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

---

Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin-1 (ET-1) can stimulate insulin-responsive glucose transporter (GLUT4) translocation in 3T3-L1 adipocytes (Wu-Wong, J. R., Berg, C. E., Wang, J., Chiou, W. J., and Fissel, B. (1999) J. Biol. Chem. 274, 8103-8110), and in the current study, we have evaluated the signaling pathway leading to this response. First, we inhibited endogenous Galpha(q/11) function by single-cell microinjection using anti-Galpha(q/11) antibody or RGS2 protein (a GTPase activating protein for Galpha(q)) followed by immunostaining to quantitate GLUT4 translocation in 3T3-L1 adipocytes. ET-1-stimulated GLUT4 translocation was markedly decreased by 70 or 75% by microinjection of Galpha(q/11) antibody or RGS2 protein, respectively. Pretreatment of cells with the Galpha(i) inhibitor (pertussis toxin) or microinjection of a Gbetagamma inhibitor (glutathione S-transferase-beta-adrenergic receptor kinase (GST-BARK)) did not inhibit ET-1-induced GLUT4 translocation, indicating that Galpha(q/11 )mediates ET-1 signaling to GLUT4 translocation. Next, we found that ET-1-induced GLUT4 translocation was inhibited by the phosphatidylinositol (PI) 3-kinase inhibitors wortmannin or LY294002, but not by the phospholipase C inhibitor U-73122. ET-1 stimulated the PI 3-kinase activity of the p110alpha subunit (5.5-fold), and microinjection of anti-p110alpha or PKC-lambda antibodies inhibited ET-stimulated GLUT4 translocation. Finally, we found that Galpha(q/11) formed immunocomplexes with the type-A endothelin receptor and the 110alpha subunit of PI 3-kinase and that ET-1 stimulation enhances tyrosine phosphorylation of Galpha(q/11). These results indicate that: 1) ET-1 signaling to GLUT4 translocation is dependent upon Galpha(q/11) and PI 3-kinase; and 2) Galpha(q/11) can transmit signals from the ET(A) receptor to the p110alpha subunit of PI 3-kinase, as does insulin, subsequently leading to GLUT4 translocation.
...
PMID:Endothelin-1-induced GLUT4 translocation is mediated via Galpha(q/11) protein and phosphatidylinositol 3-kinase in 3T3-L1 adipocytes. 1055 59

The presence of functional endothelin receptors and their signal transduction mechanism has not been determined so far in the pineal gland. We examined the effect of endothelin-1 (ET-1) on phosphoinositide turnover in whole pineal gland. Endothelin-1 increased monophosphate accumulation in a dose-dependent manner. The phosphoinositide (PI) response elicited by ET-1 was dependent on the presence of extracellular Ca (++) since its chelation resulted in a marked decrease in ET-1-stimulated InsP(1) accumulation. On the contrary, phosphoinositide hydrolysis was not changed by the calcium blocker amlodipine. ET-1 induced PI breakdown was inhibited by neomycin, an inhibitor of phospholipase C. However, mastoparan 7, a G protein activator via Gi/Go s timulation, did not alter ET-1-induced InsP(1) accumulation. Our data indicate that stimulation of PI turnover constitutes one of the signaling pathways of ET in rat pineal gland through the stimulation of a receptor-coupled phospholipase C. And they demonstrate, for the first time, the presence of functional binding sites for endothelin in the pineal gland.
...
PMID:Endothelin-1 stimulates phosphoinositide hydrolysis in the rat pineal gland. 1065 Mar 47

Endothelin-1 (ET-1) induces severe pathologic conditions such as coronary spasm followed by vasospastic angina pectoris and acute myocardial infarction. The related pathophysiologic mechanisms have remained obscure. Endothelin-1 receptor (ET(A) and ET(B)) is reported to couple with several types of G protein-involved pathways that participate in phospholipase C activation and atrial myofibrils organization into sarcomeric units. Here we demonstrate that ET-1 induces histologic and pathologic dysfunction in the rabbit myocardium and that such pathologic events are prevented by the Rho-kinase inhibitor fasudil. Although the bolus injection of ET-1 (1.4 nmol/kg) via the auricular vein of the rabbit induced only transient T-wave elevation, irreversible, severe histologic changes were observed in papillary muscles of the ventricle, and multifocal myocardial necrosis with infiltration of neutrophils and macrophages in the left ventricle occurred. Oral administration of fasudil (10 mg/kg) significantly reduced the occurrence of myocardial injury determinants, whereas conventional Ca2+ channel blockers (nifedipine, diltiazem) and a K+ channel opener (nicorandil; 10 mg/kg, p.o. each) showed a lesser or no effect on such determinants. These results suggest that ET-1 induces severe myocardial dysfunction based not only on the occurrence of vasospastic ischemia but also on its direct effects on the myocardium.
...
PMID:The protein kinase inhibitor fasudil protects against ischemic myocardial injury induced by endothelin-1 in the rabbit. 1067 51

Endothelin-1 (ET-1), a 21 amino acid peptide originally purified from conditioned medium of cultures of porcine aortic endothelial cells, is recognized also as a product of many other cells such as epithelial cells, glial cells, and neurons. It is now recognized that at least ET-1 plays an important role in bone metabolism. It has been shown that ET-1 inhibits osteoclast bone resorption by a direct effect on cell motility and it can also activate phospholipase C in the osteoblast. Furthermore, several studies have shown that ET-1 stimulates the formation of inositol phosphates, the synthesis of DNA, the mobilization of calcium from extra- and intracellular pools, the activation of phospholipase D, and the stimulation of tyrosine phosphorylation in osteoblast-like (MC3T3-E1 and UMR-106) cells. The aim of the present study was to detect and characterize the presence of endothelin in transformed human osteoblast cell culture medium (HTb96) by radioimmunoassay and chromatography methods. Immunoreactive endothelin (IR-ET) was undetectable in the medium incubated at 0.5 and 1 h and was 3.2 +/- 0.2 fmol/10(5) cells (mean +/- SEM, n = 6) at 2 h, 9.5 +/- 0.5 fmol/10(5) cells at 6 h, 19.8 +/- 2.1 fmol/10(5) cells at 24 h, and 23.7 +/- 2.0 fmol/10(5) cells at 48 h, respectively. Sephadex G-25 superfine chromatography and fast protein liquid chromatography studies showed that >90% of IR-ET in the culture medium coeluted with synthetic ET-1. These results show that ET-1 could be formed by transformed human osteoblasts. Further studies should be conducted to elucidate the physiological role of endothelins as possible autocrine, paracrine, or endocrine factors in calcium and bone metabolism.
...
PMID:Detection and characterization of endothelin in transformed human osteoblast cell culture medium. 1085 94

Endothelin-1 (ET-1) has been reported to modulate bone metabolism both in vivo and in vitro. In the present study, we investigated the effect of ET-1 on inorganic phosphate (Pi) transport in osteoblast-like cells, which is now considered to be important for the initiation of bone matrix calcification. ET-1 time- and dose-dependently stimulated Na-dependent Pi transport in mouse calvaria-derived osteoblast-like MC3T3-E1 cells, and this effect was dependent on transcriptional and translational process. Kinetic analysis indicated that the change in Pi transport activity induced by ET-1 was due to alteration in the number of the Pi transporter. BQ123, a selective antagonist for ET(A) receptor, suppressed the ET-1-induced Pi transport, but BQ788, a selective antagonist for ET(B) receptor, had no effect. The inhibition of phosphoinositide hydrolysis by phospholipase C (PLC) partially attenuated the Pi transport by ET-1. Propranolol, which inhibits phosphatidic acid phosphohydrolase, also suppressed ET-1-induced Pi transport. On the contrary, indomethacin did not affect the stimulatory effect of Pi transport by ET-1. Calphostin C, a protein kinase C (PKC) inhibitor, significantly blunted the stimulatory effect of ET-1 on Pi transport. Combined effect of PMA and ET-1 on Pi transport was not additive. Pi transport induced by ET-1 was also suppressed in PKC down-regulated cells. In conclusion, the results of the present study indicate that in MC3T3-E1 osteoblast-like cells, ET-1 acting through ET receptor links to a stimulation of Pi transport via activation of PKC through both phosphoinositide and phosphatidylcholine hydrolyses.
...
PMID:Stimulatory effect of endothelin-1 on Na-dependent phosphate transport and its signaling mechanism in osteoblast-like cells. 1150 Sep 53

Endothelins are potent mitogens that stimulate extracellular signal-regulated kinases (ERK/MAP kinases) through their cognate G-protein-coupled receptors, ET(A) and ET(B). To address the role of post-translational ET receptor modifications such as acylation on ERK activation and to identify relevant downstream effectors coupling the ET receptor to the ERK signaling cascades we have constructed a panel of palmitoylation-deficient ET receptor mutants with differential G(alpha) protein binding capacity. Endothelin-1 stimulation of wild-type ET(A) or ET(B) induced a fivefold to sixfold increase in ERK in COS-7 and CHO cells whereas full-length nonpalmitoylated ET(A) and ET(B) mutants failed to stimulate ERK. A truncated ET(B) lacking the C-terminal tail domain including putative phosphorylation and arrestin binding site(s) but retaining the critical palmitoylation site(s) was still able to fully stimulate ERK activation. Using mutated ET receptors with selective G-protein-coupling we found that endothelin-induced stimulation of G(alpha)q, but not of G(alpha)i or G(alpha)s, is essential for endothelin-mediated ERK activation. Inhibition of protein kinases A and C or epidermal growth factor receptor kinase failed to prevent ET(A)- and ET(B)-mediated ERK activation whereas blockage of phospholipase C-beta completely abrogated endothelin-promoted ERK activation through ET(A) and ET(B) in recombinant COS-7 and native C6 cells. Complex formation of Ca2+ or inhibition of Src family tyrosine kinases prevented ET-1-induced ERK-2 activation in C6-cells. Our results indicate that endothelin-promoted ERK/MAPK activation criticially depends on palmitoylation but not on phosphorylation of ET receptors, and that the G(alpha)q/phospholipase C-beta/Ca2+/Src signaling cascade is necessary for efficient coupling of ET receptors to the ERK/MAPK pathway.
...
PMID:Coupling of endothelin receptors to the ERK/MAP kinase pathway. Roles of palmitoylation and G(alpha)q. 1160 8

We compared agonist-evoked responses in the perfused mesenteric vascular bed (MVB) of streptozotocin (STZ) diabetic Sprague-Dawley rats 2 and 14 weeks after induction of diabetes. Endothelin-1 (ET-1)-, methoxamine (MTX)-, and KCl-evoked vasoconstrictor responses were unchanged in 2-week-old diabetic rats. In contrast, both the sensitivity (P < 0.01) and the maximal vasoconstrictor responses (P < 0.05) to ET-1 were attenuated in 14-week-old diabetic rats, whereas endothelin plasma levels were increased (P < 0.05). Although no differences were observed in responses to KCl in either the 2- or 14-week-old diabetic groups, MTX-evoked maximal responses were attenuated in the 14-week-old group (P < 0.01). Changes in agonist-evoked responses in the 14-week-old diabetic group were unaffected by the protein kinase C (PKC) inhibitor, staurosporine, the phospholipase C (PLC) inhibitor, U73122, the calcium channel blocker, nifedipine, the calcium pump inhibitor, cyclopiazonic acid (CPA), or by endothelial denudation. Sodium fluoride (NaF), an activator of guanosine triphosphate binding proteins (G proteins) normalized the responses in the 14-week-old diabetic group. These data suggest that advanced stages of STZ are associated with alterations in G protein receptor coupling and/or activity leading to the attenuation of responses to vasoconstrictor agonists.
...
PMID:Attenuated agonist evoked vasoconstrictor responses in the perfused mesenteric vascular bed of streptozotocin diabetic rats. 1168 1

Folliculo-stellate cells of the anterior pituitary are thought to modulate pituitary hormone secretion through a paracrine mechanism. Angiotensin II and pituitary adenylate cyclase-activating polypeptide (PACAP) have previously been shown to increase the intracellular Ca2+ concentration ([Ca2+]i) of these cells. In the present study, we examined the effects of various peptides such as bradykinin, angiotensin II, endothelin-1, PACAP, galanin and neurotensin by Ca2+-imaging of folliculo-stellate cells in primary culture. Bradykinin and angiotensin II increased [Ca2+]i in folliculo-stellate cells. Both responses were completely suppressed by thapsigargin and were significantly suppressed by the phospholipase C inhibitor, U-73122. Ryanodine did not significantly modify the responses. A B2 antagonist and angiotensin II receptor antagonist inhibited the response induced by bradykinin and angiotensin II, respectively. Endothelin-1 and PACAP increased [Ca2+]i in fewer than 50% of folliculo-stellate cells but galanin and neurotensin did not influence [Ca2+]i in any of the folliculo-stellate cells tested. These results indicate that bradykinin and angiotensin II increase [Ca2+]i in folliculo-stellate cells by activating phospholipase C through B2 receptor and AT1 receptor, respectively, and that endothelin-1 and PACAP also increase [Ca2+]i in some folliculo-stellate cells.
...
PMID:Bradykinin and angiotensin II-induced [Ca2+]i rise in cultured rat pituitary folliculo-stellate cells. 1173 52

Endothelin-1 (ET-1) is an autocrine factor in the mammalian heart important in enhancing cardiac performance, protecting against myocardial ischemia, and initiating the development of cardiac hypertrophy. The ETA receptor is a seven-transmembrane G-protein-coupled receptor whose precise subcellular localization in cardiac muscle is unknown. Here we used fluorescein ET-1 and 125I-ET-1 to provide evidence for ET-1 receptors in cardiac transverse tubules (T-tubules). Moreover, the ETA receptor and downstream effector phospholipase C-beta 1 were co-localized within T-tubules using standard immunofluorescence techniques, and protein kinase C (PKC)-epsilon-enhanced green fluorescent protein bound reversibly to T-tubules upon activation. Localized photorelease of diacylglycerol further suggested compartmentation of PKC signaling, with release at the myocyte "surface" mimicking the negative inotropic effects of bath-applied PKC activators and "deep" release mimicking the positive inotropic effect of ET-1. The functional significance of T-tubular ET-1 receptors was further tested by rendering the T-tubule lumen inaccessible to bath-applied ET-1. Such "detubulated" cardiac myocytes showed no positive inotropic response to 20 nM ET-1, despite retaining both a nearly normal twitch response to field stimulation and a robust positive inotropic response to 20 nm isoproterenol. We propose that ET-1 enhances myocyte contractility by activating ETA receptor-phospholipase C-beta 1-PKC-epsilon signaling complexes preferentially localized in cardiac T-tubules. Compartmentation of ET-1 signaling complexes may explain the discordant effects of ET-1 versus bath applied PKC activators and may contribute to both the specificity and diversity of the cardiac actions of ET-1.
...
PMID:Localization of functional endothelin receptor signaling complexes in cardiac transverse tubules. 1297 33

Endothelin-1 has been implicated as an important modulator or mediator of acute and chronic hypoxic pulmonary hypertension. It has been shown that endothelin-1 increases [Ca2+]i and contraction in pulmonary arterial smooth muscle cells. Recently, we have identified local Ca2+ release transients or Ca2+ sparks, which represent Ca2+ release from clusters of ryanodine receptors on the sarcoplasmic reticulum, in pulmonary arterial smooth muscle cells. These pulmonary Ca2+ sparks were associated with membrane depolarization, and activated specifically by endothelin-1 via endothelin-A receptor activation of phospholipase C and inositol trisphosphate production, possibly through local Ca2+ signaling between inositol trisphosphate receptors and ryanodine receptors. To test this hypothesis, we measured Ca2+ sparks in intralobar pulmonary arterial smooth muscle cells using laser scanning microscopy, and compared the spatiotemporal properties of Ca2+ sparks activated by endothelin-1 and by photorelease of inositol trisphosphate. We found that both endothelin-1 and inositol trisphosphate had similar effects on Ca2+ sparks. They both increased spark frequency, elevated spark amplitude and prolonged duration, without any significant effect on the spatial spread or size of Ca2+ sparks. These results provide further support to the suggestion that inositol trisphosphate production stimulated by endothelin-1 can account for the activation of Ca2+ sparks in pulmonary arterial smooth muscle cells.
...
PMID:Endothelin-1 and IP3 induced Ca2+ sparks in pulmonary arterial smooth muscle cells. 1583 59


<< Previous 1 2 3 4 5 6 Next >>

---