Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thromboxane (TX) stimulation of fibronectin (FN) synthesis in mesangial cells (MC) is dependent on protein kinase C (PKC)-mediated increases in transforming growth factor beta (TGF beta), and is suppressed by increases in cellular cGMP. The current studies evaluate the role of cGMP-dependent and -independent actions of nitric oxide (NO) in modulating the responses of MC to the TX analogue U46619. TX-stimulated increases in PKC activity, TGF beta, and FN synthesis in MC were suppressed by either 8-Br-PET-cGMP or the NO donor S-nitroso-N-acetylpenicillamine (SNAP). By contrast, NO, but not cGMP, inhibited basal PKC activity, TGF beta bioactivity and FN synthesis. The cGMP-dependent protein kinase 1-alpha inhibitor 8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate (Rp) restored the PKC, TGF beta, and the FN synthetic responses to TX when added to MC before exposure of the cells to either cGMP or SNAP. However, neither Rp nor the guanylate cyclase inhibitor Ly83583 significantly altered SNAP inhibition of basal PKC. In addition, Rp failed to alter the decreases in basal TGF beta bioactivity and FN synthesis seen in the presence of SNAP. In contrast to the FN response to U46619, cGMP and SNAP did not affect the stimulation of FN synthesis by exogenous TGF beta. The later findings are consistent with inhibitory actions of NO and cGMP at, or proximal to, U46619-induced increases in TGF beta in the suppression of TX-signaled increases in FN synthesis. Thus, NO depresses basal PKC and TGF beta bioactivity in MC by mechanisms that are largely independent of cGMP, whereas NO inhibition of these MC responses to TX is mediated primarily by increases in cGMP and activation of protein kinase 1-alpha.
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PMID:Nitric oxide suppresses increases in mesangial cell protein kinase C, transforming growth factor beta, and fibronectin synthesis induced by thromboxane. 882 14

This study tests the hypothesis that the control of vascular smooth muscle cell (VSMC) apoptosis is regulated by the antagonistic balance between vasoactive substances such as NO and angiotensin II (Ang II). Moreover, it is postulated that the cellular signaling pathways involved in regulating vessel tone are also coupled to the regulation of programmed cell death. Using an in vitro model system, we documented that the addition of NO donor molecules S-nitroso-N-acetylpenicillamine or sodium nitroprusside to VSMC dose-dependently induced apoptosis as documented by DNA laddering and quantified by analysis of cellular chromatin morphology. The mediator role of the guanylate cyclase signaling pathway in NO-induced apoptosis was evidenced by (1) induction of apoptosis by the 8-bromo-cGMP analogue, (2) potentiation of NO-induced apoptosis by cGMP-specific phosphodiesterase inhibition, and (3) the prevention of NO-induced apoptosis by the inhibition of the cGMP-dependent protein kinase 1 alpha. In contrast, Ang II directly antagonized NO donor- and cGMP analogue-induced apoptosis via activation of the type I Ang II receptor. These findings suggest that the countervailing balance between NO and Ang II may determine the overall cell population within the vessel wall by regulating genetic programs determining cell death as well as cell growth.
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PMID:Vasoactive substances regulate vascular smooth muscle cell apoptosis. Countervailing influences of nitric oxide and angiotensin II. 883 98

1. In rat aortic rings precontracted by phenylephrine, H7 (10(-5)M) and staurosporine (10(-7)M), which inhibit PKA, PKG and PKC, and H-89 (10(-6)M), which inhibits PKA and PKG, potentiated relaxations induced by nitroglycerin. Forskolin-induced relaxations were not affected by H7 (10(-5)M). 2. Nitroglycerin-induced relaxations were not affected by calphostin-C (10(-7)M), which inhibits PKC, H-89 (10(-7)M), which inhibits PKA, and staurosporine (2 x 10(-9)M), which inhibits PKC. 3. Iberiotoxin (3 x 10(-8)M), an inhibitor of large conductance Kca channels, partly inhibited the relaxation induced by nitroglycerin and completely inhibited the potentiating effect of H7 on nitroglycerin-induced relaxations. 4. The potentiating effect of zaprinast (10(-5)M), an inhibitor of cGMP-phosphodiesterase, on nitroglycerin-induced relaxation was not affected by iberiotoxin. In the presence of methylene blue (10(-5)M), an inhibitor of guanylate cyclase, the residual relaxing response to nitroglycerin was not affected by H7, but it was inhibited by iberiotoxin. 5. These results suggest that the potentiation of nitroglycerin-induced relaxation by H7, staurosporine and H-89 may be due to inhibition of PKG.
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PMID:The potentiation of nitroglycerin-induced relaxation by PKG inhibition in rat aortic rings. 885 8

Early studies in whole heart indicated that cGMP antagonized the positive inotropic effects of catecholamines and cAMP. Since the L-type Ca2+ channel current (ICa) plays a predominant role in the initiation and development of cardiac electrical and contractile activities, regulation of ICa by cGMP pathways has received much attention over the last ten years. Patch-clamp measurements of ICa in isolated cardiac myocytes reveal at least three different cGMP effectors that may participate to different degrees in different animal species and cardiac tissues in the regulation of ICa by cGMP. In frog ventricular myocytes, cGMP inhibits ICa by stimulation of a cGMP-stimulated cAMP phosphodiesterase (PDE2), whereas in rat ventricular myocytes, cGMP predominantly inhibits ICa via a mechanism involving activation of a cGMP-dependent protein kinase (cGMP-PK). In guinea pig, frog and human cardiomyocytes, cGMP can also stimulate ICa via an inhibition of a cGMP-inhibited cAMP phosphodiesterase (PDE3). This effect is most predominant in human atrial myocytes and appears readily during an activation of the soluble guanylate cyclase activity by low concentrations of nitric oxide (NO)-donors. Biochemical characterization of the endogenous phosphodiesterases and cGMP-PK in purified cardiac myocytes provide further evidence in support of these mechanisms of cGMP action on ICa. However, the regulation of cGMP levels by a variety of agents is not always consistent with their effects on contractility. In particular, the participation of cGMP and NO pathways in the regulation of cardiac ICa and contractility by acetylcholine is still questionable.
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PMID:[Regulation of cardiac calcium current by cGMP/NO route]. 886 31

The effects of bath-applied sodium nitroprusside (SNP), a nitric oxide (NO) donor, on an acetylcholine ACh-induced K+ current recorded from identified neurons (R9 and R10) of Aplysia kurodai were investigated with conventional voltage-clamp and pressure ejection techniques. Bath-applied SNP (25-50 microM) reduced the ACh-induced K+ current in the neurons without affecting the resting membrane conductance and holding current. The suppressing effects of SNP on the current were completely reversible. Intracellular injection of 1 mM guanosine 3',5'-cyclic monophosphate (cGMP) or bath-applied 50 microM 3-isobutyl-1-methylxanthine (IBMX), a nonspecific phosphodiesterase (PDE) inhibitor, also inhibited the ACh-induced current, thus mimicking the effect of the NO donor on the ACh-induced current. In contrast, pretreatment with methylene blue (10 microM), an inhibitor of guanylate cyclase, and hemoglobin (50 microM), a nitric oxide scavenger, decreased the SNP-induced inhibition of the ACh-induced current. These results suggest that SNP, a NO donor, inhibits the ACh-induced K+ current, and that the mechanism of NO inhibition of the ACh-induced current recorded from identified Aplysia neurons involves cGMP-dependent protein kinase.
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PMID:Nitric oxide donor sodium nitroprusside inhibits the acetylcholine-induced K+ current in identified Aplysia neurons. 892 26

The purpose of this study was to investigate the direct effect of vascular endothelial growth factor (VEGF) on microvascular permeability and its signaling mechanisms. The apparent permeability coefficient to albumin was measured in isolated coronary venules. Topical application of VEGF dose-dependently and transiently increased albumin permeability by two- to threefold. Inhibition of nitric oxide (NO) synthesis with NG-monomethyl-L-arginine abolished VEGF-induced venular hyperpermeability. Furthermore, because NO exerts vasoactive effects through stimulation of guanylate cyclase (GC) and the subsequent production of guanosine 3',5'-cyclic monophosphate (cGMP), we examined the role of GC and cGMP-dependent protein kinase (PKG) in the mediation of VEGF's action. The permeability response to VEGF was measured in the presence of the selective GC inhibitor 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one and the specific PKG inhibitor KT-5823. Both inhibitors reduced basal permeability and prevented the hyperpermeability response to VEGF. Therefore, we suggest that VEGF modulates microvascular permeability via a signaling cascade involving NO synthesis, GC stimulation, and PKG activation.
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PMID:VEGF induces NO-dependent hyperpermeability in coronary venules. 899 38

We have previously demonstrated that agonists increase microvascular permeability through a phospholipase C-nitric oxide synthase-guanylate cyclase cascade. The aim of this study was to further investigate the downstream end of the signaling pathway with a focus on myosin light chain (MLC) phosphorylation. The apparent permeability coefficient to albumin was measured in isolated coronary venules. Under control conditions, the nitric oxide donor sodium nitroprusside, as well as the guanosine 3',5'-cyclic monophosphate-dependent protein kinase (PKG) activator 8-bromoguanosine 3',5'-cyclic monophosphate, increased venular permeability two- to threefold. Similarly, activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate significantly elevated permeability. Inhibition of MLC phosphorylation with ML-7 significantly attenuated the hyperpermeability responses to the agonists. Furthermore, ML-7 dose dependently reduced basal venular permeability. Consistently, inhibition of dephosphorylation with the protein phosphatase inhibitor calyculin dramatically increased basal permeability. These results suggest that 1) PKG and PKC play an important signaling role in the regulation of endothelial barrier function and 2) MLC phosphorylation contributes to basal and agonist-stimulated microvascular permeability.
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PMID:Myosin light chain phosphorylation: modulation of basal and agonist-stimulated venular permeability. 908 22

It is well established that nitric oxide (NO) acts as a signalling molecule in the nervous system of both mammals and insects. In contrast to classical transmitters, the membrane-permeant NO can act on neighbouring targets limited by half-life and diffusion barriers. This type of diffuse signalling seems to be evolutionarily highly conserved and recent findings concerning the characterization and function of the NO system in insects are summarized in this review. Firstly, the properties and the localization of the NO forming enzyme, the NO synthase (NOS), are described. In the nervous system the brain contains by far the highest NOS activity. As an evolutionary peculiarity, a blood-feeding bug exhibits high NOS activity in the salivary glands. Secondly, the soluble guanylate cyclase (sGC), a major target of NO action, and cGMP-regulated enzymes like cGMP-dependent protein kinase and cyclic nucleotide gated channels are described. Anatomical organization of the NO/cGMP system in insects reveals evidence for a cellular separation of the release site and target site of NO, although in the antennal lobes of the locust an exception from this rule exists. Thirdly, the implication of the NO system in neuronal function in insects is described. In the honeybee, the NO/cGMP system in the antennal lobes is implicated in the processing of adaptive mechanisms during chemosensory processing, and recent findings support a specific role of the NO system in memory formation. Discussion of the results in insects with regard to properties and functions of the vertebrate NO system is attempted.
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PMID:The nitric oxide system in insects. 908 93

1. To elucidate the role of the nitric oxide (NO) transmitter system in the regulation of gap junctional channel gating, we have examined the effects of the NO donor sodium nitroprusside (SNP) on the electrical synapses of hybrid bass H2-type horizontal cells. 2. SNP reversibly reduced the macroscopic junctional conductance without significantly changing voltage sensitivity. 3. Kinetic analyses showed that SNP made the voltage-dependent decay of junctional currents more rapid. 4. Single-channel data showed that SNP reduced channel open probability by reducing channel open frequency. 5. The action of SNP can be prevented or largely reduced by the NO scavenger, haemoglobin. NO release by SNP solutions was detected directly by a NO sensor. 6. NO appears to modulate the gap junctional conductance by activating the cGMP-cGMP-dependent protein kinase G (PKG) pathway. A membrane-permeable cGMP analogue, 8-Br-cGMP, mimics the action of SNP. A soluble guanylate cyclase inhibitor (LY-83583) and a highly specific cGMP-dependent protein kinase inhibitor (RKRARKE) blocked the action of NO. 3-Isobutyl-1-methylxanthine (IBMX), a non-specific phosphodiesterase inhibitor, potentiated the effect of SNP. 7. [Ca2+]i image studies showed that NO donors did not change [Ca2+]i in horizontal cells, suggesting that the regulation of junctional channels by NO is [Ca2+]i independent.
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PMID:Modulation of hybrid bass retinal gap junctional channel gating by nitric oxide. 913 Jan 65

Parallel fiber synapses onto Purkinje neurons in acute cerebellar slices undergo long-term depression (LTD) when presynaptic activity coincides with postsynaptic depolarization. These electrical inputs can be respectively replaced by nitric oxide (NO) and Ca2+ photolytically released inside the Purkinje neuron, showing that these two messengers are sufficient for LTD induction. NO acts via cGMP production because inhibitors of guanylate cyclase prevent LTD but can be circumvented by photoreleased cGMP combined with Ca2+ elevation. Three inhibitors of cGMP-dependent protein kinase, Rp-8Br-PET-cGMPS, KT5823, and a novel pseudosubstrate peptide, all block LTD. LTD induction permits <10 ms gap between NO release and Ca2+ elevation, whereas 200-300 ms is allowed between uncaged cGMP and Ca2+ increase. This surprising difference in timing precision can be explained either by tighter localization and faster decay of cGMP when generated by NO rather than uncaging, or by two independent coincidence detectors in series.
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PMID:Synergies and coincidence requirements between NO, cGMP, and Ca2+ in the induction of cerebellar long-term depression. 920 68


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