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)

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.
 ...
PMID:Inhibitory effects of nordihydroguaiaretic acid on ETA-receptor-mediated contractions to endothelin-1 in rat trachea. 800 99

This study was conducted to investigate whether endothelin-1 (ET-1) has direct effects on the functions of porcine granulosa cells harvested from small or medium follicles. Positive ET-1-like immunoreactivity (ET-1-LI) was observed in the cultured porcine granulosa cells, and Northern blot analysis demonstrated the expression of mRNA for prepro-ET-1 in these cells. The binding study showed the presence of a nonselective, single class of binding sites which predominantly included the subtype ETB. Increased ET-1-LI was detected in human follicular fluid obtained from the patients with stimulated ovarian cycles. ET-1 stimulated basal and follicle-stimulating hormone (FSH)-stimulated secretion of progesterone during short-term incubation (2 h), while it inhibited FSH- and human-chorionic-gonadotropin-stimulated accumulation of progesterone during long-term incubation (48 h) of immature or moderately mature granulosa cells. ET-1 significantly increased DNA synthesis in the cells. These biological actions were induced by ET-1, probably via a cAMP-protein kinase A pathway and intracellular calcium mobilization-protein kinase C pathway. The results suggest that ET-1 exerts autocrine/paracrine effects on porcine granulosa cell functions.
 ...
PMID:Endothelin-1 as a local ovarian regulator in porcine granulosa cells. 808 93

Endothelin (ET) B-type receptor-mediated signal transduction after stimulation with ET-3 was examined in cultured aortic endothelial cells obtained from spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. The purpose of this study was to elucidate ETB receptor-mediated response in endothelial cells from hypertensive rat models. Non-isopeptide-selective displacement and affinity in these binding experiments suggest that aortic endothelial cell receptors for ET-3 correspond to ETB receptor subtypes. These receptors for ET-3 were similar in WKY and SHR endothelial cells. ETB receptor mRNA expression in cultured endothelial cells was also similar in WKY and SHR. However, the cytosolic free Ca2+ level in the absence of extracellular Ca2+ as well as the inositol 1,4,5-trisphosphate level in response to ET-3 were greater in endothelial cells from SHR than in those from WKY. Phospholipase C and protein kinase C activities after stimulation with ET-3 were also greater in SHR than in WKY. The 6-ketoprostaglandin F1 alpha production was also augmented in SHR, although nitric oxide formation and guanosine 3',5'-cyclic monophosphate production after stimulation with ET-3 were similar in WKY and SHR. We conclude that the phosphoinositide turnover signaling stimulated by ET-3 is augmented in cultured aortic endothelial cells from SHR compared with those from WKY.
 ...
PMID:Phosphoinositide turnover signaling stimulated by ET-3 in endothelial cells from spontaneously hypertensive rats. 809 6

The goal of this study was to characterize endothelin (ET) receptors mediating contraction of the rabbit saphenous vein. For this purpose, binding and functional studies were performed. Two receptor subtypes mediated contraction in response to ET-1. The first, responsible for 80-90% of maximal contraction, was stimulated with equal potency by ET-1, ET-3, and sarafotoxin S6c. The second, responsible for the remaining contraction, was stimulated more potently by ET-1 than by ET-3 and not by sarafotoxin S6c. The specific ETA receptor antagonist BQ-123 and the inhibitor of protein kinase C (PKC) Ro 31-8220 inhibited ET-1 contraction via the second but not the first receptor. In plasma membranes 125I-labeled ET-1 bound predominantly to a site with characteristics of ETA receptor, whereas 125I-ET-3 bound to two sites with characteristics of ETB receptor, one of high and one of low affinity. Comparison of binding affinity constants and 50% effective concentrations shows that the high-affinity ETB receptor corresponds to the receptor mediating the major part of contraction independently of PKC activation and ETA to the receptor mediating the minor part of contraction via a PKC-dependent mechanism.
 ...
PMID:Characterization of endothelin receptors mediating contraction of rabbit saphenous vein. 816 Aug 44

Endothelin-1 (ET-1) is a potent stimulator of atrial natriuretic factor (ANF) secretion from myocardial cells. In heart tissue there are two ET receptor subtypes (ETA-R and ETB-R), which can be pharmacologically distinguished by the ET isopeptides ET-1 and ET-3. However, the identification of the ET-R subtype responsible for the rapid enhancement of ANF release, which occurs within minutes of exposing cardiac myocytes to ET, has not been investigated. In the present study ET-1 was about 100-fold more potent than ET-3 at stimulating membrane phosphoinositide hydrolysis, protein kinase C activation, and ANF release from purified primary atrial myocytes. These responses were completely abolished by BQ123, an ETA-R antagonist. Radioligand binding analyses showed that competitor peptides displaced 125I-ET-1 binding to atrial myocyte ET-Rs with a rank order of potency of ET-1 >> BQ123 > ET-3, a characteristic ETA-R pharmacological profile. While neither ET-1 or ET-3 altered forskolin-stimulated cAMP levels, suggesting the absence of the ETB-R, basal cAMP levels were also unaffected by the ETs. Northern analysis using ET-R subtype-specific probes demonstrated that the ETA-R transcript was present in the cultures at levels at least 50-fold greater than the ETB-R transcript. These findings demonstrate that the stimulation of the phosphatidylinositol/protein kinase C pathway, which is required for maximal ET-stimulated ANF release from primary atrial myocytes, is associated with the activation of only the ETA-R, thus defining a specific function for an endogenous ET-R in myocardial cells.
 ...
PMID:Identification of the receptor subtype responsible for endothelin-mediated protein kinase C activation and atrial natriuretic factor secretion from atrial myocytes. 822 66

Addition of endothelin-1 or endothelin-3 to rat renal papillary tubules produced a dose-dependent inhibition of the cAMP response to vasopressin stimulation. The average EC50 values were 1.1 +/- 0.6 and 2.6 +/- 1.1 nM, respectively, indicating mediation by an endothelin ETB receptor. Phorbol myristate acetate (1 microM) also inhibited the vasopressin-cAMP response and this inhibition was not additive with that to endothelin, indicating that the endothelin inhibition is mediated by activation of protein kinase C. These findings demonstrate functionally relevant endothelin ETB receptors on renal papillary tubules. Such receptors are a possible target for endothelin-3 produced within the kidney.
 ...
PMID:Functional endothelin ETB receptors on renal papillary tubules. 825 66

We studied whether endothelin (ET)-1 regulates its own transcription in cultured rat aortic endothelial cells (ECs) in an autocrine manner and attempted to elucidate its cellular and molecular mechanism. By Northern blot analysis using rat preproET-1 cDNA as a probe, ET-1 increased steady-state levels of preproET-1 mRNA as early as 30 min, which persisted during 4 h incubation. ET-1 also increased steady-state c-fos mRNA levels, which returned to an undetectable level by 2 h. ET-1 dose-dependently upregulated preproET-1 mRNA expression. The effect was inhibited by nonselective ETA/ETB receptor antagonist but not a selective ETA receptor antagonist. The ET-1-induced preproET-1 mRNA expression was suppressed by a protein kinase C (PKC) inhibitor and by pretreatment with phorbol ester, which depeleted engdogenous PKC. The approximate half-life of preproET-1 mRNA stimulated by ET-1 (approximately 20 min) was similar to that stimulated by phorbol ester. Our data demonstrate that ET-1 upregulates its own gene expression through ETB receptor-mediated PKC activation, suggesting a possible autocrine positive feedback system in vascular endothelium.
 ...
PMID:Autocrine regulation of the endothelin-1 gene in rat endothelial cells. 858 76

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.
 ...
PMID:Different endothelin receptor subtypes are involved in phospholipid signalling in the proximal tubule of rat kidney. 866 90

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.
 ...
PMID:Endothelin receptors and activity differ in human, dog, and rabbit lung. 877 25

The role of protein kinase C in the endothelin-induced contraction was examined in the isolated rabbit saphenous vein in which endothelin-1, endothelin-3, sarafotoxin S6c and IRL 1620 (succinyl-[Glu9,Ala11,15]endothelin-1-(8-21))-induced contraction at the threshold concentrations of 0.1-1 pM. A selective inhibitor of protein kinase C, 500 nM calphostin C (2-[12-[2-(benzyloxy)propyl]-3, 10-dihydro-4,9-dihydroxy-2,6,7,11-tetramethoxy-3, 10-dioxo-1-perylenyl]-1-methylethyl carbonic acid 4-hydroxyphenyl ester), shifted the concentration-response curves for these agonists to the right 7.4- to 109-fold. In the vein in which the endothelin ETB receptor was desensitized, sarafotoxin S6c and IRL 1620 were ineffective whereas endothelin-1 and higher concentrations of endothelin-3 induced contractions by activating the endothelin ET(A) receptor. Calphostin C (500 nM) shifted the concentration-response curves for endothelin-1 and endothelin-3 to the right more than 155-fold. Down-regulation of protein kinase C (by treatment with phorbol 12-myristate 13-acetate for 20 h) shifted the concentration-response curves for these agonists to the right before and after desensitization of the endothelin ETB receptor 3.7- to 59-fold. In the permeabilized smooth muscle, Ca(2+)-induced contraction was enhanced by endothelin-1, endothelin-3 and sarafotoxin S6c at concentrations much higher than those needed to induce contraction (threshold concentration was 3 nM). Calphostin C and down-regulation of protein kinase C shifted the concentration-response curves for endothelin-1 and endothelin-3 to the right and downwards without changing the effect of sarafotoxin S6c. In the permeabilized muscle in which the endothelin ETB receptor was desensitized, endothelin-1 and endothelin-3 still augmented the Ca(2+)-induced contraction. Calphostin C and down-regulation of protein kinase C shifted the concentration-response curves for endothelin-1 and endothelin-3 to the right and downwards. These results suggest that protein kinase C is involved in the contraction mediated by the endothelin ET(A) and ETB receptors; and Ca2+ sensitization mediated by the endothelin ET(A) receptor is due to activation of protein kinase C whereas Ca2+ sensitization mediated by the endothelin ETB receptor may be due not only to the activation of protein kinase C but also to other mechanisms.
 ...
PMID:Role of protein kinase C in the endothelin-induced contraction in the rabbit saphenous vein. 878 40


<< Previous 1 2 3 4 5 6 7 8 Next >>