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)

Steroids have potent actions on the brain which can be categorized as; (i) fast (approximately ms-s), (ii) intermediate (h-days), (iii) long-term reversible (days-weeks) and (iv) long-term irreversible. Here attention is focussed on the intermediate and long-term reversible effects of steroids with emphasis on glucocorticoids and oestrogen. Glucocorticoid negative feedback is generally classified as fast, delayed and long-term. Fast negative feedback would appear to depend mainly on a reduction in pituitary responsiveness to corticotrophin releasing factor-41 (CRF-41) and possibly arginine vasopressin (AVP). Delayed feedback is mediated by reduced AVP release into hypophysial portal blood and blockade of the ACTH response to CRF-41. Long-term negative feedback is a consequence of reduced CRF-41 and AVP release into portal blood. Lesion and electrical stimulation studies pinpoint the paraventricular nuclei as the main site at which glucocorticoids act to control ACTH release. Oestrogen at physiologically low plasma concentrations inhibits gonadotrophin secretion. At physiologically high plasma concentrations, such as those that occur during the preovulatory surge, oestradiol-17 beta stimulates the biosynthesis of LHRH mRNA and LHRH and the release of LHRH into hypophysial portal blood. Oestradiol also increases pituitary responsiveness to LHRH. The action of oestrogen on LHRH neurons is probably mediated by interneurons and may involve disinhibition; this view is supported by our in situ hybridization studies which show that oestrogen, in its positive feedback mode, significantly reduces the synthesis of proopiomelanocortin mRNA in arcuate neurons which when active are likely to inhibit LHRH neurons. The mechanism of action of oestrogen on the pituitary gland is not yet established, but clues from the action of the priming effect of LHRH suggests that oestrogen may potentiate phosphoinositide second messenger cascades. LHRH priming involves the synthesis of a 70 kDa protein the N-terminus of which is identical to an oestrogen-induced protein in the ventromedial hypothalamic nucleus involved in lordosis, and to that of phospholipase C alpha. Attention is drawn to the remarkable economy of the system by which a single steroid, oestrogen, has effects on the brain and pituitary gland which result in a co-ordinated sequence of amplifier cascades which lead first to the ovulatory surge of luteinizing hormone and then to mating behaviour, both of which are obviously essential for continuation of the species.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Steroid control of central neuronal interactions and function. 165 73

The action of thyrotropin-releasing hormone (TRH) on melanotrope cells maintained in primary culture was studied with biochemical and electrophysiological techniques. TRH effects on polyphosphoinositide (PPI) breakdown was measured in [3H]myoinositol labelled cells maintained in suspension for 24 hours or in primary culture. TRH (50 nM) or its potent analogue (3Me-His2)-TRH increased total PPI levels by 50-125% in separate experiments after 30 min of treatment whereas corticotropin-releasing hormone (CRF) was without effect. The effect of TRH was dose-dependent (ED50 = 5 nM), the maximal effect being reached with 50 nM TRH. Using the patch-clamp technique in the cell-attached configuration spikes were recorded extracellularly. In 6 of the 13 cells tested, (3Me-His2)-TRH (10 nM) elicited an increase in the spontaneous spiking rate. Furthermore, TRH (50 nM) increased melanocyte-stimulating hormone (alpha-MSH) secretion 2-fold after 8 h of treatment. These results suggested that TRH activated phospholipase C and electrical activity in melanotrope cells; the resulting phosphoinositide breakdown and increase in intracellular free Ca2+ ultimately led to a stimulation of hormone release.
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PMID:Thyrotropin-releasing hormone stimulates porcine melanotrope cells in primary culture. 254 Apr 65

The involvement of protein kinase C in normal corticotroph function was studied by analysis of the effects of the phorbol ester derivative phorbol 12-myristate-13-acetate (PMA) and the synthetic diacylglycerol dioctanoylglycerol (DOG) on basal and stimulated ACTH release in cultured rat anterior pituitary cells. Incubation of rat pituitary cells with increasing concentrations of PMA or DOG caused dose-related increases in ACTH release up to 13.4 +/- 2.1- and 10.1 +/- 0.9-fold, respectively, similar to that caused by CRF (9.8 +/- 1.6-fold). Also, stimulation of endogenous diglyceride formation by phospholipase C (100 mU/ml) stimulated ACTH release by 2.5 +/- 0.1-fold. In cells incubated with maximum stimulatory concentrations of CRF (10 nM) or 8-bromo-cAMP (8-Br-cAMP; 5 mM), addition of either 100 microM DOG or 100 nM PMA caused significantly higher ACTH responses than those obtained with CRF, 8-Br-cAMP, DOG, or PMA alone. 8-Br-cAMP (5 mM) and 10 nM CRF significantly increased the effect of 100 nM PMA by 1.4 +/- 0.2- and 1.5 +/- 0.1-fold, respectively. Combinations of 10 nM CRF with either vasopressin (VP) or angiotensin II (AII) increased ACTH secretion to values higher than those produced by CRF, VP, or AII alone. However, addition of maximal stimulatory concentrations of VP or AII (10 nM) did not further increase the effects of either PMA alone or PMA/CRF combinations, indicating that their mechanisms of action may be similar to that of PMA. These results indicate that in addition to the established cAMP-dependent mechanism, stimulation of ACTH release in normal pituitary cells may be elicited by activation of protein kinase C. The evidence also suggests that protein kinase C is involved during stimulation of ACTH release by the cAMP-independent regulators VP and AII and in the synergistic effects of VP and AII with CRF on the corticotroph.
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PMID:Involvement of protein kinase C in the regulation of adrenocorticotropin release from rat anterior pituitary cells. 300 Jul 34

The steroidogenic activity of the Leydig cell is regulated by glycoprotein and peptide hormones with the potential to activate both adenylate cyclase and phospholipase C. Although the control of androgen production by LH is clearly mediated by cAMP, the extent to which Ca(2+)-mobilizing stimuli control Leydig cell function is less well defined. The basal level of intracellular calcium ([Ca2+]i) in adult rat Leydig cells was 70-160 nM and was unaffected by high K+ or the dihydropyridine calcium channel agonist, Bay K 8644. These findings are consistent with the absence of voltage-sensitive calcium channels in the Leydig cell. In addition, no increase in [Ca2+]i was observed in cells treated with LH, CRF, and serotonin. However, both GnRH and endothelin-1 (ET-1) induced rapid and transient elevations of [Ca2+]i that were not associated with a sustained plateau phase and were unaffected by removal of Ca2+ from the incubation medium. The amplitude of the [Ca2+]i response was not altered by increasing concentrations of GnRH and ET-1, but the number of responsive cells increased progressively to a maximum of about 30% of the Leydig cell population. The calcium-mobilizing actions of GnRH and ET-1 were abolished by the GnRH and ETA receptor antagonists, [Dp-Glu1,D-Phe2,D- Trp3,6]GnRH and BQ-123, respectively. The majority of the cells expressed solely GnRH or ETA receptors, and about 10% expressed both receptors. GnRH-induced Ca2+ responses were observed almost exclusively in medium-sized Leydig cells, whereas ET-induced responses were most frequent in large Leydig cells. These data demonstrate that single Leydig cells expressing GnRH and ETA receptors exhibit monophasic [Ca2+]i responses that are activated in an all-or-none fashion. Such transient Ca2+ signaling may trigger short term cellular responses or could modulate the actions of gonadotropins acting through the cAMP signaling pathway.
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PMID:Calcium signaling in single rat Leydig cells. 762 78

The administration of recombinant erythropoietin (rHuEpo) to anemic chronic renal failure patients may be associated with an increase in blood pressure, possibly by direct effects on peripheral blood vessels. In the present study, experiments were designed to explore the hypothesis that rHuEpo could enhance vascular resistance through mitogenic effect on vascular smooth muscle cells (VSMCs), and that preexisting hypertension might be a predisposing condition. Cultured VSMCs from the thoracic aortae of spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats were studied for DNA synthesis, phospholipase C activity, and cell growth related proto-oncogene expression in the presence of rHuEpo. In cells from both strains, rHuEpo dose-dependently increased DNA synthesis and stimulated phospholipase C activity, as indicated by 3H-thymidine incorporation and 3H-inositol phosphate formation, respectively (EC50 approximately 4 U/ml). Exposure of VSMCs to rHuEpo for various times gradually increased the levels of c-myc and junB and transiently induced c-fos expression, as determined by Northern analysis. rHuEpo-induced DNA synthesis was markedly enhanced in VSMCs from SHR compared to those from WKY. In contrast, rHuEpo-induced phospholipase C activity and proto-oncogene expression did not differ between the two strains. Taken together, these results suggest that rHuEpo may function as a vascular smooth muscle cell growth promoting factor through activation of the phospholipase C cascade and modulation of proto-oncogene expression. It could thereby contribute to vascular hypertrophy and arterial hypertension.
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PMID:[Mitogenic effect of erythropoietin on cultured aortic myocytes]. 775 57

The administration of recombinant human erythropoietin (rHuEpo) to anemic chronic renal failure patients may be associated with an increase in blood pressure, possibly by direct effects on peripheral blood vessels. The experiments of the present study were designed to explore the hypothesis that rHuEpo might exert mitogenic effects on vascular smooth muscle cells (VSMCs), and that pre-existing hypertension might be a predisposing condition. Cultured aortic VSMCs from spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats were studied for DNA synthesis, phospholipase C activity, and cell growth related proto-oncogene expression in the presence of rHuEpo. In cells from both rat strains, rHuEpo dose-dependently increased DNA synthesis and stimulated phospholipase C activity, as indicated by 3H-thymidine incorporation and inositol phosphate formation, respectively. Exposure of VSMCs to rHuEpo for various periods gradually increased the levels of c-myc and JunB mRNAs and transiently induced c-fos mRNA expression as determined by Northern analysis. The hormone-induced DNA synthesis was markedly enhanced in VSMCs from SHR compared to those from WKY. In contrast, rHuEpo-induced phospholipase C activity and proto-oncogene expression did not differ between the two strains. Taken together, these results suggest that rHuEpo may function as a vascular smooth muscle cell growth promoting factor through activation of the phospholipase C cascade and a modulation of proto-oncogene expression. It could thereby contribute to vascular hypertrophy and arterial hypertension.
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PMID:Effect of erythropoietin on DNA synthesis, proto-oncogene expression and phospholipase C activity in rat vascular smooth muscle cells. 813 47

The current understanding of the cellular mode of action of PTH has undergone deep changes during the last decade and the major acquisitions can be summarized as follows. First, results from biochemical and cell biology studies suggest the existence of at least two receptor types coupled to two distinct intracellular signaling pathways by G proteins: the phospholipase C-calcium-protein kinase C pathway would be coupled to high-affinity receptors, whereas the adenylate cyclase-cAMP-protein kinase A pathway would be coupled to low-affinity receptors. Until now, only one type of PTH receptor has been identified at the molecular level. It is very likely that additional PTH receptor types will be evidenced. Second, both PTH receptor-coupled transduction pathways are involved in the inhibitory effect of the hormone on the activity of two transport systems of the apical membrane of proximal tubular cells: Na-Pi cotransport and Na-H exchanger. These effects are the cellular basis for PTH inhibition of Pi and bicarbonate reabsorption. Which proteins are the targets of the different protein kinases remains to be established. Concerning the other effects of PTH on the proximal tubule (stimulation of neoglucogenesis and of calcitriol synthesis, and Na, K-ATPase inhibition), protein kinase C seems to play a major role. Third, in Henle's loop, PTH stimulates reabsorption of divalent cations through a dual effect under the dependence of protein kinase A, i.e., enhanced epithelial potential difference and opening of paracellular pathway. Finally, stimulation of distal calcium reabsorption results from multiple events: membrane insertion of apical calcium channels, opening of basolateral chloride channels resulting in cellular hyperpolarization, and modulation of Ca-ATPase. Again, while it is commonly acknowledged that both transduction systems are involved, their precise molecular targets remain to be identified (Table 1). The elucidation of the cellular mode of action of PTH, some examples of which have been reviewed, holds major interest far beyond the field of cell or organ physiology. It is the basis for understanding and, ultimately, for comprehensive treatment of genetic diseases characterized by functional abnormalities of molecules involved in the cascade of events leading to the effect of PTH on its cellular targets (hormone receptors, G proteins, and kinases). The second perspective is pharmacologic: molecular and structural identification of PTH-receptor interactions will be a prelude to design and synthesis of new selective, nonpeptidic hormonal analogs and antagonists that are easier to handle. The high incidence and severity of secondary hyperparathyroidism during chronic renal failure highlights the importance of this research.
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PMID:Cellular mode of action of parathyroid hormone. 815 58

It has long been known that parathyroid hormone (PTH) exerts its effects on target tissues via its binding to a membrane receptor. Recently, several types of PTH receptors have been identified. The first receptor which has been cloned and well characterized is "PTH/PTHrP receptor-1". It is activated not only by PTH, but also by PTH-related peptide (PTHrP), via a signal transduction system involving G-proteins, adenylate cyclase and phospholipase C. It is expressed in many tissues, in addition to kidney and bone. The results of recent studies are suggestive of the existence of additional PTH receptors. One or several receptors are probably expressed in the keratinocyte and the glomerular podocyte which are not identical with PTH/ PTHrP receptor-1. A third receptor, which has been cloned recently and called "PTH2 receptor", recognizes solely PTH. It is expressed in brain, pancreas, testis and placenta. Its function is unknown. There is also evidence for a fourth receptor, called "C-PTH receptor", recognizing C-terminal PTH fragments which are generally considered to be biologically inactive. The regulation of these receptors is subject to intensive research. Down-regulation of PTH/PTHrP receptor-1 mRNA expression could explain the well-known resistance to the action of PTH in chronic renal failure. In contrast, the receptor mRNA is up-regulated in vitamin D deficiency, despite a similar tissue resistance to PTH. A mutation of PTH/PTHrP receptor-1 causes Jansen-type metaphyseal chondrodysplasia. However, no alteration of the PTH/PTHrP receptor-1 gene structure has been found in type 1b pseudohypoparathyroidism.
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PMID:[Parathyroid hormone receptors: from cloning to physiological, physiopathological and clinical implications]. 912 3

1. Glomerular diseases frequently cause chronic renal failure which ultimately requires dialysis and kidney transplantation. The events leading to destruction of the glomerular filtration apparatus include injury of glomerular cells, aggregation of thrombocytes and infiltration of immune cells into the glomerulus. 2. Nucleotides (e.g. ATP and UTP) are present in all glomerular cell types as well as in thrombocytes. The release of nucleotides into the extracellular space occurs after damage of glomerular cells and aggregation of thrombocytes. Several in vitro and in vivo findings indicate that extracellular nucleotides may play a role as pro-inflammatory mediators in glomerulonephritis. 3. A hallmark finding in kidney biopsies from patients with glomerulonephritis is proliferation of glomerular mesangial cells. Cell culture studies demonstrated that extracellular ATP (10-300 microM) stimulated growth of mesangial cells. The mitogenic effect of ATP was potentiated in the presence of multiple growth factors. 4. Nucleotide-induced signalling in mesangial cells included an increase of intracellular calcium, activation of phosphatidylinositol-specific phospholipase C and phospholipase D, inhibition of adenylylcyclase, stimulation of mitogen-activated protein kinase and increased expression of the immediate early genes, c-fos, c-jun and Egr-1. 5. In previous studies of experimental mesangioproliferative glomerulonephritis, exogenously given ADP beta S and ATP gamma S have been shown to aggravate the course of the disease, while 2-chloroadenosine had beneficial effects. 6. Taken together, these findings support the concept that nucleotides may function as proinflammatory mediators in glomerulonephritis while adenosine may have antiinflammatory effects.
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PMID:Extracellular nucleotides as signalling molecules for renal mesangial cells. 913 21

CRF exerts a key neuroregulatory control on the function of the hypothalamic-pituitary-adrenal axis. These effects are thought to be mediated primarily through activation of Gs-coupled plasma membrane receptors. In the present study, we investigated the effects of activation of CRF receptors by sauvagine on signaling pathways that converge on phosphorylation of the transcription factor calcium/cAMP response element-binding protein (CREB). Studies were undertaken using CHO cell lines transfected with either rat CRF-1 or CRF-2alpha receptors. Signaling pathways were investigated using immunocytochemical, Western blot, and imaging techniques. Treatment with sauvagine increased phosphorylation of p42/p44, but not of p38 or stress-activated protein kinase (SAPK)/JUN N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases correlating with increased p42/p44 MAP kinase activity. Mobilization of intracellular Ca2+ stores was observed in cells treated with high concentrations (100 nM, 1 microM) of sauvagine. A time- and dose-dependent increase in phosphorylation of the transcription factor CREB was observed in cultures treated with sauvagine. Phosphorylation of CREB occurred at lower concentrations of sauvagine than those required to mobilize intracellular calcium stores, and phosphorylation was not blocked by the mitogen-activated protein kinase kinase inhibitor PD98059 at a concentration (1 microM) that fully inhibited phosphorylation of MAP kinase. Cotreatment of cultures with the protein kinase A inhibitor H89 (10 microM) blocked fully the stimulatory actions of sauvagine (0.1 nM, 1 nM) on phosphorylation of CREB, but not those on phosphorylation of MAP kinase. Phosphorylation of MAP kinase was partially blocked by the phosphoinositide 3-kinase inhibitor LY294002 (5 microM) and by the phosphoinositide-phospholipase C inhibitor U73122 (10 microM). These data demonstrate that cAMP-, Ca2+-, and MAP kinase-dependent signaling pathways are activated by stimulation of CRF-1 and CRF-2alpha receptors. However, in these cells, only protein kinase A-dependent pathways contribute significantly to enhanced phosphorylation of CREB. These represent the first reported observations of CRF receptor-mediated phosphorylation of the transcription factor CREB and activation of MAP kinase signal transduction pathways.
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PMID:Corticotropin-releasing factor type 1 and type 2alpha receptors regulate phosphorylation of calcium/cyclic adenosine 3',5'-monophosphate response element-binding protein and activation of p42/p44 mitogen-activated protein kinase. 1009 84


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