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)

We have previously shown that treatment of rats with the nitric oxide (NO) synthase inhibitor N6-nitro-L-arginine methyl ester for 4 weeks resulted in the augmentation of blood pressure and enhanced levels of Gialpha proteins. The present studies were undertaken to investigate if NO can modulate the expression of Gi proteins and associated adenylyl cyclase signaling. A10 vascular smooth muscle cells (VSMC) and primary cultured cells from aorta of Sprague-Dawley rats were used for these studies. The cells were treated with S-nitroso-N-acetylpenicillamine (SNAP) or sodium nitroprusside (SNP) for 24 h and the expression of Gialpha proteins was determined by immunobloting techniques. Adenylyl cyclase activity was determined by measuring [32P]cAMP formation for [alpha-32P]ATP. Treatment of cells with SNAP (100 microM) or SNP (0.5 mM) decreased the expression of Gialpha-2 and Gialpha-3 by about 25-40% without affecting the levels of Gsalpha proteins. The decreased expression of Gialpha proteins was reflected in decreased Gi functions (receptor-independent and -dependent) as demonstrated by decreased or attenuated forskolin-stimulated adenylyl cyclase activity by GTPgammaS and inhibition of adenylyl cyclase activity by angiotensin II and C-ANP4-23, a ring-deleted analog of atrial natriuretic peptide (ANP) that specifically interacts with natriuretic peptide receptor-C (NPR-C) in SNAP-treated cells. The SNAP-induced decreased expression of Gialpha-2 and Gialpha-3 proteins was not blocked by 1H[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylyl cyclase, or KT5823, an inhibitor of protein kinase G, but was restored toward control levels by uric acid, a scavenger of peroxynitrite and Mn(111)tetralis (benzoic acid porphyrin) MnTBAP, a peroxynitrite scavenger and a superoxide dismutase mimetic agent that inhibits the production of peroxynitrite, suggesting that NO-mediated decreased expression of Gialpha protein was cGMP-independent and may be attributed to increased levels of peroxynitrite. In addition, Gsalpha-mediated stimulation of adenylyl cyclase by GTPgammaS, isoproterenol, and forskolin was significantly augmented in SNAP-treated cells. These results indicate that NO decreased the expression of Gialpha protein and associated functions in VSMC by cGMP-independent mechanisms. From these studies, it can be suggested that NO-induced decreased levels of Gi proteins and resultant increased levels of cAMP may be an additional mechanism through which NO regulates blood pressure.
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PMID:Nitric oxide modulates Gi-protein expression and adenylyl cyclase signaling in vascular smooth muscle cells. 1696 41

Dopamine (DA) and atrial natriuretic factor (ANF) share a number of physiological effects. We hypothesized that ANF and the renal dopaminergic system could interact and enhance the natriuretic and diuretic effects of the peptide. We have previously reported that the ANF-stimulated DA uptake in renal tubular cells is mediated by the natriuretic peptide type-A receptor (NPR-A). Our aim was to investigate the signaling pathways that mediate ANF effects on renal 3H-DA uptake. Methylene blue (10 microM), an unspecific inhibitor of guanylate cyclase (GC), blunted ANF elicited increase of DA uptake. ODQ (10 microM) a specific inhibitor of soluble GC, did not modify DA uptake and did not reverse ANF-induced increase of DA uptake; then the participation of nitric oxide-dependent pathways must be discarded. The second messenger was the cGMP since the analogous 125 microM 8-Br-cGMP mimicked ANF effects. The specific inhibitor of the protein kinase G (PKG), KT 5823 (1 microM) blocked ANF effects indicating that PKG is involved. We examined if ANF effects on DA uptake were able to modify Na+, K+ -adenosine triphosphatase (Na+, K+ -ATPase) activity. The experiments were designed by means of inhibition of renal DA synthesis by carbidopa and neuronal DA uptake blocked by nomifensine. In these conditions renal Na+, K+ -ATPase activity was increased, in agreement with the decrease of DA availability. When in similar conditions, exogenous DA was added to the incubation medium, the activity of the enzyme tended to decrease, following to the restored availability of DA. The addition of ANF alone had similar effects to the addition of DA on the sodium pump, but when both were added together, the activity of Na(+), K(+)-ATPase was decreased. Moreover, the extraneuronal uptake blocker, hydrocortisone, inhibited the latter effect. In conclusion, ANF stimulates extraneuronal DA uptake in external cortex tissues by activation of NPR-A receptors coupled to GC and it signals through cGMP as second messenger and PKG. Dopamine and ANF may achieve their effects through a common pathway that involves reversible deactivation of renal tubular Na+, K+ -ATPase activity. This mechanism demonstrates a DA-ANF relationship involved in the modulation of both decreased sodium reabsorption and increased natriuresis.
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PMID:Signaling pathways involved in atrial natriuretic factor and dopamine regulation of renal Na+, K+ -ATPase activity. 1700 63

The present study investigated whether cAMP-dependent cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel current (i.e., I(Cl.CFTR) or I(Cl.cAMP)) would be expressed in pig cardiac myocytes using whole-cell patch technique and reverse transcription polymerase chain reaction (RT-PCR). It was found that the beta-adrenoceptor agonist isoproterenol activated a time-independent current in myocytes from the ventricle, but not the atrium of pig heart. Histamine and forskolin (an adenylate cyclase activator) induced a similar current in pig ventricular cells. The current induced by isoproterenol was blocked by the PKA inhibitor H-7, reduced by the replacement of external Cl(-) ion, and inhibited by the application of 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB), but not 4'-diisothiocynatostilbene-2,2'-disulfonic acid (DIDS), typical of I(Cl.CFTR). I(Cl.CFTR) showed a small difference in regional myocytes across the left ventricular wall from epicardium to endocardium. Isoproterenol-induced current was 3.1+/-0.2 (n=33), 2.8+/-0.2 (n=25) and 2.3+/-0.2 pA/pF (n=31) respectively in subepicardial, midmyocardial, and subendocardial myocytes (P<0.05, subepicardium vs. subendocardium). RT-PCR and Western blotting analysis revealed that significant differences in CFTR channel mRNA and protein levels were present in atrial and ventricular cells, but not in regional ventricular cells across the ventricular wall from subepicardium to subendocardium. These results indicate that the functional CFTR channel (i.e., I(Cl.CFTR)) is present in ventricular myocytes, but not in atrial cells of pig heart.
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PMID:Evidence for cystic fibrosis transmembrane conductance regulator chloride current in swine ventricular myocytes. 1711 38

The effects of monocarboxylic acid-derived Cl(-) channel blockers on cardiac depolarization-activated K(+) currents were investigated. Membrane currents in rat ventricular myocytes were recorded using the whole-cell configuration of the patch-clamp technique. 5-Nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) and niflumic acid (NFA) induced an outward current at 0 mV. Both NPPB and NFA failed to induce any current when used intracellularly or after K(+) in the bath and pipette solutions was replaced by equimolar Cs(+). Voltage pulse protocols revealed that NPPB and NFA enhanced the steady-state K(+) current but inhibited the transient outward K(+) current. Genistein, a tyrosine kinase (PTK) inhibitor, inhibited NPPB- and NFA-induced outward current. Another PTK inhibitor, lavendustin A, produced a comparable effect. In contrast, the inactive analogue of genistein, daidzein, was ineffective. Orthovanadate, a tyrosine phosphatase inhibitor, markedly slowed the deactivation of the outward current induced by NPPB and NFA. The protein kinase A (PKA) inhibitor H-89 inhibited NPPB-induced outward current at 0 mV. In contrast, the protein kinase C (PKC) inhibitor H-7 was without significant effect on the action of NPPB. Pretreatment of the myocytes with genistein or H-89 prevented the enhancing effect of NPPB. Increasing intracellular Cl(-) from 22 to 132 mm slightly reduced NPPB-induced outward current at 0 mV. These results demonstrate that the monocarboxylic acid-derived Cl(-) channel blockers NPPB and NFA enhance cardiac steady-state K(+) current, and suggest that the enhancing effect of the Cl(-) channel blockers is mediated by stimulation of PKA and PTK signalling pathways.
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PMID:Effects of monocarboxylic acid-derived Cl- channel blockers on depolarization-activated potassium currents in rat ventricular myocytes. 1730 47

Exposure to nitrates causes tachyphylaxis to nitric oxide (NO), which reduces the effects of the second messenger cyclic guanosine-3',-5'-monophosphate (cyclic GMP). We tested the hypothesis that prolonged exposure to NO would also blunt the effects of natriuretic peptides. Cardiac myocytes were isolated from control (N=7) and chronic nitroglycerin (patched, N=7) rabbits. Patched animals received a transdermal nitroglycerin patch (0.3mg/h for 5 days). Myocyte function was determined at baseline, after C-type natriuretic peptide (CNP, 10(-8) and 10(-7)M) or brain natriuretic peptide (BNP, 10(-8) and 10(-7)M) or S-nitroso-N-acetyl-penicilliamine (SNAP, a NO donor, 10(-6) and 10(-5)M) followed by KT5823 (a cyclic GMP protein kinase inhibitor, 10(-6)M). Soluble and particulate guanylyl cyclase activities were measured in vitro and phosphoprotein analysis was performed. In control animals, CNP 10(-8)M (5.14+/-0.5%) and 10(-7)M (4.4+/-0.7%) significantly reduced percentage shortening from baseline (6.1+/-1.6%). KT5823 restored percentage shortening to 4.9+/-0.8%. Similar data were obtained with BNP and SNAP. In patched animals, CNP, BNP, SNAP had no significant effects on percentage shortening. The data on maximal rate of shortening and relaxation were consistent with these results. Guanylyl cyclase activities were not different in the control and patched animals. The myocytes from control and patched animals had similar protein phosphorylation patterns. Our data suggested that in addition to NO, the responses to both natriuretic peptides were downregulated after chronic exposure to nitroglycerin, but these effects were not due to changes in either guanylyl cyclase or cyclic GMP protein kinase, suggesting an altered downstream pathway.
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PMID:Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes. 1748 33

We tested the hypothesis that brain natriuretic peptide (BNP) would decrease the effects of myocardial stunning in rabbit hearts. We also examined the mechanisms responsible for these effects. In two groups of anesthetized open-chest rabbits, myocardial stunning was produced by 2 15-min occlusions of the left anterior descending artery separated by 15 min of reperfusion. The treatment group had BNP (10(-3) mol/l) topically applied to the stunned area. Hemodynamic and functional parameters were measured. Coronary flow and O2 extraction were used to determine myocardial O2 consumption. In separate animals, we measured the function of isolated control and simulated ischemia (95% N2/5% CO2, 15 min)-reperfusion ventricular myocytes with BNP or C-type natriuretic peptide (10(-8)-10(-7) mol/l) followed by KT5823 (10(-6) mol/l, cyclic GMP protein kinase inhibitor). In the in vivo control group, baseline delay to contraction was 47+/-4 ms and after stunning it increased to 71+/-10 ms. In the treatment group, baseline delay to contraction was 40+/-7 ms, and after stunning and BNP it did not significantly increase (43+/-6 ms). Neither stunning nor BNP administration affected regional O2 consumption. In control myocytes, BNP (10(-7) mol/l) decreased the percent shortening from 6.7+/-0.4 to 4.5+/-0.2%; after KT5823 administration, the percent shortening increased to 5.4+/-0.5%. In ischemia-reperfusion myocytes, BNP (10(-7) mol/l) decreased the percent shortening less from 5.0+/-0.5 to 3.8+/-0.2%; KT5823 administration did not increase the percent shortening (3.8+/-0.2%). BNP similarly and significantly increased cyclic GMP levels in control and stunned myocytes. The data illustrated that BNP administration reversed the effects of stunning and its mechanism may be independent of the cyclic GMP protein kinase.
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PMID:Brain natriuretic peptide reverses the effects of myocardial stunning in rabbit myocardium. 1751 32

In the case of left ventricle remodeling after myocardial infarction, cardiomyocyte apoptosis is attributed to increased cardiac workload by the stimulus such as chronic hypoxia. B-Type natriuretic peptide, being known as a reliable prognostic of cardiovascular pathology, plays an important role in the myocardial infarction. However, the action of B-type natriuretic peptide on cardiomyocytes undergoing apoptosis is unclear. In the present study, B-type natriuretic peptide have exhibited the enhancive effects on the mild hypoxia-induced cardiomyocyte apoptosis with the manifestation of facilitating phosphatidylserine evagination and increasing typical fragmented nuclei. In addition, B-type natriuretic peptide aggravated the dissipation of delta psi(m), the depletion of intracellular ATP and the increase of caspase-3 activity. 8-Bromo-cGMP, which increased cGMP independent of B-type natriuretic peptide, could mimic B-type natriuretic peptide's effects; whereas cGMP-dependent protein kinase inhibitor, Rp-8-br-cGMP inhibited that. Further study revealed the enhancive effect of BNP on down-regulation of Bcl-2 mRNA expression in the presence of mild hypoxia. In conclusion, the present study demonstrated that B-type natriuretic peptide aggravated the cardiomyocyte apoptosis by influencing hypoxia-induced mitochondrial death pathway, which is true at least in this oxygen deprivation model; and this effect was partially realized through intracellular cGMP.
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PMID:B-type natriuretic peptide enhances mild hypoxia-induced apoptotic cell death in cardiomyocytes. 1754 Nov 58

Over the past several years, the C-natriuretic peptide (CNP) has emerged as an important regulator of cartilage homeostasis and endochondral bone growth. In mice, genetic ablation of CNP or its cognate receptor NPRB results in marked dwarfism. When a downstream component of CNP signaling, protein kinase-G II (PKGII), is removed from cartilage, the mice have disturbed chondrocyte proliferation and cartilage matrix production. In contrast, activating mutations in PKGII as well as overexpression of CNP result in significant skeletal overgrowth in mice, demonstrating the positive role of CNP signaling in regulation of mammalian chondrocyte proliferation and cartilage matrix production. This is further supported by the existence of a human dwarfism, acromesomelic dysplasia Maroteaux-type (MIM #602875) that is caused by loss-of-function of NPRB. In comparison with other signaling systems, the molecular basis of CNP signaling in cartilage remains largely unknown, thus leaving many important questions open for future investigation. This review summarizes our current knowledge about the mechanism of CNP signaling in cartilage, areas for future investigation and its potential therapeutic uses.
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PMID:C-natriuretic peptide: an important regulator of cartilage. 1768 81

Several studies show that C-type natriuretic peptide (CNP) has a modulatory role in the digestive system. CNP administration reduces both jejunal fluid and bile secretion in the rat. In the present study we evaluated the effect of CNP on amylase release in isolated pancreatic acini as well as the receptors and intracellular pathways involved. Results showed that all natriuretic peptide receptors were expressed not only in the whole pancreas but also in isolated pancreatic acini. CNP stimulated amylase secretion with a concentration-dependent biphasic response; maximum release was observed at 1 pM CNP, whereas higher concentrations gradually attenuated it. The response was mimicked by a selective natriuretic peptide receptor (NPR-C) agonist and inhibited by pertussis toxin, strongly supporting NPR-C receptor activation. CNP-evoked amylase release was abolished by U-73122 (PLC inhibitor) and 2-aminoethoxydiphenyl borate (2-APB) [an inositol 1,4,5-triphosphate (IP(3)) receptor antagonist], partially inhibited by GF-109203X (PKC inhibitor), and unaltered by ryanodine or protein kinase A (PKA) and protein kinase G (PKG) inhibitors. Phosphoinositide hydrolysis was enhanced by CNP at all concentrations and abolished by U-73122. At 1 and 10 pM, CNP did not affect cAMP or guanosine 3',5'-cyclic monophosphate (cGMP) levels, but at higher concentrations it increased cGMP and diminished cAMP content. Present findings show that CNP stimulated amylase release through the activation of NPR-C receptors coupled to the PLC pathway and downstream effectors involved in exocytosis. The attenuation of amylase release was likely related to cAMP reduction. The augmentation in cGMP supports activation of NPR-A/NPR-B receptors probably involved in calcium influx. Present findings give evidence that CNP is a potential direct regulator of pancreatic function.
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PMID:C-type natriuretic peptide enhances amylase release through NPR-C receptors in the exocrine pancreas. 1770 53

This study tested the hypothesis that activation of atrial natriuretic peptide (ANP)/cGMP/protein kinase G signaling inhibits transforming growth factor (TGF)-beta1-induced extracellular matrix expression in cardiac fibroblasts and defined the specific site(s) at which this molecular merging of signaling pathways occurs. Left ventricular hypertrophy and fibrosis, collagen deposition, and myofibroblast transformation of cardiac fibroblasts in response to pressure overload by transverse aortic constriction were exaggerated in ANP-null mice compared with wild-type controls. ANP and cGMP inhibited TGF-beta1-induced myofibroblast transformation, proliferation, collagen synthesis, and plasminogen activator inhibitor-1 expression in cardiac fibroblasts isolated from wild-type mice. Following pretreatment with cGMP, TGF-beta1 induced phosphorylation of Smad3, but the resultant pSmad3 could not be translocated to the nucleus. pSmad3 that had been phosphorylated with recombinant protein kinase G-1alpha was analyzed by use of Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and ion trap tandem mass spectrometry. The analysis revealed phosphorylation of Ser309 and Thr388 residues, sites distinct from the C-terminal Ser423/425 residues that are phosphorylated by TGF-beta receptor kinase and are critical for the nuclear translocation and down-stream signaling of pSmad3. These results suggest that phosphorylation of Smad3 by protein kinase G is a potential molecular mechanism by which activation of ANP/cGMP/protein kinase G signaling disrupts TGF-beta1-induced nuclear translocation of pSmad3 and downstream events, including myofibroblast transformation, proliferation, and expression of extracellular matrix molecules in cardiac fibroblasts. We postulate that this process contributes to the antifibrogenic effects of the natriuretic peptide in heart.
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PMID:Atrial natriuretic peptide inhibits transforming growth factor beta-induced Smad signaling and myofibroblast transformation in mouse cardiac fibroblasts. 1823 44


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