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)

Phospholipid signalling mediated by endothelin (ET) receptor subtypes was studied in the rat proximal tubule. In freshly isolated proximal tubule cells, ET-1, ET-2 and sarafotoxin S6c (S6c) evoked an increase in 1,2-diacylglycerol (DAG), inositol 1,4,5-trisphosphate (InsP3) and phosphocholine (PCho), suggesting stimulation of both phosphatidyl-inositol 4,5-bisphosphate- and phosphatidyl-choline-specific phospholipase C (PLC), while ET-3 increased only DAG and PCho, presumably via phosphatidyl-choline-dependent PLC. Renal cortical slices were also stimulated by the above-mentioned agonists, followed by isolation of either brush border (BBM) or basolateral (BLM) membranes for which mass measurements of inositol lipids and DAG were performed. In BBM, DAG increased in response to ET-1, ET-2 and ET-3, and was followed by protein kinase C (PKC) translocation to the BBM, while in BLM, DAG formation and translocation of PKC were observed only in response to ET-3, suggesting spatial segregation of signalling systems between two membane domains of proximal tubule cells. Tyrphostine, pertussis toxin (PTX) or cholera toxin (CTX) did not influence ET-mediated signalling in either of the membranes, suggesting involvement of PTX- and CTX-insensitive G-protein-mediated stimulation of PLCbeta by ET receptors. ET-dependent stimulation of PLC in BBM and BLM was used as a tool to examine the presence of different ET receptor subtypes in these two cell membrane domains. BQ123, an inhibitor of ETA receptors, did not prevent ET-1-mediated signalling in BBM, but an ETA,B antagonist, bosentan, inhibited ET-3-mediated signalling in BBM. In addition, an ETB agonist, S6c, stimulated PLC in BBM. Neither BQ123 nor bosentan inhibited ET-3 signalling in BLM. Therefore, these data strongly suggest the presence of ETB receptors coupled to phosphatidyl-inositol 4,5-bisphosphate- and phosphatidyl-choline-dependent PLC in BBM and ETC receptors linked to phosphatidyl-choline-dependent PLC in BLM.
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PMID:Different endothelin receptor subtypes are involved in phospholipid signalling in the proximal tubule of rat kidney. 866 90

This study attempted to define the role of endothelin (ET) in preconditioning. We previously showed that ET Is produced during myocardial ischemia and reperfusion. Because both preconditioning and ET act through protein kinase C, ET could play a role in preconditioning. Dogs were randomized to three groups subjected to 40 minutes of ischemia, with (groups A and B) or without (group C) preconditioning, followed by 4 hours of reperfusion. Groups A and C received saline infusions; group B received continuous infusions of the ETA-selective antagonist FR139317. Both preconditioned groups had smaller infarct sizes (group A, 7.9% +/- 2.5%; group B, 8.4% +/- 2.6%) than the nonpreconditioned group (group C, 16.2% +/- 3.3%). Administration of the ETA antagonist FR139317 did not alter infarct size. This study demonstrated that ETA-receptor blockade did not alter infarct size in preconditioned animals and suggests that endothelin does not play a significant role in this process.
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PMID:Endothelin-1 and myocardial preconditioning. 870 80

In this study, we have examined dog and rabbit airways as potential models for human airways in regard to the activity of endothelin. The receptors involved in the response to endothelin-1 (ET-1) in airway tissue from human, rabbit, and dog lung were investigated, as was the mechanism responsible for the contraction to ET-1 in tissue from the three species. By using specific endothelin receptor agonists and antagonists, we have demonstrated that ETB receptors predominate in rabbit and human airways and ETA receptors in dog airways. The contraction to ET-1 is not dependent on cyclooxygenase products of arachidonic acid, as indomethacin had no effect on the response to ET-1. Extracellular calcium influx via voltage-dependent channels is necessary for contraction to ET-1 in rabbit and dog airways. These results are in contrast to our previously reported results in human airways, in which neither removal of extracellular calcium nor verapamil affected the ET-1 response. The sustained phase of the contraction to ET-1 in all three species may be mediated in part by activation of protein kinase C (PKC), as the inhibitor staurosporine significantly altered the time course of the response to endothelin. We therefore conclude that in rabbit airways ET-1 activates ETB receptors, triggers the influx of extracellular calcium through voltage-dependent channels, and induces a contractile response that is, in part, dependent upon stimulation of PKC. The same mechanism is triggered in dog bronchus; however, the receptors involved in this species are of the ETA type. Finally, in human airways, the contractile response to ET-1, while independent of extracellular calcium influx, is dependent upon PKC activation after binding of the peptide to ETB receptors.
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PMID:Endothelin receptors and activity differ in human, dog, and rabbit lung. 877 25

Endothelins (ET) are potent vasoconstricting peptides with 21 amino acid residues. Endothelin-1 (ET-1) stimulates arachidonic acid (AA) release in human pericardial smooth muscle cells (HPSMC), which is primarily mediated through the ETA receptor. Manoalide, an inhibitor for phospholipase A2, inhibited the ET-1-evoked response by 50% at 1 microM. RHC-80267, an inhibitor for diacylglycerol lipase, did not have a significant effect. The Ca2+ ionophore A-23187 at 2 microM greatly stimulated AA release in the presence of extracellular Ca2+. ET-1 (10 nM) evoked a robust Ca2+ response. The intracellular Ca2+ concentration reached a peak after 10 s and gradually decreased to a new plateau level in the presence of extracellular Ca2+. ET-1-evoked AA release closely followed the change in the intracellular Ca2+ concentration. Removal of extracellular Ca2+ or treating cells with 250 microM bis(2-amino-5-methylphenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester (MAPTAM; an intracellular Ca2+ chelator) greatly reduced ET-1-stimulated AA release. The protein kinase C (PKC) inhibitors, staurosporine (1 microM) and chelerythrine chloride (2.5 microM), inhibited ET-1-evoked AA release by 70%. Phorbol 12-myristate 13-acetate, a PKC activator, potentiated the effect of ET on AA release. The data suggest that the effect of ET on AA release in HPSMC is via phospholipase A2, which is modulated by Ca2+ and PKC.
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PMID:Endothelin-1-evoked arachidonic acid release: a Ca(2+)-dependent pathway. 884 17

Possible mechanisms of action by which endothelin (ET)-1 has an effect on pulmonary vascular resistance and compliance in the canine pulmonary circulation were investigated in the isolated blood-perfused dog lung by use of vascular occlusion techniques. In the present study, ET-1 (10(-8) M) increased pulmonary vascular resistance and pulmonary capillary pressure by postcapillary vasoconstriction. In addition, ET-1 decreased total vascular compliance and middle-compartment compliance. Pretreatment with the ETA receptor antagonist BQ-610 (10(-7) M) or the protein kinase C inhibitors staurosporine (10(-6) M) and calphostin C (10(-6) M) completely blocked the pressor effect of ET-1. Elimination of extracellular calcium mobilization through voltage-dependent calcium channels by verapamil (10(-5) M) or modulation of G protein signal transduction by pertussis toxin challenge (15 micrograms/kg) had no significant effect on the ET-1-induced pulmonary vascular response. The results of the present study indicate that ET-1 causes pulmonary vasoconstriction in the canine pulmonary circulation through ETA receptor mediation and protein kinase C activation, possibly leading to intracellular calcium release. In contrast, the ET-1-induced pulmonary vascular response does not appear to involve extracellular calcium entry through voltage-dependent calcium-channel activation or pertussis toxin-sensitive G protein-signaling mechanisms.
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PMID:Mechanism of action of endothelin-1 in the canine pulmonary circulation. 884 68

We investigated the vascular effects and mechanism of action of endothelin-1 (ET-1) in the skin by intra-arterial infusion of ET-1 and its precursor Big ET-1 via a direct cutaneous artery in isolated perfused pig skin flaps (6 x 16 cm). The vascular contractivity was studied by monitoring the perfusion pressure in the skin flap. There was evidence to indicate local conversion of Big ET-1 to ET-1 in the pig skin. It was also observed that ET-1 was a potent long-lasting vasoconstrictor with a potency of approximately 10- and 300-fold higher than those of Big ET-1 and norepinephrine, respectively. The vasoconstrictor action of ET-1 was blocked (P < 0.01) by a selective ETA-receptor antagonist (BQ-123 or BQ-610; 10(-7) M) and enhanced (P < 0.05) by a nitric oxide synthase inhibitor (NG-monomethyl-L-arginine or N omega-nitro-L-arginine methyl ester; 10(-5) M). ET-1-induced increase in perfusion pressure was attenuated (P < 0.05) by an L-type Ca(2+)-channel antagonist (nitrendipine, verapamil, or nifedipine; 10(-5) M) and by removal of Ca2+ from the perfusate. ET-1-induced increase in perfusion pressure was also attenuated (P < 0.05) by a phospholipase C inhibitor (neomycin; 10(-2) M), a protein kinase C (PKC) inhibitor (chelerythrine or H-7; 10(-5) M), and an intracellular Ca2+ chelator [1,2-bis(2-aminophenoxy)]ethane-N,N,N',N'-tetraacetic acid (BAPTA); 10(-5) M]. Furthermore, it was observed that the concentration-dependent (5 x 10(-8) to 10(-5) M) increase in perfusion pressure induced by phorbol 12,13-dibutyrate, a PKC activator, was not affected by verapamil (10(-5) M) or removal of Ca2+ from the perfusate. Taken together, these observations suggest that the vasoconstrictor mechanism of ET-1 in the pig skin involved activation of ETA receptors, L-type Ca2+ channels, phospholipase C, and PKC and that the vasoconstrictor effect caused by activation of PKC was independent of L-type Ca2+ channels.
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PMID:Vascular effects and mechanism of action of endothelin-1 in isolated perfused pig skin. 884 80

Endothelin-1 (ET-1) was shown to exert direct cardiac effects by complex signaling pathways and to interact with neurotransmitter regulation of cardiac activity. The effect of ET-1 was investigated on the beta-adrenergic stimulation of cardiac L-type Ca2+ current (ICaL) on isolated rat atrial myocytes by using the patch-clamp technique. ET-1 (5 x 10(-8) M) reversed the increase in ICaL induced by isoprenaline (10(-6) M) but had no effect on basal ICaL and on (-) Bay K 8644-increased ICaL (10(-6) M); so ET-1 might exert an effect only when the Ca2+ channels are phosphorylated. The antiadrenergic action of ET-1, blocked by BQ-123 (10(-6) M) and unaffected by IRL 1038 (3.5 x 10(-8) M) should be mediated by ET-A receptors. The inhibitory action of ET-1 was still observed when ICaL was previously increased by forskolin (3 x 10(-6) M), 8-bromo-cyclic adenosine monophosphate (8-Br-cAMP; 200 microM), or cAMP (100 microM) in presence of isobutyl methyl xanthine (IBMX; 10(-6) M), suggesting that the antiadrenergic action of ET-1 on ICaL was exerted independent of the cAMP-dependent phosphorylation pathway. ET-1 is known to be an activator of phosphoinositide hydrolysis, resulting in an increased production of IP3 and diacylglycerol (DAG). A Ca(2+)-dependent inhibition of ICaL consequently to an elevation of the intracellular Ca2+ pool via IP3 might be excluded in the action of ET-1, because of the presence of EGTA in the intrapipette medium. ET-1 reversed the isoprenaline-induced increase in ICaL in the presence of protein kinase C inhibitor [PKC(19-31); 100 microM), making unlikely the involvement of a DAG-dependent activation of PKC. Therefore the antiadrenergic action of ET-1 might also be independent on the phosphoinositide pathway.
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PMID:Endothelin-1 inhibits L-type Ca2+ current enhanced by isoprenaline in rat atrial myocytes. 900 83

This report describes the fractional separation of microvessels from human brain for establishment of segmentally derived endothelial cell (EC) cultures. The investigation comprised evaluation of media constituents and purity of the cell culture and focused on functional biochemical characterization of endothelium derived from large microvessels (EC) Cells contained endothelial marker factor VIII (von Willebrand antigen), secreted endothelin-1 (ET-1) and prostaglandins, and took up 86Rb+ as a measure of K+. Exogenous ET-1 stimulated phosphatidylinositol hydrolysis and K+ uptake; BQ-123 (selective ETA receptor antagonist) but not IRL-1038 or BQ-788 (selective ETB receptor antagonists) inhibited both. Ouabain (inhibitor of Na(+)-K(+)-ATPase) and bumetanide (inhibitor of Na(+)-K(+)-Cl- cotransport) reduced (74-80 and 20-40%, respectively) the ET-1-stimulated K+ uptake. Staurosporine [protein kinase C (PKC) inhibitor] selectively reduced Na(+)-K(+)-Cl- cotransport, whereas verapamil but not nifedipine (L-type voltage-dependent Ca2+ channel blockers) decreased Na(+)-K(+)-ATPase activity induced by ET-1. Phorbol 12-myristate 13-acetate (PMA; activator of PKC) stimulated K+ uptake, which was only decreased with bumetanide. N-ethylisopropylamiloride (inhibitor of Na+/H+ exchange) reduced the ET-1-stimulated but not the PMA-induced K+ uptake. Results indicate that phosphatidylinositol hydrolysis and ion transport systems in large microvascular EC are stimulated by ET-1 through activation of ETA receptors. The findings also suggest that the ET-1-stimulated Na(+)-K(+)-ATPase activity, in contrast to Na(+)-K(+)-Cl- cotransport, is not mediated by PKC. In addition, the data suggest a linkage between Na(+)-K(+)-ATPase activity and Na+/H+ exchange.
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PMID:Functional properties of cultured endothelial cells derived from large microvessels of human brain. 903 29

Endothelin-1 (ET-1) is known to induce the contraction and proliferation of glomerular mesangial cells. ET-1 has been shown to activate p42 and p44 mitogen-activated protein kinases (MAPKs), also known as extracellular signal regulated kinases (ERKs), through both protein kinase C (PKC) and protein tyrosine kinase (PTK)-dependent pathways. However, an involvement of c-Jun NH2-terminal kinase (JNK), one of members of the MAPK family, in ET-1 signaling in mesangial cells has not yet been elucidated. To clarify this point, we examined whether ET-1 could activate JNK and the mechanism of activation in cultured mesangial cells. ET-1 enhanced the activities of JNK in a dose-dependent (10(-8) M maximum) and time-dependent manner, with a peak at 15 minutes. ET-1-induced activation of JNK was blocked by BQ-123, an antagonist for the ETA receptor. The depletion of PKC by prolonged treatment with phorbol 12,13 dibutyrate or the inhibition of PKC by GF 109203X failed to inhibit ET-1-induced activation of JNK. In contrast, ET-1-induced activation of JNK was significantly reduced by calcium chelation (with BAPTA/AM and EGTA). In addition, ionomycin, a calcium ionophore, and thapsigargin, an intracellular calcium-rising agent, were able to induce the activation of JNK. ET-1-induced activation of JNK was also inhibited by PTK inhibitors (herbimycin A and genistein). Furthermore, ET-1 increased the DNA-binding activity of AP-1 containing c-Jun and c-Fos proteins. These results indicate that ET-1 is able to activate JNK in glomerular mesangial cells through PKC-independent and PTK-dependent pathways and intracellular calcium is necessary to the activation of JNK.
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PMID:Endothelin-1 activates c-Jun NH2-terminal kinase in mesangial cells. 906 93

The endothelins (ET-1, 2, and 3) constitute a family of 21 amino-acid peptides with potent biological activities. They are synthesized in several tissues, including the vascular endothelium (ET-1 exclusively) and smooth muscle cells. The production and release of endothelin is stimulated by many factors, hormonal and metabolic, and by growth factors, hypoxia, and shear stress. Released endothelin binds to the endothelin receptors ETA and ETB, the ETA receptors on vascular smooth muscle cells mediating vasoconstriction, and the ETB receptors on the endothelium linked to nitric oxide (NO) and prostacyclin release. The ETA receptors activate the PLC-IP3-DAG transduction pathway, which through an increase in cytosolic Ca2+ and protein kinase C (PKC) causes vasoconstriction and stimulation of vascular smooth muscle cell growth and proliferation. In the pathogenesis of vascular hypertrophy in hypertension, there is a complex interaction between endothelin, angiotensin II, alpha-adrenergic agonists, Ca2+, and other growth factors. In animal models of hypertension, endothelin causes vascular hypertrophy, more pronounced in deoxycorticosterone acetate (DOCA)-salt hypertension in the rat than in the spontaneously hypertensive rate. In humans there is an increase in the plasma concentration of endothelin in severe atherosclerotic disease, but not consistently in hypertension. Evidence for the role of endothelin in the vascular hypertrophy of human hypertension is scanty, but the development of nonpeptide and receptor subtype-selective antagonists will permit meaningful studies, including clinical trials of a new class of antihypertensive agents.
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PMID:Endothelin, vascular hypertrophy, and hypertension. 911 Jan 24


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