple lipid signals propagated via collateral stimulation of PLC and PLD are generated by specific activation of the vascular type 1a ANG II receptor.
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PMID:Lipid signal transduction pathways in angiotensin II type 1 receptor-transfected fibroblasts. 765 25

Angiotensin II (ANG II) receptors of the AT1 subtype are present on the apical and basolateral membranes of renal proximal tubule cells. Cells of the proximal tubulelike cell line, LLC-PK1/Cl4, were transfected with an expression plasmid containing cDNA encoding the rabbit AT1 ANG II receptor. In transfected cells, specific binding of 125I-ANG II was detected on both apical and basolateral membranes; wild-type LLC-PK1/Cl4 cells did not express ANG II receptors. In transfected cells, apical or basolateral ANG II increased both S6 kinase activity and incorporation of [3H]leucine. In cells pretreated with pertussis toxin, the stimulatory effect of apical or basolateral ANG II on [3H]leucine incorporation was abolished. In contrast, ANG II did not affect mitogenesis, determined by [3H]thymidine incorporation. Apical or basolateral ANG II (10(-6) M) stimulated phosphoinositide turnover by 13.4 +/- 4.4% (n = 8) and 16.3 +/- 4.2% (n = 9), respectively. The activity of protein kinase C, determined by phosphorylation of a specific protein kinase C peptide substrate, was also stimulated by ANG II in transfected cells. Apical or basolateral ANG II had no significant effect on cellular adenosine 3',5'-cyclic monophosphate levels. In permeabilized transfected cells, apical ANG II (10(-6) M) inhibited the phosphorylation of a specific peptide substrate of protein kinase A; lower apical concentrations or basolateral ANG II were without significant effect. These results indicate that AT1 ANG II receptors sort to both apical and basolateral membranes in renal epithelial cells and are coupled to activation of phospholipase C. ANG II stimulates protein synthesis by binding to either apical or basolateral receptors; this effect requires coupling to G proteins and may be mediated by activation of S6 kinase. Because high concentrations of ANG II exist in proximal tubule, binding to apical and basolateral receptors may regulate proximal tubule cell growth under physiological conditions.
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PMID:Signaling and growth responses of LLC-PK1/Cl4 cells transfected with the rabbit AT1 ANG II receptor. 773 40

We previously reported that the Ca(2+)-activated K+ channel (KCa-channel) in cultured smooth muscle cells from porcine coronary artery was inhibited by protein kinase C (C-kinase). In this study, inhibition of the KCa-channel by receptor-mediated vascular contractile agonists, such as angiotensin II (ANG II) and endothelin-1 (ET-1), was investigated by the patch-clamp technique. In cell-attached patches, addition of ANG II (500 nM) or ET-1 (50 nM) to the bath inhibited the KCa-channel activated by the calcium ionophore A23187 (10-20 microM). Phorbol 12-myristate 13-acetate (PMA, 1 microM), a C-kinase activator, also decreased the open probability of the KCa-channel. The PMA-induced decrease in the open probability was reversed by subsequent application of staurosporine (1 nM), a C-kinase inhibitor, but the ANG II- and ET-1-induced decreases were not reversed by subsequent application of staurosporine (> 30 nM). Pretreatment of smooth muscle cells with 30 nM staurosporine, a protein kinase inhibitor, or 1 mM neomycin, an inhibitor of phospholipase C, also did not abolish the inhibition of the KCa-channel by ANG II. Furthermore, ANG II inhibited the KCa-channel in cells in which C-kinase was down-regulated. These results indicate that, in porcine coronary artery smooth muscle cells, ANG II and ET-1 inhibit the KCa-channel by a C-kinase-independent mechanism.
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PMID:Protein kinase C-independent inhibition of the Ca(2+)-activated K+ channel by angiotensin II and endothelin-1. 774 84


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