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)

Extracellular sphingosylphosphorylcholine (SPC) and galactosylsphingosine (psychosine) induced Ca2+ mobilization in a dose-dependent manner in HL60 leukemia cells. The rapid and transient increase in intracellular Ca2+ concentration ([Ca2+]i) elicited by SPC and psychosine at concentrations lower than 30 microM was inhibited by treatment of the cells with pertussis toxin (PTX) and U73122, a phospholipase C inhibitor, as was the case for UTP, a P2-purinergic agonist. The increase in [Ca2+]i induced by these lysosphingolipids was associated with inositol phosphate production, which was also sensitive to PTX and U73122. The inositol phosphate response is not secondary to the increase in [Ca2+]i as evidenced by the observation that thapsigargin and ionomycin, Ca2+ mobilizing agents, never induced inositol phosphate production and, unlike lysosphingolipids, the [Ca2+]i rise by these agents was totally insensitive to PTX and U73122. When HL60 cells were differentiated into neutrophil-like cells by dibutyryl cyclic AMP, inositol phosphate and Ca2+ responses to AlF4- were enhanced, probably reflecting an increase in the amount of Gi2 and Gi3 compared with undifferentiated cells. In the neutrophil-like cells, however, the responses to SPC and psychosine were markedly attenuated. This may exclude the possibility that the lysosphingolipids activate rather directly PTX-sensitive GTP-binding proteins or the phospholipase C itself. Other lysosphingolipids including glucosylsphingosine (glucopsychosine) and sphingosylgalactosyl sulfate (lysosulfatides) at 30 microM or lower concentrations also showed PTX- and U73122-sensitive Ca2+ mobilization and inositol phosphate response in a way similar to SPC and psychosine. However, platelet-activating factor and lysoglycerophospholipids such as lysophosphatidylcholine and lysophosphatidic acid were less effective than these lysosphingolipids in the induction of Ca2+ mobilization. Taken together, the results indicate that a group of lysosphingolipids at appropriate doses induces Ca2+ mobilization through inositol phosphate production by phospholipase C activation. The lysosphingolipids-induced enzyme activation may be mediated by PTX-sensitive GTP-binding protein-coupled receptors, which may be different from previously identified platelet-activating factor receptor or lysophosphatidic acid receptor.
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PMID:Pertussis toxin inhibits phospholipase C activation and Ca2+ mobilization by sphingosylphosphorylcholine and galactosylsphingosine in HL60 leukemia cells. Implications of GTP-binding protein-coupled receptors for lysosphingolipids. 759 44

In SH-SY5Y cells, activation of delta-opioid receptors with [D-Pen(2,5)]-enkephalin (DPDPE; 1 microM) did not alter the intracellular free Ca(2+) concentration [Ca(2+)](i). However, when DPDPE was applied during concomitant Gq-coupled m3 muscarinic receptor stimulation by carbachol or oxotremorine-M, it produced an elevation of [Ca(2+)](i). The DPDPE-evoked increase in [Ca(2+)](i) was abolished when the carbachol-sensitive intracellular Ca(2+) store was emptied. There was a marked difference between the concentration-response relationship for the elevation of [Ca(2+)](i) by carbachol (EC(50) 13 microM, Hill slope 1) and the concentration-response relationship for carbachol's permissive action in revealing the delta-opioid receptor-mediated elevation of [Ca(2+)] (EC(50) 0.7 mM; Hill slope 1.8). Sequestration of free G protein beta gamma dimers by transient transfection of cells with a beta gamma binding protein (residues 495-689 of the C terminal tail of G protein-coupled receptor kinase 2) reduced the ability of delta opioid receptor activation to elevate [Ca(2+)](i). However, DPDPE did not elevate either basal or oxotremorine-M-evoked inositol phosphate production indicating that delta-opioid receptor activation did not stimulate phospholipase C. Furthermore, delta-opioid receptor activation did not result in the reversal of muscarinic receptor desensitization, membrane hyperpolarization or stimulation of sphingosine kinase. There was no coincident signalling between the delta-opioid receptor and the lysophosphatidic acid receptor which couples to elevation of [Ca(2+)](i) in SH-SY5Y cells by a PLC-independent mechanism. In SH-SY5Y cells the coincident signalling between the endogenously expressed delta-opioid and m3 muscarinic receptors appears to occur in the receptor activation-Ca(2+) release signalling pathway at a step after the activation of phospholipase C.
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PMID:Coincident signalling between the Gi/Go-coupled delta-opioid receptor and the Gq-coupled m3 muscarinic receptor at the level of intracellular free calcium in SH-SY5Y cells. 1125 87

Lysophosphatidylserine (LPS) may be generated after phosphatidylserine-specific phospholipase A2 activation. However, the effects of LPS on cellular activities and the identities of its target molecules have not been fully elucidated. In this study, we observed that LPS stimulates an intracellular calcium increase in L2071 mouse fibroblast cells, and that this increase was inhibited by 1-[6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione (U-73122) but not by pertussis toxin, suggesting that LPS stimulates calcium signaling via G-protein coupled receptor-mediated phospholipase C activation. Moreover, LPS-induced calcium mobilization was not inhibited by the lysophosphatidic acid receptor antagonist, (S)-phosphoric acid mono-{2-octadec-9-enoylamino-3-[4-(pyridine-2-ylmethoxy)-phenyl]-propyl} ester (VPC 32183), thus indicating that LPS binds to a receptor other than lysophosphatidic acid receptors. It was also found that LPS stimulates two types of mitogen-activated protein kinase [i.e., extracellular signal-regulated protein kinase (ERK) and p38 kinase] in L2071 cells. Furthermore, these LPS-induced ERK and p38 kinase activations were inhibited by pertussis toxin, which suggests the role of pertussis toxin-sensitive G-proteins in the process. In terms of functional issues, LPS stimulated L2071 cell chemotactic migration, which was completely inhibited by pertussis toxin, indicating the involvement of pertussis toxin-sensitive G(i) protein(s). This chemotaxis of L2071 cells induced by LPS was also dramatically inhibited by 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) and by 2'-amino-3'-methoxyflavone (PD98059). This study demonstrates that LPS stimulates at least two different signaling cascades, one of which involves a pertussis toxin-insensitive but phospholipase C-dependent intracellular calcium increase, and the other involves a pertussis toxin-sensitive chemotactic migration mediated by phosphoinositide 3-kinase and ERK.
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PMID:Lysophosphatidylserine stimulates L2071 mouse fibroblast chemotactic migration via a process involving pertussis toxin-sensitive trimeric G-proteins. 1636 94