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)

Porcine galanin (1-29)-NH2, galantide (M15) and galanin (1-14)-(alpha-aminobutyric acid8)-scyliorhinin-I used in concentrations of 300, 1,000 and 3,000 nM respectively caused contractions of rat fundus strips. The contractile responses to galanin(1-29)-NH2 were not modified by atropine (10 microM), guanethidine (10 microM), naloxone (1 microM), a mixture of propranolol (10 microM) and phentolamine (10 microM), indomethacin (10 microM), a mixture of mepyramine (10 microM) and cimetidine (10 microM), saralasin (10 microM), and spantide (100 microM). The effects of M15 and galanin(1-14)-(alpha-aminobutyric acid8)-scyliorhinin-I were significantly decreased by atropine for 36 and 18% and by spantide for 37 and 26% respectively. Indomethacin inhibited the muscle response to M15 without influence on the galanin (1-14)-(alpha-aminobutyric acid8)-scyliorhinin-I-induced action. These results support findings that galanin (1-29)-NH2 contracts rat gastric fundus strips by stimulating specific receptors localized on the surface of smooth muscle cells. M15 and galanin(1-14)-(alpha-aminobutyric acid8)-scyliorhinin-I seem to contract smooth muscles not only by acting at galanin receptors, but by interacting with muscarinic or tachykinin receptors or modulating the release of acetylcholine and substance P. Diltiazem (EC50 825 nM), dantrolene (EC50 30.2 microM) and the phospholipase C inhibitors U-73122 (EC50 549 microM) and U-73343 (EC50 751 microM) lowered the contraction to galanin(1-29)-NH2 in a concentration-dependent manner. These observations imply that though the extracellular Ca2+ influx plays a major role in the action of galanin(1-29)-NH2, the release of Ca2+ ions from the intracellular stores contributes to the response of smooth muscles of galanin(1-29) NH2. Norepinephrine (30, 60, 100 and 300 nM) concentration-dependently reduced the Emax to galanin (1-29)-NH2 and reduced the slopes of the concentration-contraction curves, without a notable change in EC50. Pertussis toxin pre-treatment (10 and 30 mg/kg intravenous [i.v.]), 120 h before the experiment, notably increased the maximal response of the rat gastric fundus to galanin(1-29)-NH2, without a significant change in the properties of the concentration-contraction curves (EC50, slopes). The observations may suggest that pertussis toxin-sensitive GTP-binding proteins are involved in the modulation of the excitatory effects of galanin(1-29)-NH2 in the rat gastric fundus.
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PMID:Pharmacological characterization of the contractile effects of galanin (1-29)-NH2, galantide and galanin (1-14)-(alpha-aminobutyric acid8)scyliorhinin-I in the rat gastric fundus. 944 26

As the first step to investigate the physiological function of phospholipase C (PLC), we determined the distribution patterns of PLC isozymes in normal rat kidneys using Western blotting analysis and immunohistochemistry. Western blotting analysis was performed in four regions (cortex, outer stripe and inner stripe of the outer medulla, and the inner medulla). PLC-beta1 and beta3 were detected in the inner stripe of the outer medulla and the inner medulla. PLC-gamma1 was distributed homogeneously along the corticomedullary axis. PLC-gamma2 was observed in the medulla and PLC-delta1 showed a gradual increase from the cortex to the inner medulla. In contrast, no PLC-beta4 was detected in all regions. On immunohistochemistry, the immunoreactivities to PLC antibodies were observed as follows: PLC-beta1, from the thick ascending limb (TAL) to the inner medullary collecting tubule (IMCT); PLC-beta3, in the glomerulus (Glm), the ascending thin limb (ATL) and the collecting tubule; PLC-beta4, Glm, the proximal convoluted tubule (PCT), ATL, the distal convoluted tubule, the connecting tubule, and the collecting tubules; PLC-gamma1, PCT, TAL and IMCT; PLC-delta1, homogeneously from PCT to IMCT. PLC-beta3 immunoreactivities were detected in the nuclei of the TAL, ATL, outer medullary collecting tubule (OMCT) and IMCT. PLC-beta4 and gamma2 were observed in Glm, MTAL, ATL, OMCT and IMCT. These results suggest the intrarenal site-specific existence of PLC isozymes that may regulate kidney functions through the PLC-mediated signal transductions.
Nephron 1998 Nov
PMID:Distributional patterns of phospholipase C isozymes in rat kidney. 980 41

In the present study, we investigated the generation of lipid peroxides and changes in total phospholipid levels in the kidney tissue of rats with acquired resistance to gentamicin (GM). GM resistance was induced in Sprague-Dawley male rats by subcutaneously administering each rat a dose of 80 mg/kg/day of GM for 40 consecutive days. Twelve days after the GM administration, serum urea nitrogen peaked at 35 mg/dl. The urinary creatinine excretion progressively decreased, beginning 4 days after the start of GM administration. The fractional excretion of sodium progressively increased, beginning 4 days after the start of GM administration, peaking on the 10th day. However, despite the continuation of GM administration, the urinary creatinine excretion gradually increased, and the serum urea nitrogen concentrations recovered to previous levels after 21 days. We also analyzed the relationship between the acquired resistance to GM and changes in the reduced glutathione content and glutathione peroxidase activity. Simultaneously, we investigated sequential changes in the activities of phospholipase A2 and phospholipase C, which release peroxidized membrane phospholipids into the cytoplasm via hydrolysis, as well as the relationship between changes in the kidney tissue phospholipid composition (sphingomyelin/phosphatidylcholine ratio) and renal function. We found that (1) the kidney tissue glutathione content rapidly decreased after GM administration before subsequently increasing and being maintained at a higher level; (2) the glutathione peroxidase activity showed a persistent decrease after GM administration; (3) the kidney tissue phospholipase A2 activity decreased after GM administration, while the phospholipase C activity exhibited a sustained increase from 21 days, and (4) the spingomyelin/phosphatidylcholine ratio decreased on the 4th day before stabilizing when acquired resistance was obtained. Based on these findings, we conclude that an increased supply of reduced glutathione and the induction of an antioxidase, substituting for glutathione peroxidase, may play a significant role in the acquisition of resistance to acute renal failure which occurs with continuous GM administration. Improved membrane fluidity, achieved by maintenance of the membrane phospholipid composition by increased phospholipase C activity, may be an additional factor contributing to the recovery of the renal function.
Nephron 1998 Nov
PMID:Biochemical renal manifestations induced by consecutive administration of gentamicin in rats. 980 43

The role of diacylglycerol (DAG) in hormonal induction of S phase was investigated in primary cultures of rat hepatocytes. In this model, several agonists that bind to G protein-coupled receptors act as comitogens when added to the cells soon after plating (i.e., in Go/early Gl phase), while the cells are most responsive to the mitogenic effect of epidermal growth factor (EGF) at 24-48 h of culturing (i.e., mid/late Gl). It was found that the cellular concentration of DAG rose markedly and progressively during the first 24 h of culturing. Exposure of the hepatocytes at 3 h to alpha1-adrenergic stimulation (norepinephrine with timolol), vasopressin, or angiotensin II further increased this rise, producing a sustained increase in the DAG level. Norepinephrine, which was the most efficient comitogen, produced the most prolonged DAG elevation. In contrast, no significant increase of DAG was found in response to EGF, neither at 3 nor at 24 h, using concentrations that markedly stimulated the ERK subgroup of the mitogen-activated protein kinases (MAPK) and DNA synthesis. Addition of Bacillus cereus phosphatidylcholine-specific phospholipase C (PC-PLC) strongly elevated DAG, while Streptomyces phospholipase D (PLD) increased phosphatidic acid (PA) but not DAG. B. cereus PC-PLC and the protein kinase C (PKC) activator tetradecanoyl phorbol-acetate (TPA), like norepinephrine, vasopressin, and angiotensin II, stimulated MAPK and enhanced the stimulatory effect of EGF on DNA synthesis. The PKC inhibitor GF109203X did not diminish the effect of EGF on MAPK or DNA synthesis, but strongly inhibited the effects of norepinephrine, vasopressin, angiotensin II, TPA and B. cereus PC-PLC on MAPK and almost abolished the enhancement by these agents of EGF-stimulated DNA synthesis. These results suggest that although generation of DAG is not a direct downstream response mediating the effects of the EGF receptor in hepatocytes, a sustained elevation of DAG with activation of PKC markedly increases the responsiveness to EGF. Mechanisms involving DAG and PKC seem to play a role in the comitogenic effects of various agents that bind to G protein-coupled receptors and activate the cells early in Gl, such as norepinephrine, angiotensin II, and vasopressin.
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PMID:Role of diacylglycerol (DAG) in hormonal induction of S phase in hepatocytes: the DAG-dependent protein kinase C pathway is not activated by epidermal growth factor (EGF), but is involved in mediating the enhancement of responsiveness to EGF by vasopressin, angiotensin II, and norepinephrine. 1039 90

Thromboxane A2 (TXA2) analogue STA2 produced a tonic contraction in rabbit aortic smooth muscles. In the present study, we examined phosphatidylcholine (PC) hydrolysis as a signaling pathway for the tonic contraction in rabbit aortic smooth muscles. In the primary cultured cells labeled with [3H]choline, STA2 caused an accumulation of [3H]phosphorylcholine, a metabolite of PC by PC-specific PLC, in a concentration-dependent manner. The accumulation of [3H]phosphorylcholine was inhibited by SQ29548, a TXA2 receptor antagonist. In the muscle strips, STA2-induced tonic contraction was potently inhibited by D609, an inhibitor of PC-specific phospholipase C in a concentration-dependent manner with the IC50 of about 10 microM. Norepinephrine-induced tonic contraction was also inhibited by D609 with a weaker potency. These results strongly suggest that stimulation of TXA2 receptor results in the activation of PC-specific phospholipase C to yield diacylglycerol that contributes to the tonic contraction.
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PMID:Thromboxane A2 receptor-mediated tonic contraction is attributed to an activation of phosphatidylcholine-specific phospholipase C in rabbit aortic smooth muscles. 1067 Aug 35

The regulation of the alpha(1)-adrenoceptor-G protein-phospholipase C (PLC) cascade was investigated in rat cerebral cortex at adult (6-month-old) and senescent (24-month-old). Norepinephrine (NE)-stimulated inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] production was enhanced 30% during aging. Moreover, maximal NE (50 microM) stimulation was much more effective in stimulating G protein low-K(m) GTPase in cortical membranes from old than adult rats. Immunoreactive G protein subunits (Gqalpha, Gialpha, Goalpha and Gcommonbeta) and PLC-beta(1) isozyme were detected in all membrane preparations. No changes in the G protein subunits and PLC-beta(1) expression were observed with aging. Nanomolar concentration of Gpp[NH]p inhibited basal Ins(1,4,5)P(3) production with a maximum inhibition of 25% in both adult and aged cortical membranes. In contrast, 100 microM Gpp[NH]p-induced stimulation of Ins(1,4,5)P(3) production was potentiated with aging. The two principal divergent pathways of old cortical Ins(1,4,5)P(3) production resulting in the activation and inhibition of PLC-beta(1) activity are abolished by treatment of the membranes with 1 microM U-73122, a putative PLC-beta inhibitor. These results suggest that the cortical PLC-beta(1) isozyme activity may be regulated by both inhibitory and stimulatory G proteins-mediated mechanisms, and that the altered PLC-beta(1) dual regulatory systems could be involved in the pathogenesis of brain aging.
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PMID:Modulation of phospholipase C pathway in rat cerebral cortex during aging. 1113 3

Apolipoprotein E isoforms may have differential effects on a number of pathological processes underlying Alzheimer's disease. Recent studies suggest that the amount, rather than the type, of apolipoprotein E may also be an important determinant for Alzheimer's disease. Therefore, understanding the regulated synthesis of apolipoprotein E is important for determining its role in Alzheimer's disease. We show here that in rat primary hippocampal astrocyte cultures, dibutyryl-cAMP increased apolipoprotein E secretion with time in a dose-dependent manner (to 177% at 48 h) and that retinoic acid potentiated this effect (to 298% at 48 h). Dibutyryl-cAMP also gave a rapid, albeit transient, increase of apolipoprotein E mRNA expression (to 200% at 1 h). In contrast, the protein kinase C activator phorbol 12-myristate 13-acetate decreased both apolipoprotein E secretion (to 59% at 48 h) and mRNA expression (to 22% at 1 h). Phorbol 12-myristate 13-acetate also reversed the effects of dibutyryl-cAMP. Apolipoprotein E secretion was also modulated by receptor agonists for the adenylyl cyclase/cAMP pathway. Isoproterenol (50 nM, a beta-adrenoceptor agonist) enhanced, while clonidine (250 nM, an alpha2-adrenoceptor agonist) decreased, secreted apolipoprotein E. We also analysed the effects of agonists for the phospholipase C/protein kinase C pathway. Arterenol (1 microM, an alpha1-adrenoceptor agonist) and serotonin (2.5 microM) enhanced, whereas carbachol (10 microM, an acetylcholine muscarinic receptor agonist) decreased secreted apolipoprotein E. The effects of these non-selective receptor agonists were modest, probably due to effects on different signalling pathways. Arterenol also potentiated the isoproterenol-mediated increase. We also show that phorbol 12-myristate 13-acetate and dibutyryl-cAMP have opposite effects on nerve growth factor, as compared to apolipoprotein E, secretion, suggesting that the results obtained were unlikely to be due to a general effect on protein synthesis. We conclude that astrocyte apolipoprotein E production can be regulated by factors that affect cAMP intracellular concentration or activate protein kinase C. Alterations in these signalling pathways in Alzheimer's disease brain may have consequences for apolipoprotein E secretion in this disorder.
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PMID:Regulation of apolipoprotein E secretion in rat primary hippocampal astrocyte cultures. 1151 30

1. We investigated whether catecholamines through activation of alpha(1)-adrenergic receptors (alpha(1)-AR) are involved in mouse uterine contraction at parturition. Myometrial phospholipase C (PLC) activity and uterine contraction were measured in response to noradrenaline (NA), the specific alpha(1)-AR agonist phenylephrine (Phe) and oxytocin (OT). 2. Using the reverse transcription-polymerase chain reaction RT-PCR, we detected the alpha(1a)-AR subtype in late pregnant mouse myometrium. We also detected, by immunoblotting studies, PLCbeta(1), PLCbeta(3) and different alpha-subunits of pertussis toxin-insensitive (Galpha(q/11)) and -sensitive G proteins (Galpha(o/i3), Galpha(i1/2)). 3. Phenylephrine and NA did not alter the myometrial inositol phosphate (InsP) production of late pregnant or parturient mouse. In similar conditions, OT increased InsP production in a dose-dependent manner. Consistent with these results, only OT (10 microM) recruited PLCbeta(1) and PLCbeta(3) to myometrial plasma membranes. The OT-induced InsP response was not altered by pertussis toxin (300 ng ml(-1), 2 h pretreatment), suggesting the involvement of a member of the Galpha(q) family. 4. Noradrenaline and Phe failed to increase uterine contraction at late pregnancy and at parturition. In contrast, OT induced uterine contraction in a dose-dependent manner with maximal increase (400 %) at a concentration of 1 microM. 5. The results indicate that OT receptors (OTR) but not alpha(1)-AR are linked to myometrial PLC activation and uterine contraction in late pregnant and parturient mouse. This discrepancy between mouse and other mammals could be attributed to the alpha(1)-AR subtype expressed in myometrium at this time.
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PMID:Catecholamines are not linked to myometrial phospholipase C and uterine contraction in late pregnant and parturient mouse. 1157 62

alpha(1a)-Adrenergic receptors (ARs) couple to phosphoinositide hydrolysis, adenylyl cyclase, and mitogen-activated protein kinase (MAPK) pathways. However, the interaction among these signaling pathways in activating extracellular signal-regulated kinase 1/2 (ERK1/2) is not well understood. We investigated the coupling of alpha(1a)-ARs to ERK1/2 in Chinese hamster ovary (CHO)-K1 cells stably transfected with mouse alpha(1a)-ARs, as well as the interaction between ERK1/2 and norepinephrine-induced cAMP accumulation. alpha(1a)-AR activation by norepinephrine increased the cytosolic Ca(2+) concentration and phosphorylated ERK1/2 in a time- and concentration-dependent manner. ERK1/2 phosphorylation was blocked by the MAPK kinase 1/2 inhibitor 2'-amino-3'-methoxyflavone (PD 98059) and the alpha(1)-AR antagonist prazosin. A transient elevation in intracellular Ca(2+) was required for the phosphorylation of ERK1/2; however, activation of protein kinase C did not seem to be required for ERK1/2 phosphorylation. Norepinephrine also stimulated cAMP accumulation in transfected CHO-K1 cells in a concentration-dependent manner via alpha(1a)-ARs, which was blocked by the Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. Norepinephrine-induced ERK1/2 phosphorylation was inhibited by the adenylyl cyclase activator forskolin and was enhanced by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ 22536) and the protein kinase A inhibitor 4-cyano-3-methylisoquinoline. In conclusion, in transfected CHO-K1 cells, alpha(1a)-AR activation activates both phospholipase C and adenylyl cyclase-mediated signaling pathways. alpha(1a)-AR-mediated ERK1/2 phosphorylation was dependent on a rise in intracellular Ca(2+), and this pathway was reciprocally regulated by the concomitant activation of adenylyl cyclase, which inhibits ERK1/2 phosphorylation. Thus, alpha(1a)-AR stimulation of cAMP production may play an important role in regulating ERK1/2 phosphorylation in cell lines and native tissues.
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PMID:Tonic inhibitory role for cAMP in alpha(1a)-adrenergic receptor coupling to extracellular signal-regulated kinases 1/2. 1223 58

Endemic nephropathy has been linked to exposure of ochratoxin-A (OA) in grains and animal products. The underlying events surrounding this form of renal injury are not well known, partly due to the lack of a suitable animal model of the disease. Therefore, in this study, a pig model of OA-induced renal injury was established and used to examine whether elements of the phosphoinositide signalling pathway are altered in this disease. Weanling piglets were fed diets containing 0, 2, and 4 ppm OA for 6 weeks. Serum creatinine and urea and renal fibrosis were monitored biweekly using serial blood samples and renal biopsies. At termination, the protein levels of renal phosphatidylinositol 4-kinase-beta (PtdIns4Kbeta) and phospholipase C(gamma1) (PLC(gamma1)) were determined using immunoblotting and scanning densitometry. Serum creatinine was elevated by 2 weeks and renal fibrosis was elevated by 4 weeks at both levels of inclusion of OA. At the end of the experimental period, kidney size and water content were elevated, as were the protein levels of renal PtdIns4Kbeta and PLC(gamma1) in OA-exposed animals. Therefore, serial biopsies can be used to track changes in renal pathology in the OA-exposed piglet. We conclude that this is a useful model for OA-induced renal injury in which the underlying molecular events associated with this form of renal injury can be studied.
Nephron Physiol 2004
PMID:Increased renal fibrosis and expression of renal phosphatidylinositol 4-kinase-beta and phospholipase C(gamma1) proteins in piglets exposed to ochratoxin-A. 1475 40


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