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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sildenafil, a potent inhibitor of phosphodiesterase-5 (PDE-5) induces powerful protection against myocardial ischemia-reperfusion injury. PDE-5 inhibition increases cGMP levels that activate cGMP-dependent protein kinase (PKG). However, the cause and effect relationship of PKG in sildenafil-induced cardioprotection and the downstream targets of PKG remain unclear. Adult ventricular myocytes were treated with sildenafil and subjected to simulated ischemia and reoxygenation. Sildenafil treatment significantly decreased cardiomyocyte necrosis and apoptosis. The PKG inhibitors, KT5823, guanosine 3',5'-cyclic monophosphorothioate, 8-(4-chloro-phenylthio) (R(p)-8-pCPT-cGMPs), or DT-2 blocked the anti-necrotic and anti-apoptotic effect of sildenafil. Selective knockdown of PKG in cardiomyocytes with adenoviral vector containing short hairpin RNA of PKG also abolished sildenafil-induced protection. Furthermore, intra-coronary infusion of sildenafil in Langendorff-isolated mouse hearts prior to ischemia-reperfusion significantly reduced myocardial infarct size after 20 min ischemia and 30 min reperfusion, which was abrogated by KT5823. Sildenafil significantly increased PKG activity in intact hearts and cardiomyocytes. Sildenafil also enhanced the Bcl-2/Bax ratio, phosphorylation of Akt, ERK1/2, and glycogen synthase kinase 3beta. All these changes (except Akt phosphorylation) were significantly blocked by KT5823 and short hairpin RNA of PKG. These studies provide the first evidence for an essential role of PKG in sildenafil-induced cardioprotection. Moreover, our results demonstrate that sildenafil activates a PKG-dependent novel signaling cascade that involves activation of ERK and inhibition of glycogen synthase kinase 3beta leading to cytoprotection.
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PMID:Protein kinase G-dependent cardioprotective mechanism of phosphodiesterase-5 inhibition involves phosphorylation of ERK and GSK3beta. 1872 5

Recent studies have shown that nitric oxide (NO) signaling plays a crucial role in memory consolidation of Pavlovian fear conditioning and in synaptic plasticity in the lateral amygdala (LA). In the present experiments, we examined the role of the cGMP-dependent protein kinase (PKG), a downstream effector of NO, in fear memory consolidation and long-term potentiation (LTP) at thalamic and cortical input pathways to the LA. In behavioral experiments, rats given intra-LA infusions of either the PKG inhibitor Rp-8-Br-PET-cGMPS or the PKG activator 8-Br-cGMP exhibited dose-dependent impairments or enhancements of fear memory consolidation, respectively. In slice electrophysiology experiments, bath application of Rp-8-Br-PET-cGMPS or the guanylyl cyclase inhibitor LY83583 impaired LTP at thalamic, but not cortical inputs to the LA, while bath application of 8-Br-cGMP or the guanylyl cyclase activator YC-1 resulted in enhanced LTP at thalamic inputs to the LA. Interestingly, YC-1-induced enhancement of LTP in the LA was reversed by concurrent application of the MEK inhibitor U0126, suggesting that the NO-cGMP-PKG signaling pathway may promote synaptic plasticity and fear memory formation in the LA, in part by activating the ERK/MAPK signaling cascade. As a test of this hypothesis, we next showed that rats given intra-LA infusion of the PKG inhibitor Rp-8-Br-PET-cGMPS or the PKG activator 8-Br-cGMP exhibit impaired or enhanced activation, respectively, of ERK/MAPK in the LA after fear conditioning. Collectively, our findings suggest that an NO-cGMP-PKG-dependent form of synaptic plasticity at thalamic input synapses to the LA may underlie memory consolidation of Pavlovian fear conditioning, in part, via activation of the ERK/MAPK signaling cascade.
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PMID:The NO-cGMP-PKG signaling pathway regulates synaptic plasticity and fear memory consolidation in the lateral amygdala via activation of ERK/MAP kinase. 1883 66

Increased myocardial cGMP, achieved by enhancing cyclase activity or impeding cGMP hydrolysis by phosphodiesterase type-5 (PDE5A), suppresses cellular and whole organ hypertrophy. The efficacy of the latter also requires cyclase stimulation and may depend upon co-activation of maladaptive signaling suppressible by cGMP-stimulated kinase (cGK-1). Thus, PDE5A inhibitors could paradoxically be more effective against higher than lower magnitudes of pressure-overload stress. To test this, mice were subjected to severe or moderate trans-aortic constriction (sTAC, mTAC) for 6 wks +/-co-treatment with oral sildenafil (SIL 200 mg/kg/d). LV mass (LVM) rose 130% after 3-wks sTAC and SIL blunted this by 50%. With mTAC, LVM rose 56% at 3 wks but was unaffected by SIL, whereas a 90% increase in LVM after 6 wks was suppressed by SIL. SIL minimally altered LV function and remodeling with mTAC until later stages that stimulated more hypertrophy and remodeling. SIL stimulated cGK-1 activity similarly at 3 and 6 wks of mTAC. However, pathologic stress signaling (e.g. calcineurin, ERK-MAPkinase) was little activated after 3-wk mTAC, unlike sTAC or later stage mTAC when activity increased and SIL suppressed it. With modest hypertrophy (3-wk mTAC), GSK3beta and Akt phosphorylation were unaltered but SIL enhanced it. However, with more severe hypertrophy (6-wk mTAC and 3-wk sTAC), both kinases were highly phosphorylated and SIL treatment reduced it. Thus, PDE5A-inhibition counters cardiac pressure-overload stress remodeling more effectively at higher than lower magnitude stress, coupled to pathologic signaling activation targetable by cGK-1 stimulation. Such regulation could impact responses of varying disease models to PDE5A inhibitors.
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PMID:Pressure-overload magnitude-dependence of the anti-hypertrophic efficacy of PDE5A inhibition. 1915 28

We tested the hypothesis that GnRH, PGE2 and db-cAMP act via the nitric oxide (NO)-cGMP and MAPK pathways to facilitate estrous behavior (lordosis and proceptivity) in estradiol-primed female rats. Estradiol-primed rats received intracerebroventricular (icv) infusions of pharmacological antagonists of NO synthase (L-NAME), NO-dependent soluble guanylyl cyclase (ODQ), protein kinase G (KT5823), or the ERK1/2 inhibitor PD98059 15 min before icv administration of 50 ng of GnRH, 1 microg of PGE2 or 1 microg of db-cAMP. Icv infusions of GnRH, PGE2 and db-cAMP enhanced estrous behavior at 1 and 2 h after drug administration. Both L-NAME and ODQ blocked the estrous behavior induced by GnRH, PGE2 and db-cAMP at some of the times tested. The protein kinase G inhibitor KT5823 reduced PGE2 and db-cAMP facilitation of estrous behavior but did not affect the behavioral response to GnRH. In contrast, PD98059 blocked the estrous behavior induced by all three compounds. These data support the hypothesis that the NO-cGMP and ERK/MAPK pathways are involved in the lordosis and proceptive behaviors induced by GnRH, PGE2 and db-cAMP. However, cGMP mediation of GnRH-facilitated estrous behavior is independent of protein kinase G.
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PMID:Nitric oxide and ERK/MAPK mediation of estrous behavior induced by GnRH, PGE2 and db-cAMP in rats. 1916 55

PAI-1 is a multifunctional protein stimulated by infectious agents and its activation is mediated by inflammatory cytokines such as TNFalpha. Recent studies demonstrate that natriuretic peptides, particularly C-type (CNP), can affect PAI-1 expression in bovine aortic smooth muscle cells and rat aortic endothelial cells. We have previously shown that CNP inhibits both basal and TNFalpha induced expression of PAI-1 in human endothelial cells. Herein, we describe mechanism by which CNP modulates signaling engaged in controlling PAI-1 expression in human endothelial cells. To examine which pathway initiated by TNFalpha is influenced, we tested kinase activity of MAP, PI3K/AKT and involvement of cGMP in endothelial cells exposed to CNP. CNP significantly increased cGMP level in endothelial cells. Its analogue, 8-Br-cGMP alone had no effect but significantly inhibited TNFalpha induced expression of PAI-1. Similarly, CNP and the inhibitors of ERK1/2 (PD098059) and PI3K (LY294002) attenuated PAI-1 expression induced by TNFalpha. CNP almost abolished TNFalpha induced phosphorylation of ERK1/2 but did not affect JNK phosphorylation, indicating that its effect on ERK1/2 was specific. These data suggest that CNP might function as the natural defense of vascular wall against cytokine induced PAI-1 release through its ability to inactivate PI3K/AKT and MEK/ERK pathways.
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PMID:Intracellular signaling pathways involved in inhibition of PAI-1 expression by CNP in endothelial cells. 1921 19

The study was aimed at investigating in vivo and in vitro the involvement of the cGMP/cGMP-dependent protein kinase (PKG) signaling pathway in MPP(+)-induced cytosolic phospholipase A(2) (cPLA(2)) activation of dopaminergic neurons. MPP(+) activated neuronal nitric oxide synthase (NOS)/soluble guanylyl cyclase/cGMP pathway in mouse midbrain and striatum, and in pheochromocytoma cell line 12 cells, and caused an upward shift in [Ca(2+)](i) level in the latter. The activation was accompanied by increases in total and phosphorylated cPLA(2), and increased arachidonic acid release. Effects of selective inhibitors [2-oxo-1,1,1-trifluoro-6,9-12,15-heneicosatetraene (AACOCF(3)), (E)-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)2h-pyran-2-one (BEL)] indicated the main impact of cPLA(2) on arachidonic acid release in pheochromocytoma cell line 12 cells. Treatment of the cells with the protein kinase inhibitors GF102610x, UO126, and KT5823, and with the nitric oxide synthase (NOS) inhibitor NNLA revealed the involvement of protein kinase C (PKC) and extracellular signal-regulated kinases 1 and 2 (ERK 1/2), with the possible key role of PKG, in cPLA(2) phosphorylation at Ser505. Inhibitors of cPLA(2) and PKG increased viability and reduced MPP(+)-induced apoptosis of the cells. Our results indicate that the neuronal NOS/cGMP/PKG pathway stimulates cPLA(2) phosphorylation at Ser505 by activating PKC and ERK1/2, and suggest that up-regulation of this pathway in experimental models of Parkinson's disease may mediate dopaminergic neuron degeneration and death through activation of cPLA(2).
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PMID:Involvement of multiple protein kinases in cPLA2 phosphorylation, arachidonic acid release, and cell death in in vivo and in vitro models of 1-methyl-4-phenylpyridinium-induced parkinsonism--the possible key role of PKG. 1945 7

Sildenafil was the first selective inhibitor of phosphodiesterase-5 (PDE5) to be widely used for treating erectile dysfunction. Many recent studies have investigated the cardioprotective role of sildenafil in animal models. We evaluated the protective effects of sildenafil in experimental renal ischemia-reperfusion (IR) injury in two studies. In study 1, male Sprague-Dawley rats were divided into four groups: sham, sildenafil-treated sham, vehicle-treated IR, and sildenafil-treated IR groups. In study 2, we divided the rats into two groups: sildenafil-treated IR rats and PD98059 (ERK inhibitor)+sildenafil-treated IR rats. Functional parameters of the kidney were evaluated at the molecular and structural levels. Blood urea nitrogen (BUN) and serum creatinine levels were lower in sildenafil-treated IR rats than in vehicle-treated IR rats. The expression of inducible (iNOS) and endothelial nitric oxide synthase (eNOS) proteins in sildenafil-treated IR rats was significantly higher than in vehicle-treated IR rats. Pretreatment with sildenafil in IR rats increased ERK phosphorylation and reduced the renal Bax/Bcl-2 ratio, renal caspase-3 activity, and terminal dUTP nick end-labeling-positive apoptotic cells. In contrast, PD98059 treatment increased BUN and serum creatinine levels and attenuated the sildenafil-induced expression of pERK, iNOS, eNOS, and Bcl-2. PD98059 also increased caspase-3 activity but did not decrease the sildenafil-induced accumulation of cGMP. In conclusion, this study suggests that sildenafil has antiapoptotic effects in experimental IR renal injury via ERK phosphorylation, induction of iNOS and eNOS production, and a decrease in the Bax/Bcl-2 ratio.
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PMID:Pretreatment of sildenafil attenuates ischemia-reperfusion renal injury in rats. 1947 86

Collagen-induced platelet activation is a complex process involving multiple signaling pathways. The role(s) of MAP kinases (ERKs and p38(MAPK)) are unclear, although at high, but not low, collagen concentrations p38(MAPK) is involved in cPLA(2)-mediated arachidonic acid release, prior to thromboxane generation. Cyclic nucleotides are conventionally regarded as mediators of platelet inhibition. However recent studies suggested a role for cGMP early in a MAP kinase pathway in platelet activation. In the current study the roles and relationships of MAP kinases, cyclic nucleotides and cPLA(2) in platelet activation by low-dose collagen and a thromboxane analogue (U46619) have been evaluated. Stimulants of neither adenylate cyclase (PGI(2)) nor guanylate cyclase (NaNP) alone had any effect on the basal phosphorylation of either MAP kinase. PGI(2) inhibited ERK/p38(MAPK) phosphorylation in response to both agonists which was unaffected by a cPLA(2) inhibitor (AACOCF(3)). NaNP inhibited collagen-induced ERK/p38(MAPK) phosphorylation, which was enhanced by AACOCF(3) and reversed by a guanylate cyclase inhibitor (ODQ). However NaNP had no effect on U46619-induced p38(MAPK) phosphorylation. Thus adenylate cyclase activation inhibits low-dose collagen-induced MAP kinase phosphorylation both prior, and distal, to thromboxane release. The study also supports an inhibitory, rather than stimulatory, role for guanylate cyclase in platelet signaling.
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PMID:Cyclic nucleotides inhibit MAP kinase activity in low-dose collagen-stimulated platelets. 1959 42

The adult differentiated insulin-secreting pancreatic islet beta-cell experiences slow growth. This study shows that atrial natriuretic peptide (ANP) stimulates cell proliferation and [(3)H]thymidine incorporation in INS-1E glucose-sensitive rat beta-cell line cells and isolated rat islet DNA. In addition, cGMP, the second messenger of natriuretic peptide receptors (NPR) A and B, stimulated islet DNA biosynthesis. The NPR-A receptor was expressed in INS-1E cells and islets. ANP-stimulated INS-1E cell DNA biosynthesis was blocked by preincubation with LY294002 (50 microM), an inhibitor of phosphatidylinositol 3'-kinase (PI3K). An indicator of cell cycle progression, cyclin D2 mRNA was increased by 2- to 3-fold in ANP- or 8-Br-cGMP-treated INS-1E cells and islets, and these responses were inhibited by LY294002. ANP and 8-Br-cGMP stimulated the phosphorylation of Akt and Foxo1a in INS-1E cells and islets, and LY294002 inhibited these responses. In contrast, ANP reduced the levels of phospho-ERK in INS-1E cells. Pancreas duodenum homeobox-1 (PDX-1) is essential for pancreas development, insulin production, and glucose homeostasis, and ANP increased PDX-1 mRNA levels by 2- to 3-fold in INS-1E cells and islets. The levels of glucokinase mRNA in islets and INS-1E cells were also increased in response to ANP. The evidence suggests that pancreatic beta-cell NPR-A stimulation results in activation of a growth-promoting signaling pathway that includes PI3K/Akt/Foxo1a/cyclin D2. These data support the conclusion that the activation of Akt by ANP or 8-Br-cGMP promotes cyclin D2, PDX-1, and glucokinase transcription by phosphorylating and restricting Foxo1a activity.
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PMID:Atrial natriuretic peptide promotes pancreatic islet beta-cell growth and Akt/Foxo1a/cyclin D2 signaling. 1983 76

Our previous studies demonstrate a differential expression of nitric oxide (NO) signaling components in ES cells and our recent study demonstrated an enhanced differentiation of ES cells into myocardial cells with NO donors and soluble guanylyl cyclase (sGC) activators. Since NO-cGMP pathway exhibits a diverse role in cancer, we were interested in evaluating the role of the NO-receptor sGC and other components of the pathway in regulation of the tumor cell proliferation. Our results demonstrate a differential expression of the sGC subunits, NOS-1 and PKG mRNA and protein levels in various human cancer models. In contrast to sGC alpha(1), robust levels of sGC beta(1) were observed in OVCAR-3 (ovarian) and MDA-MB-468 (breast) cancer cells which correlated well with the sGC activity and a marked increase in cGMP levels upon exposure to the combination of a NO donor and a sGC activator. NOC-18 (DETA NONOate; NO donor), BAY41-2272 (3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine); sGC activator), NOC-18+BAY41-2272, IBMX (3-isobutyl-1-methylxanthine; phosphodiesterase inhibitor) and 8-bromo-cGMP (cGMP analog) caused growth inhibition and apoptosis in various cancer cell lines. To elucidate the molecular mechanisms involved in growth inhibition, we evaluated the effect of activators/inhibitors on ERK phosphorylation. Our studies indicate that BAY41-2272 or the combination NOC-18+BAY41-2272 caused inhibition of the basal ERK1/2 phosphorylation in OVCAR-3 (high sGC activity), SK-OV-3 and SK-Br-3 (low sGC activity) cell lines and in some cases the inhibition was rescued by the sGC inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). These studies suggest that the effects of activators/inhibitors of NO-sGC-cGMP in tumor cell proliferation is mediated by both cGMP-dependent and independent mechanisms.
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PMID:Role of soluble guanylyl cyclase-cyclic GMP signaling in tumor cell proliferation. 1994 39


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