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)

We demonstrated previously that alpha-1 adrenergic catecholamines modulate cardiac automaticity in a manner that is dependent upon the function of a pertussis toxin sensitive guanine nucleotide binding protein (G protein). Furthermore, we demonstrated that alpha-1 adrenergic receptor stimulation promotes the accumulation of inositol monophosphate (IP1). In the present study we used high-pressure liquid chromatography to resolve individual inositol phosphate isomers formed in norepinephrine-stimulated cultured rat ventricular myocytes. Norepinephrine stimulated a rapid, transient increase in 1,4,5-inositol trisphosphate (1,4,5-IP3) which was followed by slower, sustained increases in 1,3,4-IP3, inositol bisphosphate (IP2) and IP1. IP1 was composed of two major isomers with retention times characteristic of 1-IP1 and 4-IP1. 4-IP1 was the predominant IP1 isomer formed during stimulation with norepinephrine suggesting that the polyphosphoinositides rather than phosphatidylinositol are the principal targets of norepinephrine-stimulated phospholipase C activity in the heart. This was confirmed in studies performed on myocyte membranes which demonstrated proportionately greater IP2 and IP3 (relative to IP1) accumulation in response to norepinephrine. G protein regulation of alpha-1 adrenergic-dependent inositol phospholipid hydrolysis also was examined. In myocyte membranes, guanosine-5'-0-(3-thiotriphosphate) induced the accumulation of IP2 and IP3 and was required for the stimulatory effect of norepinephrine. This response was not impaired after pretreatment with pertussis toxin. These results indicate that the myocyte alpha-1 adrenergic receptor is coupled to a polyphosphoinositide-specific phospholipase C by a pertussis toxin insensitive G protein and suggest that under certain conditions IP3 may serve an important role in alpha-1 adrenergic modulation of cardiac function.
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PMID:Alpha-1 adrenergic stimulation of 1,4,5-inositol trisphosphate formation in ventricular myocytes. 255 Jun 17

In addition to stimulation of cyclic AMP, parathyroid hormone (PTH) may influence cellular events by utilizing other pathways of hormone action, such as the generation of inositol phosphates (IPs). We sought to examine this potential action of PTH by assessing the formation of inositol phosphates in PTH-sensitive ROS 17/2.8 cells. The polyphosphoinositides were labeled by growing the cells with [3H]inositol following which cell homogenates were prepared. The nonhydrolyzable guanine nucleotide, GTP gamma S, and calcium ion, alone and together, stimulated all three IPs, IP1, IP2, and IP3. IP1 formation was linear over 30 minutes but IP2 and IP3 accumulated more rapidly peaking by 5 minutes for all agonist conditions. The proportion of total P as IP3 was enhanced when the cells were grown with retinoic acid (1 microM) or when the assay was conducted at pH 4.5. In addition, the lower pH was associated with much more enzyme activity. PTH agonists, bPTH-(1-84) and bPTH-(1-34), both caused a small but significant stimulation of IP3 formation. When bPTH-(1-84), and the analog bPTH-(3-34)amide, that inhibits PTH-mediated adenylate cyclase activity were present together, there was additive stimulation of IP3 formation compared with that with either agent alone. The results demonstrate that inositol phosphate formation can be stimulated directly in a membrane preparation of ROS cells by GTP gamma S, calcium ion, and PTH and that the enzyme mediating this activity, phospholipase C, is regulated by a guanine nucleotide binding protein.
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PMID:Stimulation of inositol phosphate formation in ROS 17/2.8 cell membranes by guanine nucleotide, calcium, and parathyroid hormone. 276 77

Inositol phospholipids play a crucial role in the intracellular signal transduction in most cell types. Activation of an enzyme called phospholipase C or PIP2-phosphodiesterase (PIP2-PDE) leads to the production of two second messenger molecules, diacylglycerol (DG) and inositol 1,4,5-triphosphate (IP3). DG activates a kinase called protein kinase C, whereas IP3 mediates the release of Ca2+ from intracellular storage sites. The measurement of IP3 and its degradation products, inositol diphosphate (IP2) and inositol monophosphate (IP1) provides a way of assessing the extent to which this complex system has been activated. In the central nervous system (CNS) most of the studies on the neurotransmitter stimulated formation of inositol phosphates (IPs) have been performed on brain slices, a mixture of mainly neurons and glial cells. The recent development of pure neuronal cultures provides a means of determining which of these responses were of neuronal origin. The purpose of this review is to summarize the results obtained in neurons in primary culture together with a brief appraisal of the possible function of this second messenger system in neurons.
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PMID:Putative role of inositol phospholipid metabolism in neurons. 282 May 14

In human thyroid slices prelabeled with myo-[2-3H]inositol, thyrotropin (TSH, 3-30 mU/ml) stimulated IP3, IP2 and IP1 generation over a prolonged time course. The cAMP response was much more sensitive to TSH, peaking between 1 and 5 mU/ml. Forskolin (10(-5) M) and isoproterenol had no effect on basal IP levels, while carbamylcholine (10(-5) M, 10(-4) M) also increased IP accumulation. These data suggest that in the human thyroid, TSH activates a phospholipase C generating IP3 and diacylglycerol independently of the well-known adenylate cyclase stimulation. They validate in the human model a dual mode of action of the hormone previously proposed on the basis of indirect observations.
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PMID:Dual activation by thyrotropin of the phospholipase C and cyclic AMP cascades in human thyroid. 282 Aug 16

Rat intestinal epithelial cells were labelled with [32P]Pi and extracted, and the phospholipids were analysed by thin-layer chromatography. 32P-incorporation in phosphatidylinositol (PI) and phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5-phosphate (PIP2) were measured in control and heat stable enterotoxin (ST)-treated cells. ST was found to induce rapid degradation of PIP and PIP2. The degradation of inositol lipids was accompanied by an increase of water soluble inositol phosphate (IP1, IP2, IP3) compounds. There was a two-fold increase of radioactivity in IP2 and IP3 but no significant change was observed in IP1. Phospholipase C activity was increased tenfold with substrate PIP2 in ST-pretreated cells. The present study indicates that ST triggers another second messenger system by increasing the PIP2 hydrolysis with the enzyme phospholipase C.
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PMID:Stimulation of phosphoinositides breakdown by the heat stable E. coli enterotoxin in rat intestinal epithelial cells. 284 95

In cultured rabbit vascular smooth muscle cells (VSMC), platelet-derived growth factor (PDGF), a potent mitogen for VSMC, induced the dose- and time-dependent formation of inositol mono-, bis- and trisphosphates (IP1, IP2 and IP3, respectively). The doses of PDGF necessary for these reactions were similar to those for DNA synthesis. The maximal level of IP1 was comparable to, and those of IP2 and IP3 were about half of those induced by angiotensin II, a potent vasoconstrictor. However, the time courses of the PDGF-induced reactions were slower than those of the angiotensin II-induced ones. Moreover, protein kinase C-activating phorbol esters inhibited the angiotensin II-induced reactions, but did not the PDGF-induced ones. These results indicate that PDGF induces the phospholipase C reactions in VSMC but suggest that the signaling mechanism of PDGF to the phospholipase C is different from that of angiotensin II.
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PMID:Platelet-derived growth factor (PDGF)-induced phospholipase C-mediated hydrolysis of phosphoinositides in vascular smooth muscle cells--different sensitivity of PDGF- and angiotensin II-induced phospholipase C reactions to protein kinase C-activating phorbol esters. 284 20

Binding of chemoattractants to specific cell surface receptors on human polymorphonuclear leukocytes (PMNs) initiates a variety of biologic responses, including directed migration (chemotaxis), release of superoxide anions, and lysosomal enzyme secretion. Chemoattractant receptors belong to a large class of receptors which utilize the hydrolysis of polyphosphoinositides to initiate Ca2+ mobilization and cellular activation. Receptor occupancy leads to phospholipase C-mediated hydrolysis of polyphosphoinositol 4,5-bisphosphate (PIP2) yielding inositol 1,4,5-trisphosphate (IP3) and 1,2 sn-diacylglycerol (DAG). These products synergize to initiate cell activation via calcium mobilization (IP3) and protein kinase C activation (DAG). Pertussis toxin, which ADP-ribosylates and inactivates some GTP binding proteins (G proteins), abolishes all chemoattractant-induced responses, including Ca2+ mobilization, IP3 and DAG production, enzyme secretion, superoxide production and chemotaxis. Direct evidence for chemoattractant receptor: G protein coupling was obtained using PMN membrane preparations which contain a Ca2+-sensitive phospholipase C. Hydrolysis of polyphosphoinositides at resting intracellular Ca2+ levels (100 nm) was only observed when the membranes were stimulated with the chemoattractant N-formyl-methyl-leucyl-phenylalanine (fMet-Leu-Phe) in the presence of GTP. Myeloid cells contain two distinct pertussis toxin substrates of similar molecular weight (40 and 41 kD). The 41 kD substrate resembles Gi, whereas a 40 kD substrate is physically associated with a partially purified fMet-Leu-Phe receptor preparation and may therefore represent a novel G protein involved in chemoattractant-stimulated responses. Metabolism of 1,4,5-IP3 to inositol proceeds via two distinct pathways in PMNs: (1) degradation to 1,4-IP2 and 4-IP1 or (2) conversion to 1,3,4,5-IP4, 1,3,4-IP3, 3,4-IP2 and 3-IP1. Initial formation (0-30 s) of 1,4,5-IP3 and DAG occurs at ambient intracellular Ca2+ levels, whereas formation of 1,3,4-IP3 and a second sustained phase of DAG production (30 s-10 min) require elevated cytosolic Ca2+ influx. The later peak of DAG, which is not derived from phosphoinositides, appears to be required for stimulation of respiratory burst activity. Products formed during activation can feed back to attenuate chemoattractant receptor-mediated stimulation of phospholipase C by uncoupling receptor-G protein-phospholipase C interaction.
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PMID:Signal transduction in cells following binding of chemoattractants to membrane receptors. 290 Nov 61

Deoxycholate promotes phospholipase C degradation of endogenous phosphatidyl[3H]inositol (Pl), phosphatidyl[3H]inositol monophosphate (PIP) and phosphatidyl[3H]inositol bisphosphate (PIP2) in rat cornea and human platelets. Hydrolysis of phosphatidyl[3H]inositol significantly lags polyphospho[3H]inositide degradation. Concomitantly, formation of [3H]inositol monophosphate (IP1) lags behind [3H]inositol bisphosphate (IP2) and [3H]inositol trisphosphate (IP3) production. These results demonstrate that rat cornea and human platelet phospholipase C cause a preferential hydrolysis of the endogenous polyphosphoinositides rather than phosphatidylinositol.
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PMID:Deoxycholate induces the preferential hydrolysis of polyphosphoinositides by human platelet and rat corneal phospholipase C. 299 Apr 55

Clonal neurohybridoma NCB-20 cells expressed muscarinic cholinergic receptors coupled to phospholipase C. Addition of carbachol in the presence of Li+ to cells prelabeled with 3H-inositol increased 3H-inositol-l-phosphate (3H-IP1) accumulation by more than 4-fold with an EC50 of about 50 microM. This carbachol-induced response was blocked by atropine and pirenzepine with a Ki of 0.5 and 25 nM, respectively. The EC50 of Li+ for the carbachol-induced phosphoinositide turnover was 17 +/- 1.2 mM compared with a value of 1.8 +/- 0.2 mM in brain slices, suggesting the presence of an unusual type of inositol-l-phosphatase in NCB-20 cells. Carbachol-induced IP1 accumulation in these cells was potently and noncompetitively inhibited by the biologically active phorbol esters, phorbol dibutyrate (PDB) and phorbol myristate diacetate (PMA), while the biologically inactive phorbol, 4 beta-phorbol, failed to affect this phosphoinositide breakdown. The basal IP1 accumulation was also significantly attenuated by PDB and PMA but not by 4 beta-phorbol.
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PMID:Carbachol-induced accumulation of inositol-1-phosphate in neurohybridoma NCB-20 cells: effects of lithium and phorbol esters. 301 Sep 87

In the guinea pig myometrium prelabelled with myo-[2-3H]inositol, carbachol and oxytocin enhanced a concentration-dependent and rapid release of IP3 which preceded that of IP2 and IP1. The specific receptor-mediated phospholipase C activation degrading PIP2 to IP3 did not require the presence of extracellular Ca2+. The ionophore A23187 as well as K+ depolarization failed to increase inositol phosphate accumulation. It is proposed that IP3 could have a role in the contraction of uterine smooth muscle elicited by the activation of muscarinic as well as of oxytocin receptors.
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PMID:Carbachol and oxytocin stimulate the generation of inositol phosphates in the guinea pig myometrium. 301 7


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