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)

Many hormones, neurotransmitters or other signaling molecules exert their biological activities through the stimulation of a specific phospholipase C. Once activated, this enzyme hydrolyzes polyphosphoinositide into inositol trisphosphate and diacylglycerol, two products known to regulate the cytosolic calcium concentration and the activity of protein kinase C, respectively. The molecular mechanisms leading to the activation of phospholipase C after the binding of the signal molecule to its specific receptor remain unclear. Yet, recent studies demonstrated that at least three molecules were implicated: the receptor, the phospholipase C and a GTP binding protein. In this review, we have summarized the properties of such systems and, more particularly, those of the vasopressin-sensitive phospholipase C present in WRK1 cells. The existence of many functional and structural analogies for the receptors which regulate adenylate cyclase activity is discussed.
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PMID:Mechanisms of phospholipase C activation: a comparison with the adenylate cyclase system. 311 15

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 (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

Utilizing a digitonin-permeabilized cell system, we have studied the release of calcium from a non-mitochondrial intracellular compartment in cultured human fibroblasts (HSWP cells). Addition of 1 mM MgATP to a monolayer of permeabilized cells in a cytosolic media buffered to 150 nM Ca with EGTA rapidly stimulates 45Ca uptake, and the subsequent addition of the putative intracellular messenger inositol trisphosphate (InsP3) induces rapid release of 85% (+/- 6% n = 6) of the 45Ca taken up in response to ATP. Mitogenic peptides (bradykinin, vasopressin, epidermal growth factor [EGF], and insulin) and orthovanadate, which are effective in mobilizing intracellular Ca in intact cells, have little or no effect when added alone to permeabilized cells. However, in the presence of GTP these agents stimulate accumulation of inositol phosphates and release Ca from the InsP3-sensitive pool. These data suggest that a GTP binding protein is involved in receptor mediated activation of phospholipase C, which leads to release of inositol phosphates. The GTP-dependent release of InsP3 and the mobilization of 45Ca from the intracellular compartment are inhibited by pretreatment of cells, prior to permeabilization, with the protein kinase C activator 12-O-tetradecanoyl-phorbol-13-acetate (TPA). TPA pretreatment does not affect the InsP3 stimulated Ca release. These results suggest that protein kinase C is involved in down-regulation or inhibition of phospholipase C, or the GTP binding protein responsible for relaying the mitogenic signal from the cell surface receptor to the phospholipase C activity.
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PMID:Calcium mobilization in permeabilized fibroblasts: effects of inositol trisphosphate, orthovanadate, mitogens, phorbol ester, and guanosine triphosphate. 349 99

The mechanism of neutrophil activation by the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (FMLP) has been studied by pretreatment of human neutrophils with pertussis toxin. Upon stimulation with FMLP, the cytosolic-free calcium concentration, [Ca2+]i, is increased both by stimulation of calcium influx and mobilization of cellular calcium. We have measured [Ca2+]i as well as the generation of the phospholipid breakdown product inositol trisphosphate (IP3), which is thought to mediate Ca2+ mobilization. As the phosphoinositide pool in human neutrophils is difficult to prelabel with [3H]myoinositol, experiments were also carried out in the cultured human promyelocytic leukemia cell line HL-60 after differentiation with dimethylsulfoxide. Pertussis toxin pretreatment of both cell types inhibited FMLP stimulated membrane depolarization, exocytosis, and superoxide production in a dose-dependent manner. This toxin effect was selective for the receptor agonist, since stimulation of these parameters by two substances bypassing the transduction mechanism, the calcium ionophore ionomycin and the phorbolester phorbol myristate acetate, were unaffected. Rises in [Ca2+]i, as well as generation of IP3 in response to FMLP, were inhibited in parallel; for the inhibition of functional responses, slightly lower toxin concentrations were required. The attentuation of the [Ca2+]i rise was more marked in the absence of extracellular calcium, i.e., when the rise is due only to calcium mobilization. The results provide evidence that phospholipase C stimulation by FMLP resulting in IP3 generation is involved in the signal transduction mechanism. Coupling of FMLP receptor occupancy to phospholipase C activation is sensitive to pertussis toxin, suggesting the involvement of a GTP binding protein (N protein), which has been shown to be a pertussis toxin substrate. The parallel changes in [Ca2+]i and IP3 further support the hypothesis that IP3 is the calcium-mobilizing mediator in FMLP-activated cells.
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PMID:Chemotactic peptide activation of human neutrophils and HL-60 cells. Pertussis toxin reveals correlation between inositol trisphosphate generation, calcium ion transients, and cellular activation. 387 77

The GTP binding G alpha h (transglutaminase II) mediates the alpha 1B-adrenoreceptor signal to a 69-kDa phospholipase C (PLC). Thus, G alpha h possesses both GTPase and transglutaminase activities with a signal transfer role. The recognition sites of this unique GTP binding protein for either the receptor or the effector are completely unknown. A site on human heart G alpha h (hhG alpha h) has been identified that interacts with and stimulates PLC. Expressed mutants of hhG alpha h with deleted C-terminal regions lost the response to (-)-epinephrine and GTP and failed to coimmunoprecipitate PLC by the specific Gh7 alpha antibody. The interaction regions were further defined by studies with synthetic peptides of hhG alpha h and a chimera in which residues Val665-Lys672 of hhG alpha h were substituted with Ile707-Ser714 residues of human coagulation factor XIIIa. Thus, eight amino acid residues near the C terminus of hhG alpha h are critical for recognition and stimulation of PLC.
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PMID:Interaction site of GTP binding Gh (transglutaminase II) with phospholipase C. 759 56

We have previously established that 21-day-old postnatal rat oligodendrocytes, maintained in monolayer culture and subjected to 6 h of hypoxia, show reversible inhibition of synthesis of alpha-hydroxy fatty acid and myelin basic protein but a dramatic induction of a 22-kDa protein, suggesting that this is a good model to study the mechanism of CNS demyelination caused by hypoxic injury. We now report that hypoxia also dramatically inhibits the basal protein kinase C-mediated phosphorylation of myelin basic protein and myelin 2',3'-cyclic nucleotide phosphohydrolase by 80%, but that the inhibition of phosphorylation can be reversed by addition of a protein kinase C activator, phorbol 12-myristate 13-acetate. The mechanism of action appears to involve the uncoupling of signal transduction at a site before phospholipase C, because hypoxia did not affect protein kinase C activity or its translocation to the membrane fraction. The most potent activator of phospholipase C (as measured by inositol phosphate release) was carbachol (muscarinic M1 receptor agonist), followed by L-phenylephrine (alpha 1-adrenergic receptor agonist) in normal oligodendrocytes. Excitatory amino acids and histamine were ineffective. Hypoxia for 6 h completely inhibited both muscarinic and alpha 1-adrenergic receptor-mediated inositol monophosphate release but did not affect phospholipase D-coupled phosphatidylethanol production in response to carbachol. We therefore conclude from this and earlier work that early, reversible changes in oligodendrocyte metabolism result not simply from ATP depletion, but may specifically target GTP binding protein-mediated processes.
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PMID:Effects of hypoxia on oligodendrocyte signal transduction. 768 39

Muscarinic agonists and guanylyl-5'-imidodiphosphate (Gpp(NH)p) stimulated formation of inositol phosphates in permeabilized longitudinal smooth muscle of guinea pig ileum. Gpp(NH)p markedly potentiated the formation of inositol bisphosphate (IP2) and inositol trisphosphate (IP3) stimulated by carbachol, but increased inositol monophosphate formation (IP1) only slightly. Gpp(NH)p enhanced the formation of IP2 + IP3 induced by either acetylcholine or carbachol about fourfold in a synergistic manner, but enhanced the effects of oxotremorine and pilocarpine less than twofold in an additive manner. Elevation of Ca2+ concentration resulted in increases of the inositol phosphate levels stimulated by both carbachol and Gpp(NH)p. The optimal concentration of Ca2+ for carbachol-stimulated formations of IP2 + IP3 was shifted to a lower Ca2+ concentration in the presence of Gpp(NH)p. These findings suggest that muscarinic receptor-stimulated polyphosphoinositide hydrolysis in ileal smooth muscle results in inositol polyphosphate formation via GTP binding protein (G-protein). The muscarinic receptor-activated G-protein decreases the Ca2+ requirement of polyphosphoinositide hydrolysis. Muscarinic agonists stimulate inositol polyphosphate formation by interaction of the G-protein activation of a phosphoinositide specific phospholipase C with Ca2+ influx.
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PMID:The mechanism of muscarinic agonist-stimulated inositol phosphate formation in permeabilized ileal smooth muscle. 779 28

The effects of acute and chronic ethanol exposures on the stimulation of inositol specific phospholipase C by metabotropic glutamate receptor activation were determined in primary cultures of rat cortical astrocytes. Phospholipase C activity was monitored by the formation of [3H]inositol phosphates in the presence of lithium in cells prelabelled with [3H]inositol. Acute exposure to 200 mM ethanol had no significant effect on either basal or L-glutamate stimulated [3H]inositol phosphate formation. In cells chronically exposed to ethanol for 4 days, the [3H]inositol phosphate responses to L-glutamate, quisqualate, and the selective metabotropic receptor agonist, 1S,3R-1-amino-cyclopentane-1,3 dicarboxylic acid (trans-ACPD), were significantly inhibited when compared to control (untreated) cells. In contrast, chronic ethanol exposure had no significant effect on the [3H]inositol phosphate response to endothelin-1, a peptide structurally and functionally unrelated to L-glutamate. Similarly, the stimulation of [3H]inositol phosphate formation by the stable GTP analog, guanine 5'-(gamma-thiotrisphosphate), was also unaffected by chronic ethanol exposure. The results suggest that chronic ethanol exposure does not affect the coupling of GTP binding proteins to phospholipase C, but rather acts in a selective manner to either alter the metabotropic receptor number or to disrupt the normal coupling of this receptor to its GTP binding protein, which may in turn affect receptor affinity.
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PMID:Selective effects of ethanol exposure on metabotropic glutamate receptor and guanine nucleotide stimulated phospholipase C activity in primary cultures of astrocytes. 781 99

1. 5-Hydroxytryptamine (5-HT) has been shown to induce contraction of tracheal smooth muscle. However, the mechanisms of action of 5-HT are not known. We therefore investigated the effects of 5-HT on phospholipase C (PLC)-mediated phosphoinositide (PI) hydrolysis and its regulation in canine cultured tracheal smooth muscle cells (TSMCs) labelled with [3H]-inositol. 5-HT-induced inositol phosphates (IPs) accumulation was time- and dose-dependent with a half-maximal response (EC50) and a maximal response at 0.38 +/- 0.05 and 10 microM, respectively. 2. Ketanserin and mianserin (10 and 100 nM), 5-HT2 receptor antagonists, were equipotent in blocking the 5-HT-induced IPs accumulation with pKB values of 8.46 and 8.21, respectively. In contrast, the dose-response curves of 5-HT-induced IPs accumulation were not shifted until the concentrations of NAN-190 and metoclopramide (5-HT1A and 5-HT3 receptor antagonists, respectively) were increased up to 10 microM. 3. Pretreatment of TSMCs with pertussis toxin or cholera toxin did not inhibit the 5-HT-induced IPs accumulation, but partially inhibited the AlF(4-)-induced IPs response. 4. Stimulation of IPs accumulation by 5-HT required the presence of external Ca2+ and was blocked by EGTA. The addition of Ca2+ (3-620 nM) to digitonin-permeabilized TSMCs directly stimulated IPs accumulation. A further Ca(2+)-dependent increase in IPs accumulation was obtained by inclusion of either guanosine 5'-O-(3-thiotriphoshate) (GTP gamma S) or 5-HT. The combination of GTP gamma S and 5-HT elicited an additive effect on IPs accumulation. 5. Treatment with phorbol 12-myristate 13-acetate (PMA, 1 microM, 30 min) abolished the 5-HT-induced IPs accumulation. The concentrations of PMA that gave a half-maximal and maximal inhibition of 5-HT-induced IPs accumulation were 2.2 +/- 0.4 nM and 1 microM, n = 3, respectively. The protein kinase C (PKC) activator, 4 alpha-phorbol 12,13-didecanoate, at 1 microM, did not influence this response. The inhibitory effect of PMA was reversed by staurosporine, a PKC inhibitor, suggesting that the inhibitory effect of PMA is mediated through the activation of PKC. 6. The site of this inhibition was further investigated by examining the effect of PMA on AlF(4-)-induced IPs accumulation in canine TSMCs. AlF(4-)-stimulated IPs accumulation was inhibited by PMA treatment, suggesting that the effect of PMA is distal to the 5-HT receptor. 7. Acetylcholine-induced IPs accumulation was completely inhibited by atropine, but not affected by ketanserin or mianserin, suggesting that 5-HT-induced IPs accumulation is not due to release of acetylcholine.8. These results demonstrate that 5-HT directly stimulates PLC-mediated PI hydrolysis via a pertussis toxin- and cholera toxin-insensitive GTP binding protein in canine TSMCs and that this coupling process is negatively regulated by PKC. 5-HT2 receptors may be predominantly mediating IPs accumulation and presumably IP-induced Ca2+ release may function as the transducing mechanism for 5-HT stimulated contraction of tracheal smooth muscle.
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PMID:5-Hydroxytryptamine receptor-mediated phosphoinositide hydrolysis in canine cultured tracheal smooth muscle cells. 801 56


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