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

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vasoconstrictor peptide endothelin (ET-1) exerts its physiological and pathological effects via activation of ET(A) and ET(B) receptor (ET-R) subtypes. In this study, we demonstrate that both ET-R subtypes are highly expressed in rat astrocytes in vivo, indicating that these cells are potential targets of the biological effects of ET-1 in the brain. In cultured cortical astrocytes, both ET-R subtypes are expressed, and selective stimulation of ET(B)-R with ET-1 induces phosphorylation of cAMP response element-binding protein (CREB). The signal transduction pathway activated by ET-1 includes the Rap1/B-Raf and the Ras/Raf-1 complexes, protein kinase C (PKC) together with extracellular signal-regulated kinases (ERK), and the ribosomal S6 kinase (RSK) isoforms RSK2 and RSK3, two kinases that lie immediately downstream of ERK and are able to phosphorylate CREB. Moreover, ET-1 activates the p38 mitogen-activated protein kinase (MAPK)-dependent, but not the c-jun N-terminal kinase (JNK)-dependent pathway. By using selective protein kinase inhibitors and expression of dominant-negative Rap1 protein, we also found that the Rap1/PKC/ERK-dependent pathway induces the phosphorylation of activating transcription factor-1, CREB, and Elk-1, whereas the p38MAPK-dependent pathway only causes CREB phosphorylation. ET-1-induced transcription of the immediate early gene c-fos requires the concomitant activation of both the PKC/ERK- and p38MAPK-dependent pathways, because inhibitors of either pathway block the ET-1-induced increase of c-fos mRNA. Our findings indicate that changes in the expression of cAMP response element-dependent immediate and delayed response genes could play a pivotal role in the physiological effects elicited by ET-1 in astrocytes.
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PMID:Stimulation of endothelin B receptors in astrocytes induces cAMP response element-binding protein phosphorylation and c-fos expression via multiple mitogen-activated protein kinase signaling pathways. 1169 96

The purposes of the present study were to clarify the significance of the palmitoylation site and the cytoplasmic tail of the endothelin(A) receptor (ET(A)R) in coupling with G proteins and to determine the subtypes of G protein that are involved in actin stress-fiber formation in Chinese hamster ovary cells that stably express ET(A)R (CHO-ET(A)R). For these purposes, we constructed CHO cells stably expressing an unpalmitoylated (Cys(383)Cys(385-388)-->Ser(383)Ser(385-388)) ET(A)R (CHOSerET(A)R) and a series of truncated ET(A)Rs that lacked the cytoplasmic tail downstream of either of the five cysteine residues (Cys(383)Cys(385-388)). All truncated ET(A)Rs but not SerET(A)R failed to stimulate adenylyl cyclase. With the truncated ET(A)Rs holding Cys(385), ET-1 stimulated formation of inositol phosphates, but such stimulation failed with truncated ET(A)Rs lacking Cys(385). With wild-type ET(A)Rs, ET-1 induced actin stress-fiber formation, which was inhibited by (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632), a Rho-associated coiled-coil-forming protein kinase (ROCK) inhibitor. The formation was unaffected by 1-(6-[[17beta-3-methoxyestra-1,3.5(10)-trien-17-yl] amino]hexyl)-1Hpyrrole-2,5-dione (U73122), a phospholipase C (PLC) inhibitor, or dominant negative mutants of G(12) (G(12)G228A) or G(13) (G(13)G225A), whereas it was inhibited by U73122 in combination with G(12)G228A but not G(13)G225A. Dibutyryl cAMP alone did not induce stress-fiber formation. With unpalmitoylated or truncated ET(A)Rs, the formation was sensitive to G(12)G228A or U73122, respectively. These results indicate that 1) Cys(385) of ET(A)R is critical for coupling with G(q), 2) the cytoplasmic tail downstream of the palmitoylation sites of ET(A)R is essential for coupling with G(s) and G(12), and 3) the signal for ET-1-induced stress-fiber formation is transmitted through the G(q)/PLC- and G(12)-dependent pathway to the Rho/ROCK system.
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PMID:Molecular mechanism for endothelin-1-induced stress-fiber formation: analysis of G proteins using a mutant endothelin(A) receptor. 1180 51

Evidence has been provided that the 21-amino acid hypertensive peptide endothelin (ET)-1 exerts a potent secretagogue effect on human adrenocortical zona glomerulosa (ZG), acting through two receptor subtypes, called ET(A) and ET(B), the signaling mechanism(s) of which has (have) not yet been investigated. Collagenase dispersed human ZG cells were obtained from normal adrenals of patients undergoing nephrectomy/adrenalectomy for renal cancer. The selective ET(A)- and ET(B)-receptor activation was obtained by exposing dispersed cells to ET-1 plus the ET(B)-receptor antagonist BQ-788 and to the ET(B)-receptor agonist BQ-3020, respectively. The phospholipase (PL) C inhibitor U-73122 abolished ET(A) receptor-mediated secretory response, but only partially prevented the ET(B) receptor-mediated one. The phosphatidylinositol 3-kinase inhibitor wortmannin, the calmodulin inhibitor W-7 and the protein kinase (PK) C inhibitor calphostin-C significantly blunted the secretory responses ensuing from the activation of both receptor subtypes. When added together, calphostin-C and wortmannin or W-7 abolished ET(A)-mediated secretory response, but only decreased ET(B)-mediated one. The ET(B) receptor-, but not the ET(A) receptor-mediated aldosterone response was partially reversed by the cyclooxygenase (COX) inhibitor indomethacin, which when added together with U-73122 abolished it. ET(A)-receptor activation raised inositol triphosphate (IP(3)) production from dispersed ZG cells, while ET(B)-receptor stimulation enhanced both IP(3) and prostaglandin-E(2) production. Collectively, our findings indicate that ETs stimulate aldosterone secretion from human ZG cells, acting through ET(A) receptors exclusively coupled to PLC/PKC-dependent pathway and ET(B) receptors coupled to both PLC/PKC- and COX-dependent cascades.
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PMID:Mechanisms transducing the aldosterone secretagogue signal of endothelins in the human adrenal cortex. 1183 7

1. Organ culture has been shown to upregulate both endothelin (ET) and 5-hydroxytryptamine 1B/1D (5-HT(1B/1D)) receptors in rat cerebral arteries. The purpose of the present study was to investigate the involvement of protein kinases, especially protein kinases C (PKC) and A (PKA) in this process. 2. The effect of inhibiting protein kinases during organ culture with staurosporine (unspecific protein kinase inhibitor), RO 31-7549 (specific inhibitor of classical PKC's) and H 89 (specific inhibitor of PKA) was examined using in vitro pharmacological examination of cultured vessel segments with ET-1 (unspecific ET(A) and ET(B) agonist), S6c (specific ET(B) agonist) and 5-CT (5-HT(1) agonist). Levels of mRNA coding for the ET(A), ET(B), 5-HT(1B) and 5-HT(1D) receptors were analysed using real-time RT-PCR. 3. Classical PKC's are critically involved in the appearance of the ET(B) receptor; co-culture with RO 31-7549 abolished the contractile response (6.9 +/- 1.8%) and reduced the ET(B) receptor mRNA by 44 +/- 4% as compared to the cultured control. Correlation between decreased ET(B) receptor mRNA and abolished contractile function indicates upstream involvement of PKC. 4. Inhibition of PKA generally had an enhancing effect on the induced changes giving rise to a 7-25% increase in E(max) in response to ET-1, S6c and 5-CT as compared to the cultured control. 5. Staurosporine inhibited the culture induced upregulation of the response of both the ET(A) and the 5-HT(1B/1D) receptors, but had no significant effect on the mRNA levels of these receptors. This lack of correlation indicates an additional downstream involvement of protein kinases.
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PMID:Protein kinase mediated upregulation of endothelin A, endothelin B and 5-hydroxytryptamine 1B/1D receptors during organ culture in rat basilar artery. 1218 37

The existence of endothelin binding sites on the catecholaminergic neurons of the hypothalamus suggests that endothelins (ETs) participate in the regulation of noradrenergic transmission modulating various hypothalamic-controlled processes such as blood pressure, cardiovascular activity, etc. The effects of ET-1 and ET-3 on the neuronal release of norepinephrine (NE) as well as the receptors and intracellular pathway involved were studied in the rat anterior hypothalamus. ET-1 (10 nM) and ET-3 (10 nM) diminished neuronal NE release and the effect blocked by the selective ET type B receptor antagonist BQ-788 (100 nM). N(omega)-nitro-L-arginine methyl ester (10 microM), methylene blue (10 microM), and KT5823 (2 microM), inhibitors of nitric oxide synthase activity, guanylate cyclase, and protein kinase G, respectively, prevented the inhibitory effects of both ETs on neuronal NE release. In addition, both ETs increased nitric oxide synthase activity. Furthermore, 100 microM picrotoxin, a GABA(A)-receptor antagonist, inhibited ET-1 and ET-3 response. Our results show that ET-1 as well as ET-3 has an inhibitory neuromodulatory effect on NE release in the anterior hypothalamus mediated by the ET type B receptor and the involvement of a nitric oxide-dependent pathway and GABA(A) receptors. ET-1 and ET-3 may thus diminish available NE in the synaptic gap leading to decreased noradrenergic activity.
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PMID:Endothelin-1 and -3 diminish neuronal NE release through an NO mechanism in rat anterior hypothalamus. 1218 95

Cardiac hypertrophy is an end point of chronic cardiac toxicity from a number of toxicants. Doxorubicin, cocaine, acetaldehyde, monocrotaline, and azide are examples of these toxicants, which may induce hypertrophy by increasing oxidants, circulating levels of catecholamines, and hemodynamic load or by inducing hypoxia. We summarize here the major signal transduction pathways and common changes in gene expression found with the classical hypertrophy inducers angiotensin II, endothelin 1, and catecholamines. Activation of G-proteins, calcium signaling, phosphoinositide 3-kinase (PI3K), certain family members of protein kinase Cs (PKCs), and three branches of mitogenactivated protein kinases (MAPKs), i.e. extracellular signal-regulated kinases (ERKs), p38, and c-Jun N-terminal kinases (JNKs), are important for developing a hypertrophic phenotype in cardiomyocytes. Characteristic changes of gene expression in hypertrophy include the elevated transcription of atrial natriuretic factor (ANF), beta-myosin heavy chain (beta MHC), skeletal alpha-actin (SkA), certain variants of integrins and perhaps tubulin genes, and reduced expression of the sarcoplasmic reticulum proteins phospholamban and sarco(endo)plasmic reticulum Ca2+-ATPase 2 alpha (SERCA2 alpha), and of the ryanodine receptors. Although which toxicants induce these molecular changes remains to be tested, increasing lines of evidence support that oxidants play a central role in cardiac hypertrophy. Oxidants activate small G-proteins, calcium signaling, PI3K, PKCs, and MAPKs. Oxidants cause cardiomyocytes to enlarge in vitro. Recent developments in transgenic, genomic, and proteomic technologies will provide needed tools to reveal the mechanism of chronic cardiac toxicity at the cellular and molecular levels.
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PMID:Molecular mechanisms of cardiac hypertrophy induced by toxicants. 1221 66

Previous studies have demonstrated that functional interaction between endothelin (ET)-1 and nitric oxide (NO) involves changes in Ca(2+) mobilization and cytoskeleton in human brain microvascular endothelial cells. The focus of this investigation was to examine the possible existence of analogous interplay between these vasoactive substances and elucidate their signal transduction pathways in human brain capillary endothelial cells. The results indicate that ET-1-stimulated Ca(2+) mobilization in these cells is dose-dependently inhibited by NOR-1 (an NO donor). This inhibition was prevented by ODQ (an inhibitor of guanylyl cyclase) or Rp-8-CPT-cGMPS (an inhibitor of protein kinase G). Treatment of endothelial cells with 8-bromo-cGMP reduced ET-1-induced Ca(2+) mobilization in a manner similar to that observed with NOR-1 treatment. In addition, NOR-1 or cGMP reduced Ca(2+) mobilization induced by mastoparan (an activator of G protein), inositol 1,4,5-trisphosphate, or thapsigargin (an inhibitor of Ca(2+)-ATPase). Interestingly, alterations in endothelial cytoskeleton (actin and vimentin) were associated with these effects. The data indicate for the first time that the cGMP-dependent protein kinase colocalizes with actin. These changes were accompanied by altered levels of phosphorylated vasodilator-stimulated phosphoprotein, which were elevated in endothelial cells incubated with NOR-1 and significantly reduced by ODQ or Rp-8-CPT-cGMPS. The findings indicate a potential mechanism by which the functional interrelationship between ET-1 and NO plays a role in regulating capillary tone, microcirculation, and blood-brain barrier function.
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PMID:ET-1- and NO-mediated signal transduction pathway in human brain capillary endothelial cells. 1252 47

We have previously demonstrated that endothelin (ET)-1 and its subtype A receptor (ET-AR) expression are increased in lung under hypoxic conditions and that activation of ET-AR by ET-1 is a major mediator of hypoxia-induced pulmonary hypertension in the rat. The present study tested the hypothesis that the hypoxia-responsive tyrosine kinase receptor-activating growth factors fibroblast growth factor (FGF)-1, FGF-2, and platelet-derived growth factor (PDGF)-BB stimulate expression of the ET-AR in pulmonary arterial smooth muscle cells (PASMCs). Quiescent rat PASMCs were incubated under hypoxia (1% O2), or with FGF-1, FGF-2, PDGF-BB, vascular endothelial growth factor, ET-1, angiotensin II, or atrial natriuretic peptide under normoxic conditions for 24 h. FGF-1 and -2 and PDGF-BB, but not hypoxia, vascular endothelial growth factor, ET-1, angiotensin II, or atrial natriuretic peptide, significantly increased ET-AR mRNA levels. FGF-1-induced ET-AR expression was inhibited by FGF-receptor inhibitor PD-166866, MEK inhibitor U-0126, transcription inhibitor actinomycin D, and translation inhibitor cycloheximide. In contrast, the stimulatory effect of FGF-1 on ET-AR mRNA expression was not altered by PI3 kinase, PKA, PKC, or adenylate cyclase inhibitors. PASMC ET-AR gene transcription, assessed by nuclear-runoff analysis, was increased by FGF-1. These results provide novel finding that ET-AR in PASMCs in vitro is unresponsive to hypoxia per se but is robustly simulated by tyrosine kinase receptor-associated growth factors (FGF-1, FGF-2, PDGF-BB) that themselves are stimulated by hypoxia in lung. This observation suggests a novel signaling mechanism that may be responsible for overexpression of ET-AR in lung, and may contribute to the hypoxia-induced pulmonary vasoconstriction, hypertension, and vascular remodeling in hypoxia-adapted animal.
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PMID:Fibroblast growth factor mediates hypoxia-induced endothelin-- a receptor expression in lung artery smooth muscle cells. 1285 19

Three endothelin (ET) isopeptides have been identified: ET-1, ET-2 and ET-3. These have two well-established gross effects on the cardiac myocyte. They affect the contractile properties and they stimulate myocyte growth and myofibrillogenesis. There may be other effects that are less fully characterized (e.g. increased resistance apoptosis). The changes in myocyte biology are brought about by modulation of intracellular signaling pathways. ET-1 binds to the ET(A) receptor on the cell surface and stimulates hydrolysis of phosphatidylinositol 4', 5'-bisphosphate to diacylglycerol and inositol 1', 4', 5'-trisphosphate. Diacylglycerol remains in the plane of the membrane and this causes translocation of the delta- and epsilon-isoforms of protein kinase C (PKC) to that compartment, an event thought to be indicative of PKC activation. The next events (probably associated with PKC activation) are the activation of the small G-protein Ras and of the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade. Over a longer time course, two protein kinase cascades related to the ERK1/2 cascade, the c-Jun N-terminal kinase and p38-mitogen-activated protein kinase (p38-mitogen) cascades, also become activated. As the signals originating from the ET(A) receptor are transmitted through these protein kinase pathways, other signaling molecules become phosphorylated, thus changing their biological activity. Such molecules include nuclear transcription factors (e.g. GATA-4, c-Jun), protein kinases (e.g. 90-kDa ribosomal protein S6 kinase, MAPK-activated protein kinase 2), and ion exchangers/channels (e.g. the Na(+)/H(+) exchanger 1). These changes are responsible for the overall biological effects of ET isopeptides on the myocyte.
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PMID:An overview of endothelin signaling in the cardiac myocyte. 1287 73

The antihypertrophic action of angiotensin-converting enzyme inhibitors in the heart results partly from local potentiation of bradykinin. We have demonstrated that the antihypertrophic action of bradykinin is mediated by the release of nitric oxide from endothelium and elevation of cardiomyocyte cGMP. Whether other paracrine factors derived from the coronary endothelium, such as prostacyclin (PGI2), may act to prevent hypertrophy has not been explored. In the vasculature, activation by PGI2 of IP and EP1 prostanoid receptors elicits vasodilatation (via cAMP-dependent signaling) and vasoconstriction, respectively. The present objective was to determine whether IP prostanoid receptor activation has antihypertrophic actions in adult rat cardiomyocytes (ARCM). The selective IP agonist cicaprost (1 microM) virtually abolished the increase in [3H]phenylalanine incorporation (a marker of hypertrophy) induced either by endothelin-1 (ET-1; 60 nM, n = 10, P < 0.005) or by angiotensin II (1 microM, n = 6, P < 0.005). Cicaprost also inhibited ET-1 induction of c-fos mRNA expression, an additional marker of hypertrophy in ARCM (n = 5, P < 0.005). In the absence of hypertrophic stimuli, cicaprost alone did not significantly influence either marker. The antihypertrophic actions of cicaprost were mimicked by the dual IP/EP1 agonist iloprost (1 microM) in the presence of the EP1 antagonist AH-6809 (3 microM). Furthermore, cicaprost modestly but significantly increased cardiomyocyte cAMP content by 13 +/- 6% (P < 0.05, n = 4), and the antihypertrophic effect of cicaprost was lost in the presence of the cAMP-dependent protein kinase inhibitor H-89 (1 microM, n = 5, P < 0.05). However, ET-1 also induced increases in the activity of the intracellular growth signals ERK1 (by 3-fold) and ERK2 (by 5-fold) in ARCM, and these were not inhibited by cicaprost (P < 0.01, n = 5). Activation of IP receptors thus represents a novel approach to prevention of hypertrophy, and this effect is linked to cAMP-dependent signaling.
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PMID:Activation of IP prostanoid receptors prevents cardiomyocyte hypertrophy via cAMP-dependent signaling. 1507 55


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