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)

Daily s.c. injection of gentamicin at either 100 mg/kg for 4 days or 60 mg/kg for 2 weeks produced nephrotoxicity in the adult rat as judged by an increase in urinary excretion of beta-galactosidase, beta-glucuronidase and beta-N-acetylglucosaminidase. The observed enzymuria was associated with significant elevation in total renal phospholipid, phosphatidylinositol, phosphatidylcholine and phosphatidylserine. In addition, gentamicin decreased the activities of renal cortical Na+-K+-adenosine triphosphatase, alkaline phosphatase as well as phospholipase C. Pyridoxal-5'-phosphate (250 mg/kg/day) administered i.p. for 4 or 14 days did not markedly alter the metabolic markers of kidney function. In rats simultaneously given pyridoxal-5'-phosphate and gentamicin for 4 days the vitamin failed to prevent either the antibiotic-induced decrease in renal phospholipase C and alkaline phosphatase or the increase in total renal phospholipid, phosphatidylinositol, phosphatidylcholine and phosphatidylserine. However, simultaneous pyridoxal-5'-phosphate and aminoglycoside treatment for 2 weeks proved effective in blockade of the gentamicin-induced kidney phospholipidosis, elevation in urinary beta-galactosidase, beta-glucuronidase and beta-N-acetylglucosaminidase, as well as reduction in renal phospholipase C and alkaline phosphatase. The gentamicin-induced nephrotoxicity was associated with a decrease in renal pyridoxal-5'-phosphate levels. In the simultaneous 4-day-treated rat the renal concentration of pyridoxal-5'-phosphate returned to approximate control values, whereas after 2 weeks the level of vitamin B6 was approximately 2-fold higher than control. Although pyridoxal-5'-phosphate in the simultaneous group lowered kidney gentamicin content by 40% after 4 or 14 days, protection from aminoglycoside-induced nephrotoxicity was apparent only after 2 weeks in our study.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of gentamicin-induced nephrotoxicity by pyridoxal-5'-phosphate in the rat. 249 42

Phospholipase A2 (PLA2) treatment has been shown previously to stimulate the sodium-dependent high-affinity choline uptake system as assessed by both the specific binding of [3H]hemicholinium-3 ([ 3H]HCh-3) and the uptake of [3H]choline. In the present study, the specificity of PLA2-induced stimulation upon [3H]HCh-3 binding has been examined. PLA2, as well as phospholipase C (PLC), treatment of synaptic membranes produced a dose-dependent increase in the specific binding of [3H]HCh-3 whereas neither phospholipase B nor phospholipase D had any effect. PLC-induced stimulation of [3H]HCh-3 binding resulted from a significant decrease in the Kd without a change in the maximum binding of [3H]HCh-3 binding. PLC treatment of synaptosomes resulted in an inhibition of [3H]choline uptake accompanied by an inhibition of Na+, K+-adenosine triphosphatase activity. In contrast to the increase of [3H]HCh-3 binding, the specific binding of both [3H]desipramine and [3H]mazindol was decreased by PLA2 treatment. After PLA2 treatment, [3H]HCh-3 binding was increased about 2.5-fold over basal levels in different regions of the brain. Electrolytic lesions of the medial septal nucleus and kainic acid-induced lesions of the striatum resulted in a marked reduction of [3H]HCh-3 binding in the hippocampus and the striatum, respectively. Residual [3H]HCh-3 binding in the denervated hippocampus and lesioned striatum was increased by PLA2 treatment but remained lower than that in PLA2-treated controls. Finally, atropine-induced up-regulation of [3H]HCh-3 binding in vivo was not additive with PLA2-induced stimulation. These results support the hypothesis that PLA2 might be involved in the regulation of the sodium-dependent high-affinity choline uptake.
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PMID:Specificity of the activation of [3H]hemicholinium-3 binding by phospholipase A2. 273 47

1 The effect of (+/-)-, (+)- and (-)-verapamil on the Ca2+-binding, Ca2+-transporting activity, and Ca2+-dependent adenosine triphosphatase (ATPase) activity of isolated cardiac sarcolemmal preparations was studied. Enzymatic treatment was used to establish the nature of the sites facilitating [14C]-(+/-)-verapamil binding. 2 (+/-)-Verapamil 1 microM inhibited the passive binding of 45Ca2+. The (+/-)- and (-)-isomers were equiactive. 3 (+/-)-Verapamil 1 microM inhibited the ATP-dependent transport of 45Ca2+ and the associated activation of the Ca2+-sensitive ATPase. The activity resided in the (-)-isomer. 4 Lineweaver-Burk plots for the initial rates of ATP-dependent transport showed that the inhibition induced by the (-)-isomer was accompanied by a reduced Km and Vmax. 5 Enzymatic removal of N-acetyl neuraminic acid and galactose residues increased [14C]-(+/-)-verapamil binding; removal of N-acetylglucosamine and treatment with phospholipase C and trypsin decreased the binding. 6 These results have been interpreted to mean that (-)-verapamil interferes with the ATP-dependent Ca2+-transporting properties of the sarcolemma, and that this effect is accompanied by an altered activity of the intrinsic Ca2+-sensitive ATPase. N-acetylneuramic acid and galactose residues do not provide binding sites for verapamil at the cell surface.
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PMID:The effect of verapamil on the Ca2+-transporting and Ca2+-ATPase activity of isolated cardiac sarcolemmal preparations. 645 Dec 52

It has recently been shown that two novel tachykinins, ranakinin and [Leu3, Ile7]neurokinin A, are present in fibers innervating the frog adrenal gland, and it has been demonstrated that tachykinins stimulate corticosteroid secretion in vitro through activation of chromaffin cells. The purpose of the present study was to investigate the effect of ranakinin on cytosolic free calcium concentrations ([Ca2+]i) and to determine the source of calcium involved. Cultured adrenal cells were loaded with the fluorescent calcium indicator indo-1, and changes in [Ca2+]i were studied using dual emission wavelength microfluorimetry. Administration of a brief pulse of ranakinin (1 microM; 1 sec) in the vicinity of chromaffin cells caused an immediate and transient increase in [Ca2+]i. Repeated pulses of ranakinin resulted in a gradual decline in the [Ca2+]i response, suggesting the occurrence of a desensitization phenomenon. Preincubation of the cells with the calcium channel blockers nifedipine (10 microM) and omega-conotoxin (1 microM) did not alter the response of chromaffin cells to ranakinin. Chelation of extracellular calcium by EGTA (10 mM) caused a marked decrease in the basal [Ca2+]i, but did not suppress the ranakinin-induced [Ca2+]i increase. Conversely, incubation of the cells with thapsigargin (10 microM), an inhibitor of calcium adenosine triphosphatase activity, abolished the stimulatory effect of ranakinin, indicating that the increase in [Ca2+]i can be ascribed to mobilization of calcium from intracellular stores. Preincubation of adrenal cells with the phospholipase C antagonist U-73122 (1 microM; 18 min) or with pertussis toxin (10 microM; 18 h) totally blocked the ranakinin-induced [Ca2+]i rise. Taken together, these data indicate that in frog adrenochromaffin cells, ranakinin causes mobilization of calcium from intracellular stores. The effect of ranakinin is mediated through activation of a phospholipase C via a pertussis toxin-sensitive G protein.
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PMID:Effect of ranakinin, a novel tachykinin, on cytosolic free calcium in frog adrenochromaffin cells. 766 74

The mechanisms by which red wine polyphenolic compounds (RWPCs) induced endothelium-dependent relaxation were investigated in rat thoracic aorta rings with endothelium. RWPCs produced relaxation that was prevented by the nitric oxide (NO) synthase inhibitor, N(omega)-nitro-L-arginine-methyl-ester. This relaxation was abolished in the absence of extracellular calcium in the medium or in the presence of the Ca2+ entry blocker, La3+, but it was not affected by the nonselective K+ channels blocker, tetrabutylammonium. N-Ethyl-maleimide (NEM), a sulfhydryl alkylating agent, abolished vasorelaxation produced by RWPCs and acetylcholine but not that produced either by the sarcoendoplasmic reticulum Ca2+-adenosine triphosphatase (ATPase) pump inhibitor, cyclopyazonic acid (CPA) or the calcium ionophore, ionomycin. Neither pertussis toxin (PTX) nor cholera toxin (CTX) inhibited the vasorelaxant effect of RWPC. The effect of RWPC was not affected by the phospholipase C (PLC) blocker, L-alpha-glycerophospho-D-myo-inositol 4-monophosphate (Gro-pip), and the phospholipase A2 pathway blockers, quinacrine and ONO-RS-082. Finally, the protein kinase C (PKC) inhibitor, GF 109203X, and tyrosine kinase inhibitors, tyrphostin A-23 and genistein, did not impair the response to RWPCs. These results suggest that RWPCs produce endothelium-NO-derived vasorelaxation through an extracellular Ca2+-dependent mechanism via an NEM-sensitive pathway. They also show that PTX- or CTX-sensitive G proteins, activation of PLC or PLA2 pathways, PKC, or tyrosine kinase may not be involved.
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PMID:Mechanism of endothelial nitric oxide-dependent vasorelaxation induced by wine polyphenols in rat thoracic aorta. 1002 33

Cells derived from an experimental luteinized ovarian tumor are more sensitive to GnRH endocrine action than control luteal cells. In an attempt to understand the possible causes of the differential sensibility to GnRH action, we examined the number and affinity of GnRH receptors and the second messenger response to GnRH stimulation in both tissues. For GnRH receptor studies membranes were obtained from 4- to 6-week-old ovarian tumors (luteoma) and ovaries from prepubertal rats treated with 25 IU PMSG and 25 IU hCG (SPO) and were incubated with [125I]Buserelin. The number of GnRH receptors were increased in luteoma compared with that in SPO ovaries; dissociation constants were similar in both tissues. GnRH stimulation of second messenger release was assessed in cells obtained from luteoma and SPO ovaries by collagenase treatment. Buserelin (100 ng/ml) induced a significant 35% calcium increase in SPO cells, as determined by the fura-2 method; in luteoma cells no response was observed after buserelin stimulation, although a calcium transient was induced by thapsigargin (0.5 microM), an inhibitor of Ca2+-adenosine triphosphatase associated with the endoplasmic reticulum. The effect of buserelin on inositol phosphates was evaluated after incubation of luteoma and SPO cells with [3H]myoinositol for 48 h. Buserelin induced a 400% increase in inositol trisphosphate in SPO cells. Again, luteoma cells did not respond to buserelin stimulation, although NaF (10 mM), an activator of G proteins coupled to phospholipase C, induced an 800% increase in inositol trisphosphate. Although the number of GnRH receptors is augmented in luteoma cells, justifying an increased endocrine response, neither inositol phosphates nor intracellular calcium were released by a GnRH analog, indicating the uncoupling of GnRH receptors from phospholipase C. These data provide evidence that the transformation of the ovary into a luteoma implies the acquisition of novel characteristics in the GnRH receptor second messenger-generating system.
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PMID:Alterations in intracellular messengers mobilized by gonadotropin-releasing hormone in an experimental ovarian tumor. 1043 13

In a previous publication we provided evidence of a novel neuronal pathway for the control of GnRH secretion by bradykinin. The action of bradykinin appeared to be exerted through the bradykinin B2 receptor. In this study we demonstrated that the bradykinin B2 receptor is densely localized in the arcuate nucleus, median eminence, organum vasculosum of the lamina terminalis, and preoptic area, regions known to be critical for the control of GnRH secretion. To determine the mechanism of action of bradykinin in stimulating GnRH release, we used immortalized GnRH (GT1-7) cells in vitro. Bradykinin stimulation of GnRH secretion from GT1-7 cells appears to involve activation of the phospholipase C signaling pathway and mobilization of extracellular and intracellular calcium stores. Evidence to support this contention was derived from the observations that incubation of the phospholipase C inhibitor, U-73122 with bradykinin, blocked the ability of bradykinin to stimulate release from GT1-7 cells. This effect was specific, as a nitric oxide synthase inhibitor and a cyclooxygenase inhibitor were found to have no effect on bradykinin-induced GnRH secretion, suggesting that nitric oxide and PGs do not mediate bradykinin effects. Pertussis toxin also had no effect on bradykinin action. This suggests that the bradykinin B2 receptor may be coupled to a pertussis toxin-insensitive G protein in GT1-7 cells. With respect to calcium involvement in bradykinin action, fura-2 calcium indicator studies revealed that bradykinin can rapidly increase intracellular Ca2+ levels in GT1-7 cells. A role for intracellular Ca2+ in bradykinin action was further suggested by the finding that an intracellular calcium chelator, 1,2-bis(O-aminophenoxy)]ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester, significantly attenuated the effects of bradykinin on GnRH release. The elevation of intracellular calcium by bradykinin appears to be due to mobilization of calcium from the endoplasmic reticulum, as incubation of the Ca2+-adenosine triphosphatase inhibitor thapsigarin, which depletes endoplasmic reticulum Ca2+ stores, significantly attenuated bradykinin action on GnRH release. Extracellular calcium may also be involved in bradykinin action, as the L-type Ca2+ channel blockers verapamil and nifedipine had no effect on bradykinin-induced GnRH release, whereas the nonselective Ca2+ channel blocker, nickel chloride, attenuated bradykinin-induced GnRH release. Taken as a whole, these studies demonstrate that the bradykinin B2 receptor is densely localized in key hypothalamic nuclei responsible for regulation of GnRH release, and that the mechanism of bradykinin stimulation of GnRH secretion involves activation of the phospholipase C signaling pathway, with a critical role implicated for calcium in bradykinin action in GT1-7 cells.
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PMID:Bradykinin receptor localization and cell signaling pathways used by bradykinin in the regulation of gonadotropin-releasing hormone secretion. 1049 24

An immortal nonhormone-producing cell line with a characteristic star-shaped morphology, named Tpit/F1, was derived from an anterior pituitary gland of a temperature-sensitive large T antigen transgenic mouse. To characterize Tpit/F1 cells, we performed cytological studies, which revealed that Tpit/F1 cells express the messenger RNAs of neruonal nitric oxide (NO) synthase, S-100 protein, basic fibroblast growth factor, and pituitary-restricted transcription factor. The Tpit/F1 cells response to pituitary adenylate cyclase-activating peptide comprised the stimulated secretion of interleukin-6. Furthermore, glucocorticoids stimulate glutamine synthase production by Tpit/F1 cells. Considering these cytological characteristics together with their morphology, we deduced that Tpit/F1 cells are derived from pituitary folliculo-stellate (FS) cells. Our cytophysiological analyses of Tpit/F1 cells revealed that intracellular Ca2+ increased dose dependently on ATP administration (0-100 microM), and that this effect did not require the presence of extracellular Ca2+ and was not abolished by treatment with gadolinium, a Ca2+ channel blocker. The ATP-induced increase in intracellular Ca2+ ([Ca2+]i) was completely abolished by treatment with the Ca2+-adenosine triphosphatase (Ca2+-ATPase) inhibitor thapsigargin, which suggests that ATP increases [Ca2+]i by mobilizing internally stored Ca2+ followed by an influx of Ca2+. Moreover, UTP was equipotent with ATP in causing the [Ca2+]i increase in Tpit/F1 cells. Also, the Ca2+ response was prevented by the phospholipase C inhibitor, U-73122, but not by its inactive analog, U-73343. From these results we therefore concluded that ATP acts on Tpit/F1 cells via P2Y2-purinoceptors. Interestingly, both neuronal nitric oxide synthase messenger RNA and NO secretion were increased by ATP administration (10 and 100 microM). These results suggest the biological significance of the topological colocalization of FS cells and endocrine cells. Namely, ATP is cosecreted with hormones from endocrine cells and stimulates NO production by FS cells, and the released NO may regulate neighboring endocrine cell and blood vessels.
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PMID:Cytological characterization of a pituitary folliculo-stellate-like cell line, Tpit/F1, with special reference to adenosine triphosphate-mediated neuronal nitric oxide synthase expression and nitric oxide secretion. 1101 14

1. Troglitazone, an insulin sensitizing agent, has a direct positive inotropic effect. However, the mechanism of this effect remains unclear. Thus, we examined the inotropic effect of troglitazone while focusing on intracellular Ca2+ handling. 2. Troglitazone significantly increased peak isovolumic left ventricular pressure (LVP(max)), peak rate of rise of LVP (dP/dt(max)), peak rate of fall of LVP (dP/dt(min)) in isolated rat hearts perfused at a constant coronary flow and heart rate. This inotropic effect of troglitazone was not inhibited by pretreatment with carbachol (muscarine receptor agonist), H89 (protein kinase A inhibitor), U73122 (phospholipase C inhibitor), H7 (protein kinase C inhibitor), verapamil (L-type Ca2+ channel antagonist), thapsigargin (Ca(2+)-adenosine triphosphatase inhibitor) or ryanodine (ryanodine receptor opener). 3. Radioimmunoassay showed that the cyclic adenosine monophosphate concentration in the left ventricle was not increased by troglitazone. 4. Whole-cell patch clamp analysis revealed that troglitazone had no effect on inward Ca2+ currents in cardiomyocytes. 5. In fura-2 loaded perfused rat hearts, troglitazone exerted its positive inotropic effect without increasing Ca2+ concentration. 6. These results suggest that neither the inward Ca2+ currents nor Ca2+ handling in the sarcoplasmic reticulum was involved in the inotropic effect of troglitazone. Furthermore, troglitazone exerted its positive inotropic effect without affecting the intracellular concentration of Ca2+. 7. In conclusion, the positive inotropic effect of troglitazone is mediated by a sensitization of Ca2+.
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PMID:Ca(2+)-sensitizing effect is involved in the positive inotropic effect of troglitazone. 1149 16

The hypothesis that protein kinase C (PKC) and tyrosine kinases, as well as serine-threonine and tyrosine phosphatases, are involved in prolactin (PRL) signalling in theca cells harvested from porcine follicles was tested. Theca cells were incubated with PRL for 24 h to stimulate progesterone (P4) production. In addition, treatments included inhibitors of PKC and tyrosine kinases, as well as serine-threonine phosphatase inhibitor and tyrosine phosphatase inhibitor. Prolactin significantly stimulated P4 production by theca cells and all inhibitors suppressed the PRL-stimulated P4 production. After incubation with PRL for 2, 5, 10 or 20 min, theca cells were homogenized and cytosolic and membrane fractions were obtained. This was followed by determination of PKC activity in partially purified subcellular fractions by measuring the transfer of 32P from [gamma-32P] adenosine triphosphatase (ATP) to histone III-S. In unstimulated porcine theca cells the major proportion of PKC activity was present in the cytosol. Incubation of cells with PRL resulted in a rapid, time-dependent increase in the amount of PKC activity in the membrane fraction. Protein kinase C activity in the membrane fraction was maximal after 10 min of cells' exposure to PRL. Protein kinase C activation was assessed also by measuring the specific association of 3H-phorbol dibutyrate (3H-PDBu) with theca cells after treatment with PRL. Prolactin significantly increased 3H-PDBu-specific binding in theca cells. In contrast to PKC, total inositol phosphate accumulation was not affected by PRL in the current study. In summary, PRL stimulated P4 production by porcine theca cells derived from large follicles. The results of the study were consistent with the hypothesis that PKC is one of the intracellular mediators of PRL action in porcine theca cells. Protein kinase C activation does not appear to occur through the action of phosphatidylinositol-dependent phospholipase C. Moreover, the involvement of tyrosine kinases, as well as tyrosine and serine-threonine phosphatases, in PRL signalling in the examined cells is suggested.
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PMID:Prolactin signalling in porcine theca cells: the involvement of protein kinases and phosphatases. 1272 1


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