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)

The aims of this study were to investigate the effects of a selective ETA (BQ-123), a selective ETB (BQ-788), and a specific mixed ETA/ETB receptor antagonist (bosentan) on the pulmonary vasoconstriction induced by hypoxia in the isolated perfused rat lung, and the role of nitric oxide, adenosine triphosphate-sensitive (KATP), large conductance Ca+-activated (BKCa) and 4-aminopyridine-sensitive voltage-gated K channels (K+) in the relaxant effects of the selective ETA receptor antagonist BQ-123 and a protein kinase C inhibitor, bisindolylmaleimide I. K+ channels were inhibited by glibenclamide, charybdotoxin, and 4-aminopyridine and nitric oxide synthase by L-NG-nitroarginine methyl ester (L-NAME). Hypoxic ventilation produced a significant pressure response (+57%, p < 0.001). BQ-123, bosentan, and bisindolylmaleimide I induced a concentration-dependent decrease of the hypoxic pressure response (p < 0.001), whereas BQ-788 did not exhibit any inhibitory effect against hypoxic pressure response. Glibenclamide, charybdotoxin, and 4-aminopyridine partially opposed the inhibitory effects elicited by BQ-123 (p < 0.05), but L-NAME did not modify these effects. The effects of bisindolylmaleimide I on hypoxic pressure response were unaffected by glibenclamide, charybdotoxin, or 4-aminopyridine. The authors conclude that (a) ETA receptors and protein kinase C are involved in the modulation of hypoxic pulmonary vasoconstriction; and (b) the ETA antagonist BQ-123 opposes hypoxic pulmonary vasoconstriction through KATP, KV, and BKCa channels, differing in this from the protein kinase C inhibitor bisindolylmaleimide I. These results suggest that BQ-123 operates through a mechanism independent of bisindolylmaleimide I-inhibited protein kinase C isoforms.
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PMID:ETA, mixed ETA/ETB receptor antagonists, and protein kinase C inhibitor prevent acute hypoxic pulmonary vasoconstriction: influence of potassium channels. 1250 29

1. Endothelin-1 (ET-1) and tumor necrosis factor alpha (TNFalpha) by their action on adipocytes have been independently linked to the pathogenesis of insulino-resistance. In isolated adipocytes, TNFalpha induces the expression of the inducible nitric oxide synthase (iNOS). The purpose of the present work was, in the 3T3-F442A adipocyte cell line, to characterise TNFalpha-induced iNOS expression and to determine whether or not ET-1 could influence TNFalpha-induced iNOS expression and NO production. 2. In differentiated 3T3-F442A, treatment with TNFalpha (20 ng ml(-1)) induced the expression of a functional iNOS as demonstrated by nitrite assay, Western blot, reverse transcription-polymerase chain reaction and Northern blot analysis. TNFalpha-induced iNOS expression requires nuclear factor kappaB activation, but does not necessitate the activation of the PI-3 kinase/Akt and P38-MAP kinase pathways. 3. ET-1, but not ET-3, inhibited the TNFalpha-induced expression of iNOS protein and mRNA as well as nitrite production. The effects of ET-1 were blocked by a specific ETA (BQ123, pA(2) 7.4) but not by a specific ETB receptor antagonist (BQ788). 3T3-F442A adipocytes express the mRNAs for prepro-ET-1 and the ET-A receptor subtype, but not for the ET-B subtype. 4. The inhibitory effect of ET-1 was not affected by bisindolylmaleimide, SB 203580 or indomethacin, inhibitors of protein kinase C, p38-MAP kinase and cyclooxygenase, respectively, and was not associated with cAMP production. However, the effect of ET-1 was partially reversed by wortmannin, suggesting the involvement of PI3 kinase in the transduction signal of ET-1. 5. Differentiated 3T3-F442A adipocytes did not release ET-1 with or without exposure to TNFalpha, although the mRNA for preproET-1 was detected in both pre- and differentiated adipocytes. 6. Thus, these results confirm that adipocytes are a target for circulating ET-1 and demonstrate that the activation of the ETA receptor subtype can prevent TNFalpha-induced iNOS expression.
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PMID:Endothelin-1 inhibits TNF alpha-induced iNOS expression in 3T3-F442A adipocytes. 1283 67

Based upon the existence of high density of ET-receptors on catecholaminergic neurons of the hypothalamus, we studied the effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on neuronal norepinephrine (NE) release in the rat posterior hypothalamus. The intracellular pathways and receptors involved were also investigated. Neuronal NE release was enhanced by ET-1 and ET-3 (10 etaM). The selective antagonists of subtype A and B ET receptors (ETA, ETB) (100 etaM BQ-610 and 100 etaM BQ-788, respectively) abolished the increase induced by ET-1 but not by ET-3. The PLC inhibitor, U73122 (10 microM), abolished ET-1 and ET-3 response. GF-109203X (100 etaM) (PKC inhibitor) blocked the increase in NE release produced by ET-3 and partially blocked ET-1 response. The inositol 1,4,5-trisphosphate-induced calcium release inhibitor, 42 microM 2-APB, inhibited the stimulatory effect induced by ET-3 but not by ET-1. The PKA inhibitor, 500 etaM H-89, blocked the increase in neuronal NE release evoked by ET-1 but not by ET-3. Our results showed that ET-1 as well as ET-3 displayed an excitatory neuromodulatory effect on neuronal NE release in the rat posterior hypothalamus. ET-1 through an atypical ETA or ETB receptor activated the PLC/PKC signalling pathway as well as the cAMP pathway, whereas ET-3 through a non-ETA/non-ETB receptor activated the phosphoinositide pathway. Both ETs would enhance the sympathoexcitatory response elicited by the posterior hypothalamus and thus participate in cardiovascular regulation.
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PMID:Modulatory effect of endothelin-1 and -3 on neuronal norepinephrine release in the rat posterior hypothalamus. 1475 57

We have previously reported that endothelin 1 and 3 (ET-1, ET-3) through the ETB receptor decrease norepinephrine release in the anterior hypothalamus and activate the nitric oxide (NO) pathway. In the present work we sought to establish the receptors and intracellular mechanisms underlying the increase in nitric oxide synthase (NOS) activity stimulated by ET-1 and ET-3 in the rat anterior hypothalamus. Results showed that ETs-stimulated NOS activity was inhibited by a selective ETB antagonist (BQ-788), but not by a selective ETA antagonist (BQ-610). In addition, NOS activity was not altered in the presence of an ETA agonist (sarafotoxin 6b), but it was enhanced in the presence of a ETB agonist (IRL-1620). Both Nomega-nitro-L-arginine methyl ester (NOS inhibitor), and 7-nitroindazole (neuronal NOS inhibitor) diminished ETs-stimulated NOS activity. The stimulatory effect of ETs on NOS activity was inhibited in the presence of PLC, PKC, PKA and CaMK-II inhibitors (U-73122, GF-109203X, H-89 and KN-62, respectively), and the IP3 receptor selective antagonist, 2-APB. Our results showed that both ET-1 and ET-3 modulate neuronal NOS activity through the ETB receptor in the rat anterior hypothalamus involving the participation of the PLC-PKC/IP3 pathway as well as PKA and CaMK-II.
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PMID:Endothelin 1 and 3 enhance neuronal nitric oxide synthase activity through ETB receptors involving multiple signaling pathways in the rat anterior hypothalamus. 1524 72

We analyzed the signaling pathways initiated by endothelin receptors ETA and ETB in intestinal circular and longitudinal smooth muscle cells. The response to endothelin-1 (ET-1) consisted of two phases in both cell types. The initial, transient phase of contraction and phosphorylation of 20-kDa myosin light chain (MLC20) was mediated additively by ETA and ETB receptors and initiated by Galphaq-, Ca2+/calmodulin-dependent activation of MLC kinase. In contrast, the sustained phase was mediated selectively by ETA receptors via a pathway involving sequential activation of Galpha13, RhoA, and Rho kinase, resulting in phosphorylation of MYPT1 at Thr696 and phosphorylation of MLC20. Although PKC was activated, CPI-17 was not phosphorylated and hence did not contribute to inhibition of MLC phosphatase. The absence of CPI-17 phosphorylation by PKC reflected active dephosphorylation of CPI-17 by protein phosphatase 2A (PP2A). PP2A was activated via a pathway involving ETB-dependent stimulation of p38 MAPK activity. CPI-17 phosphorylation was unmasked in the presence of the ETB antagonist BQ-788, but not the ETA antagonist BQ-123, and in the presence of a low concentration of okadaic acid, which selectively inactivates PP2A. The resultant phosphorylation of CPI-17 was blocked by bisindolylmaleimide, providing direct confirmation that it was PKC dependent. We conclude that the two phases of the intestinal smooth muscle response to ET-1 involve distinct receptors, G proteins, and signaling pathways. The sustained response is mediated via selective ETA-dependent phosphorylation of MYPT1. In contrast, ETB initiates an inhibitory pathway involving p38 MAPK-dependent activation of PP2A that causes dephosphorylation of CPI-17.
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PMID:Gq/G13 signaling by ET-1 in smooth muscle: MYPT1 phosphorylation via ETA and CPI-17 dephosphorylation via ETB. 1547 16

Endothelin-1 (ET-1) affects glucose uptake in adipocytes and may play an important role in adipose physiology. One of the principal functions of adipose tissue is the provision of energy substrate through lipolysis. In the present study, we investigated the effects of ET-1 on lipolysis in 3T3-L1 adipocytes. When glycerol release in the culture medium was measured as an index of lipolysis, the results showed that ET-1 caused a significant increase that was time and dose dependent. With a concentration of 10 nM ET-1, stimulation of glycerol release plateaued after 4 h of exposure. This effect was inhibited by the ETA receptor antagonist BQ-610 (10 microM) but not by the ETB receptor antagonist BQ-788 (10 microM). To further explore the underlying mechanisms of ET-1 action, we examined the involvement of the cAMP-dependent protein kinase A-mediated, phospholipase A2 (PLA2)-mediated, protein kinase C (PKC)-mediated, phosphatidylinositol 3 (PI 3)-kinase-mediated, and the mitogen-activated protein kinase (MAPK)-mediated pathways. Inhibition of adenylyl cyclase activation by SQ-22536 (100 microM) did not block ET-1-induced lipolysis. Pretreatment of adipocytes with the PLA2 inhibitor dexamethasone (100 nM), the PKC inhibitor H-7 (6 microM), or the PI 3-kinase inhibitor wortmannin (100 nM) also had no effect. ET-1-induced lipolysis was blocked by inhibition of extracellular signal-regulated kinase (ERK) activation using PD-98059 (75 microM), whereas a p38 MAPK inhibitor (SB-203580; 20 microM) had no effect. Results of Western blot further demonstrated that ET-1 induced ERK phosphorylation. These data show that ET-1 induces lipolysis in 3T3-L1 adipocytes via a pathway that is different from the conventional cAMP-dependent pathway used by isoproterenol and that involves ERK activation.
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PMID:Endothelin-1 induces lipolysis in 3T3-L1 adipocytes. 1567 Oct 81

We have previously demonstrated that endothelin-1 (ET-1)-induced extracellular signal-regulated kinase (Erk) activity via the ETB receptor (EDNRB) is mediated through two independent pathways, a protein kinase C-dependent pathway and a pertussis toxin (PTX)-sensitive pathway, in astrocytes. In this study, we showed that the molar potency of ET-1 to induce Erk activation was two orders of magnitude higher in dibutyryl cAMP (DBcAMP)-treated astrocytes than in quiescent astrocytes. This DBcAMP-enhanced molar potency of ET-1 in Erk activation was selectively inhibited by pretreatment of astrocytes with PTX. The expression level of EDNRB in astrocytes was markedly upregulated by DBcAMP-induced cytodifferentiation. However, this up-regulation was simply attributed to the high expression of low-affinity sites. The molar potency of ET-1 to induce both stimulation of inositol trisphosphate production and activation of protein kinase C in DBcAMP-treated astrocytes was similar to that in quiescent astrocytes. On the contrary, the molar potency of ET-1 to induce accumulation of Ras-GTP was two orders of magnitude higher in DBcAMP-treated astrocytes than in quiescent astrocytes, which was consistent with the case of ET-1-induced Erk activation. Moreover, the ET-1-induced Ras activation was PTX sensitive. These results suggest that cytodifferentiation selectively enhances the PTXsensitive Ras/Erk pathway induced by ET-1 in astrocytes, and that cytodifferentiation-induced EDNRB up-regulation might not contribute to this selective potentiation of ET-1 signaling.
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PMID:Cytodifferentiation enhances Erk activation induced by endothelin-1 in primary cultured astrocytes. 1583 8

Endothelin-1 (ET-1) plays an important role in tissue remodelling and fibrogenesis by inducing synthesis of collagen I via protein kinase C (PKC). ET-1 signals are transduced by two receptor subtypes, the ETA- and ETB-receptors which activate different Galpha proteins. Here, we investigated the expression of both ET-receptor subtypes in human primary dermal fibroblasts and demonstrated that the ETA-receptor is the major ET-receptor subtype expressed. To determine further signalling intermediates, we inhibited Galphai and three phospholipases. Pharmacologic inhibition of Galphai, phosphatidylcholine-phospholipase C (PC-PLC) and phospholipase D (PLD), but not of phospholipase Cbeta, abolished the increase in collagen I by ET-1. Inhibition of all phospholipases revealed similar effects on TGF-beta1 induced collagen I synthesis, demonstrating involvement of PC-PLC and PLD in the signalling pathways elicited by ET-1 and TGF-beta1. ET-1 and TGF-beta1 each stimulated collagen I production and in an additive manner. ET-1 further induced connective tissue growth factor (CTGF), as did TGF-beta1, however, to lower levels. While rapid and sustained CTGF induction was seen following TGF-beta1 treatment, ET-1 increased CTGF in a biphasic manner with lower induction at 3 h and a delayed and higher induction after 5 days of permanent ET-1 treatment. Coincidentally at 5 days of permanent ET-1 stimulation, a switch in ET-receptor subtype expression to the ETB-receptor was observed. We conclude that the signalling pathways induced by ET-1 and TGF-beta1 leading to augmented collagen I production by fibroblasts converge on a similar signalling pathway. Thereby, long-time stimulation by ET-1 resulted in a changed ET-receptor subtype ratio and in a biphasic CTGF induction.
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PMID:Signalling and regulation of collagen I synthesis by ET-1 and TGF-beta1. 1633 67

Low-density lipoproteins (LDLs) represent the most important treatable risk factors for coronary artery disease. Although it has been previously shown that hypercholesterolemia stimulates the endothelin system, the effects of increased levels of LDL on endothelial endothelin receptors have not been previously studied. In particular, the influence of native and oxidatively modified LDLs (nLDLs and oxLDLs) and the regulatory mechanisms in endothelial cells are currently unknown. Human endothelial cells almost exclusively express the endothelin receptor type B (ET(B)). Therefore, the effect of nLDL and oxLDL on the expression of ET(B) was studied in primary cultures of human umbilical vein endothelial cells (HUVEC). HUVEC were stimulated by nLDL and oxLDL in a time-dependent (1-12 hrs) and dose-dependent (25-100 microg/ml) manner. To analyze signal transduction pathways involved in the regulation of ET(B), protein kinase C (PKC) was inhibited using 100 nM Ro-31-8220. The mRNA expression of ET(B) was determined by quantitative reverse transcription-polymerase chain reaction and ET(B) protein expression by Western blot. Native LDL induced ET(B) mRNA after 1 hr (100 microg/ml, 199 +/- 35%, n = 15, P < 0.05 vs. control). Stimulation of HUVEC with oxLDL increased ET(B) mRNA expression (1 hr, 100 microg/ml oxLDL: 308 +/- 48%, n = 15, P < 0.05 vs. control) as well. Induction of ET(B) was also found on the protein level. nLDL was even more potent than oxLDL in inducing ET(B) protein expression. Induction of ET(B) expression by oxLDL is mediated by PKC. These data demonstrate that low-density lipoproteins even independent of oxidative modification are potent inducers of ET(B) receptors at the mRNA and protein level in HUVEC. Given the nitric oxide-releasing capacity of endothelial ET(B) receptors, this effect may represent a possible vasoprotective mechanism.
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PMID:Upregulation of endothelin receptor B in human endothelial cells by low-density lipoproteins. 1674 Sep 96

In this paper we review three intra-luteal factors and their roles in the corpus luteum (CL). Insulin-like growth factor (IGF)-I, together with its receptor and IGF-binding proteins (IGFBPs), represent an important control system in the CL. IGF-I is a product of small luteal cells and has steroidogenic (i.e. luteotrophic) actions on large luteal cells via the type I receptor, while IGFBPs (e.g. BP-2 and 3; small cells) generally inhibit IGF-Is actions. IGF-I is particularly important in early CL development (up to day 7 of the oestrous cycle) in the pig. Tumour necrosis factor (TNF)-alpha is a product of luteal macrophages that infiltrate CLs in increasing numbers as the cycle progresses. TNF-alpha has been shown to play an important role in luteolysis, but we hypothesise that in the pig, this factor plays an additional role during the mid-luteal phase (days 7-13) in promoting the acquisition of luteal sensitivity to the luteolytic actions of prostaglandin (PG)F2alpha (= luteolytic sensitivity; LS). Endothelin (ET)-1 is a product of (luteal) endothelial cells, and along with its receptors (ETA and ETB) and endothelin-converting enzyme (ECE)-1, represent an intra-luteal system that also plays a role in luteolysis, in association with PGF2alpha. Since TNF-alpha induces endothelial cells to secrete ET-1, we hypothesise that ET-1 mediates the sensitising effects of TNF-alpha on the porcine CL during the mid-luteal phase (days 7-13). Finally, we hypothesise that TNF-alpha and/or ET-1 act to up-regulate luteal protein kinase C (e.g. isoforms betaII and epsilon) activity and thereby sensitises luteal cells to PGF2alpha.
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PMID:The role of intra-luteal factors in the control of the porcine corpus luteum. 1686 10


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