Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied whether a novel vasoconstrictor, endothelin-1 (ET-1), is synthesized by and released from human decidual cells in early pregnancy, and whether ET-1 acts directly on their own cells. It was observed that ET-1-like immunoreactivity (ET-1-LI) was released from cultured decidual, but not villous, cells, as a function of time. Reverse-phase high-pressure liquid chromatography of the conditioned media from the decidual cells revealed a major peak of ET-1-LI coeluting with standard ET-1. Phorbol myristate acetate, a protein kinase C activator, dose-dependently increased the release of ET-1-LI from the decidual cells, while a protein kinase C inhibitor, H7, significantly attenuated the stimulatory effect of phorbol myristate acetate on ET-1-LI release. Northern blot analysis demonstrated the expression of messenger RNA for prepro-ET-1 in the decidual tissue, but no such messenger RNA was observed in the villous tissue. The human decidual tissue contained a noninteracting, single class of binding sites demonstrating higher affinity for ET-1 and ET-2 than ET-3. This would be most consistent with the ETA receptor subtype. An ET-1-induced, dose-dependent accumulation of total inositol phosphates was also observed in human decidual cells prelabeled with myo-[3H]inositol. The present results demonstrate for the first time that human decidual cells in early pregnancy can synthesize and release ET-1. These cells also possess specific functional receptors for ET-1 which are coupled to phosphoinositide hydrolysis. Thus our data suggest a possible role for ET-1 in autocrine and/or paracrine function in human decidual cells.
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PMID:Synthesis and release of endothelin-1 by human decidual cells. 143 83

Endothelin (ET)-related peptides robustly stimulated [3H]-inositol phosphate (IP) formation in cultured cerebellar granule cells, astrocytes, and C6 glioma cells. Their agonist selectivities were ET-1 = ET-2 greater than or equal to sarafotoxin S6b greater than ET-3 greater than big ET-1 for granule cells and ET-1 greater than or equal to ET-2 greater than or equal to S6b greater than big ET-1 greater than ET-3 for cerebellar astrocytes and C6 glioma cells. These effects were Ca(2+)-dependent but insensitive to antagonists of L-type Ca2+ channels and the Na+/Ca2+ antiporter. Pretreatment of cells with ET-1 or S6b induced homologous desensitization of phosphoinositide (PI) response mediated by ET receptors. Long-term pertussis toxin (PTX) treatment attenuated the phosphoinositide (PI) response in astrocytes and glioma but not in granule cells. ET-1 and its related peptides increased [Ca2+]i in C6 glioma by two distinct pathways: IP3-induced Ca2+ mobilization or receptor-operated Ca2+ influx. La3+, Mn2+, and Cd2+ inhibited the Ca2+ influx and sustained PI turnover, while Ca2+ mobilization was attenuated by phorbol ester and TMB-8. ET-induced Ca2+ influx was essential for the sustained [Ca2+]i increase and PI turnover. Homologous desensitization of [Ca2+]i increase was also noted. In cerebellar granule cells, ET evoked the release of [3H]D-aspartate from these neurons. This action appears to be dependent on PI hydrolysis and [Ca2+]i increase and modulated by protein kinase C.
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PMID:Endothelin-induced activation of phosphoinositide turnover, calcium mobilization, and transmitter release in cultured neurons and neurally related cell types. 172 40

Ca2+ signaling by peptides of the endothelin (ET) gene family was studied in cultured glomerular mesangial cells. In addition to the increase in cytosolic free [Ca2+] ([Ca2+]i) previously described for ET-1, we also observed that ET-2, ET-3, and sarafotoxin S6b generate similar [Ca2+]i waveforms but with dissimilar potencies and kinetics. The prepro form of ET-1 was inactive, suggesting that mature ET peptides are constrained in an inactive conformation within the preproET species. ET isopeptides caused both release of Ca2+ from intracellular stores and Ca2+ influx via a voltage- and dihydropyridine-insensitive pathway. ET-mediated Ca2+ influx was independent of the increase in [Ca2+]i. Activation of protein kinase C inhibited ET-induced Ca2+ signaling, whereas addition of ET to protein kinase C-depleted cells resulted in enhanced [Ca2+]i waveforms. Mesangial cells also demonstrated a marked adaptive desensitization response to ET. These data demonstrate that Ca2+ signaling is a common response to different ET peptides in glomerular mesangial cells and that activation of protein kinase C down-regulates these Ca2+ signals.
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PMID:Ca2+ signaling by distinct endothelin peptides in glomerular mesangial cells. 184 94

Isopeptides of the newly discovered peptide family, endothelins (ET), caused a concentration-dependent increase in intracellular free [Ca2+] ([Ca2+]i) in human glomerular mesangial cells. ET isopeptides and sarafotoxin S6b caused transient and sustained [Ca2+]i waveforms which resulted from mobilization of intracellular Ca2+ stores and from Ca2+ influx through a dihydropyridine-insensitive Ca2+ channel. Ca2+ signaling evoked by ET isopeptides underwent a marked adaptive, desensitization response. Although activation of protein kinase C attenuated ET-induced Ca2+ signaling, desensitization by ET isopeptides was independent of protein kinase C. High concentrations of ET-1 and ET-2 also caused oscillations of [Ca2+]i that partially depended on extracellular Ca2+. These results suggest that an increase in [Ca2+]i constitutes a common pathway of signal transduction for the ET peptide family.
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PMID:Endothelin isopeptides evoke Ca2+ signaling and oscillations of cytosolic free [Ca2+] in human mesangial cells. 217 77

Endothelin, originally identified as a vasoconstrictive peptide derived from vascular endothelial cells, is now known to exert diverse biological effects on a wide variety of tissues and cell types through its own receptor(s). One of the outstanding actions of endothelin is a cell growth promoting activity which is demonstrated in several cell types including cultured vascular smooth muscle cells, fibroblasts, glomerular mesangial cells and osteoblasts. The mitogenic effect is likely mediated by stimulation of phospholipase C via receptor-G-protein coupling, and subsequent activation of protein kinase C. The effect of endothelin may contribute to the cell-proliferation response under various physiological and pathological conditions, such as wound healing and development of atherosclerosis and glomerulonephritis. Recently, three distinct endothelin-related genes have been cloned, suggesting that mammals, including humans, produce three members of this peptide family, endothelin (ET)-1 (the 'classical' endothelin), ET-2 and ET-3, which may act on distinct subtypes of endothelin receptor to induce different cellular responses.
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PMID:Endothelin, its diverse biological activities and mechanisms of action. 249 Dec 62

[125I]ET-1 binding to vascular smooth muscle cells showed an apparent single class of high affinity recognition sites with a Kd of 2.12 +/- 0.46 nM and a Bmax of 81.2 +/- 5.2 fmol/10(6) cells. The specific binding was equally and totally displaced by ET-1 and ET-2 whereas ET-3 presented a different pattern. We investigated heterologous regulation of ET-1 binding sites by preincubating the cells with angiotensin II (AII), Arg-vasopressin, bradykinin, enkephalins, serotonin, norepinephrine and carbachol, for 18 h at 37 degrees C. Only AII pretreatment resulted in an important and dose-dependent decrease of ET-1 binding capacity. Sar1-Ile8-AII inhibited the regulatory effect of AII. Furthermore, preexposure of the cells with phorbol-12,13 dibutyrate but not with phorbol-12,13 didecanoate also resulted in a concentration-dependent diminution of ET-1 binding sites. These findings suggest that AII may selectively down-regulate ET-1 binding sites in vascular smooth muscle cells by a mechanism involving protein kinase C.
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PMID:Angiotensin II and phorbol-esters potently down-regulate endothelin (ET-1) binding sites in vascular smooth muscle cells. 255 1

Endothelin (ET) is a novel family of three isopeptides (ET-1, ET-2, ET-3) each containing twenty-one amino acids and two disulfide bonds. Initially isolated from the supernatant of cultured porcine aortic endothelial cells, ET is stored as a preproform and released through an unusual proteolytic cleavage. In general, ET-1, ET-2, ET-3 differ quantitatively but not qualitatively in their biologic activity. ET have potent contractile activity in a variety of isolated tissues including arteries veins, trachea, duodenum urinary bladder and uterus. In vivo, ET possesses potent vasodilator and vasoconstrictor properties. Although the mechanisms mediating the hemodynamic effects of ET are not entirely clarified, recent evidence indicates a role for endothelium-derived relaxant factor (EDRF), protein kinase C and extracellular calcium. Moreover, ET appears to produce inflammation and bronchoconstriction through the formation of arachidonic acid metabolites via the cyclooxygenase pathway. The presence of ET binding sites in blood vessels and in several organ systems suggests ET may have important regulatory functions, which remain to be determined.
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PMID:Endothelin--a new family of endothelium-derived peptides with widespread biological properties. 268 85

The effect of endothelins (ETs) on sodium/hydrogen (Na+/H+) antiport system was examined in cultured rat brain capillary endothelium (RBEC). ET-1, ET-2, and ET-3 stimulated Na+ uptake into RBEC with similar half-maximal stimulation (EC50) values (0.7, 0.6, and 1.1 nM, respectively). This reaction was inhibited by the Na+/H+ antiport inhibitor, N-(ethyl-N-isopropyl)-amiloride (EIPA). The selective endothelin A (ETA) receptor-antagonist (cyclo-D-Trp-D-Asp-Pro-D-Val-Leu (BQ123)), but not endothelin B (ETB) receptor-antagonists ((Cys11, Cys15)-ET-1 (IRL1038) or N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma MeLeu-D-Trp(COOMe)-D-Nle-ONa (BQ788)), inhibited both ET-1- and ET-3-stimulated Na+ uptake, indicating ETA-receptor mediation. The protein kinase C (PKC) activator (phorbol 12-myristate 13-acetate (PMA)) failed to stimulate Na+ uptake. The calcium-calmodulin (CaM) inhibitor (W7) reduced ET-1-stimulated Na+ uptake by 50%, whereas the PKC inhibitor (staurosporine) had no effect, indicating that ET-1 stimulation of the Na+/H+ antiport system is linked to a CaM-dependent and PKC-independent pathway.
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PMID:Endothelins stimulate sodium uptake into rat brain capillary endothelial cells through endothelin A-like receptors. 764 28

1. It has been shown previously that nordihydroguaiaretic acid (NDGA) inhibits endothelin-1 (ET-1)-induced contractions in rat isolated tracheal smooth muscle. To investigate the underlying mechanisms, this study examined the effects of NDGA on various aspects of the ETA and ETB receptor-effector systems which mediate ET-1-induced contractions in this preparation. 2. NDGA inhibited contractions induced by each of the isoforms of ET (ET-1, ET-2 and ET-3) but not those induced by the ETB receptor-selective agonist, sarafotoxin S6c, the cholinoceptor agonist, carbachol or the depolarizing spasmogen, KCl. 3. Quantitative autoradiographic studies of [125I]-ET-1 binding to rat tracheal smooth muscle indicated that NDGA was not an ET receptor antagonist. 4. NDGA inhibited the ETA receptor-mediated, intracellular Ca(2+)-dependent contractions induced by 100 nM ET-1 in Ca(2+)-free solution (by 75%, P < 0.01). Furthermore, NDGA markedly inhibited the contractions induced by ryanodine and cyclopiazonic acid; contractions purportedly due to Ca2+ release from intracellular stores. 5. Like NDGA, the sarcoplasmic reticulum Ca(2+)-ATPase inhibitors cyclopiazonic acid and thapsigargin inhibited contractions to ET-1, but not carbachol or KCl. However, cyclopiazonic acid, but not NDGA, also (a) induced transient contractions in rat trachea, (b) potentiated contractions induced by KCl, and (c) potentiated the extracellular Ca(2+)-dependent phase of ET-1-induced contractions, indicating that NDGA did not inhibit ET-1-induced contractions through Ca(2+)-ATPase inhibition and depletion of sarcoplasmic reticular Ca2+. 6. In control preparations, ET-1 induced a slowly developing, sustained contraction. However, in the presence of NDGA or the ETA receptor antagonist, BQ123, ET-1-induced contractions resembled the transient contractions induced by sarafotoxin S6c. In nominally Ca2+-free solution, ETA receptor mediated contractions induced by ET-1 developed very slowly and were inhibited by NDGA.7. Additional studies indicated that the inhibitory effects of NDGA on endothelin-1-induced contractions were not the result of any significant actions of NDGA on lipoxygenase, cytochrome P450, L- orT-type Ca2+-channels, Na+-channels or protein kinase C.8. In summary, NDGA selectively inhibited ET-1-induced contractions in rat tracheal smooth muscle via a lipoxygenase-independent mechanism involving inhibition of the ETA but not the ETB, receptor effector system. NDGA did not appear to inhibit the initial events in the ETA signal transduction pathway, such as receptor binding and protein kinase C activation. However, NDGA inhibited the intracellular Ca2+-dependent component of ET-1-induced contraction, possibly by inhibiting mobilisation of intracellular Ca2+. As an apparent direct consequence of inhibiting the ETA receptor-effector system, NDGA markedly changed the time course of ET-1-induced contractions; from a slowly developing and sustained contraction into a transient contraction resembling that induced by sarafotoxin S6c.
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PMID:Inhibitory effects of nordihydroguaiaretic acid on ETA-receptor-mediated contractions to endothelin-1 in rat trachea. 800 99

The endothelins (ETs) and sarafotoxin are two structurally related classes of potently contractile peptides. To understand the mechanism of action of ETs, we have examined the effect of ETs and sarafotoxin on phosphoinositide (PI) hydrolysis in cultured canine tracheal smooth muscle cells (TSMCs). ET-1, ET-2, ET-3, and sarafotoxin caused dose-dependent accumulation of inositol phosphatase (IPs) and tracheal smooth muscle contraction. BQ-123, an ETA receptor antagonist, had a high affinity to block the ET-1-induced IP accumulation and tracheal smooth muscle contraction with pKB values of 7.3 and 7.4, respectively. Pretreatment of TSMCs with cholera toxin impaired the ability of ET-1 and ET-2 to stimulate IP formation, whereas there was no effect by treatment with pertussis toxin. Stimulation of PI turnover by these peptides required the presence of extracellular Ca2+ and was blocked by treatment with EGTA. The addition of Ca2+ (3-620 nM) to digitonin-permeabilized TSMCs directly stimulated IP accumulation. A further Ca(2+)-dependent increase in IP formation was obtained by inclusion of either GTPrS or ET-1. The combined presence of GTPrS and ET-1 elicited an additive effect on IP formation. Short-term exposure to phorbol 12-myristate 13-acetate (PMA, 1 microM) abolished the stimulation of PI hydrolysis induced by these peptides. The inhibitory effect of PMA on ET-induced response was reversed by staurosporine, a protein kinase C (PKC) inhibitor, suggesting that the inhibitory effect of PMA is mediated through the activation of PKC. Prolonged incubation of TSMCs with PMA resulted in a recovery of receptor responsiveness that may be due to downregulation of PKC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endothelin- and sarafotoxin-induced phosphoinositide hydrolysis in cultured canine tracheal smooth muscle cells. 813 73


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