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)

Carbon monoxide (CO) enhanced random migration of human neutrophils. An optimally stimulatory effect was observed with 10 microM CO. CO caused a rapid and transient increase in intracellular level of guanosine-3',5'-cyclic monophosphate (cGMP). The enhancing effect of CO on random migration was reversed to a large extent by inhibitors of cGMP accumulation, and by antagonists of cGMP-dependent protein kinase (G-kinase). These results strongly suggest that the enhancement of random migration by CO is mediated by cGMP and G-kinase. Using hemoglobin, a scavenger of CO, we could show that stimulation of soluble guanylate cyclase over an extended period of time, rather than the observed fast and transient increase in intracellular cGMP levels, is responsible for CO-activated migration. We postulate that CO, like nitric oxide (NO), acts as a biological signal in the immune system.
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PMID:Carbon monoxide enhances human neutrophil migration in a cyclic GMP-dependent way. 880 86

1. When NG-nitro-L-arginine methyl ester (L-NAME, 0.1-10 nmol) or NG-monomethyl-L-arginine (L-NMMA, 10 nmol-1 mumol) was intradermally administered with bradykinin (BK, 3 nmol) into the instep of rat hind-paws, a dose-related suppression of BK-induced hyperalgesia, assessed by the paw-pressure test, was produced. 2. L-Arginine (1 mumol) but not D-arginine (1 mumol) reversed the suppressive effects of L-NAME (10 nmol) and L-NMMA (1 mumol) on BK-induced hyperalgesia. 3. Concomitant intradermal administration of BK (3 nmol) with haemoglobin (1 nmol) significantly suppressed BK-induced hyperalgesia in the paw-pressure test. The BK-induced hyperalgesia was abolished by concomitant intradermal administration of either a guanylate cyclase inhibitor, methylene blue (10 nmol), or LY83583 (1 nmol). In addition, KT5823 (1 nmol) or Rp-8-bromoguanosine-3':5'-cyclic monophosphothioate (Rp-8-Br-cGMPS; 1 nmol), an inhibitor of cyclic GMP-dependent protein kinase, also significantly suppressed BK-induced hyperalgesia. 4. The carrageenin-induced hyperalgesia was significantly attenuated by L-NAME in a dose-dependent manner. 5. L-Arginine (1 mumol), sodium nitroprusside (1 mumol), dibutyryl cyclic GMP (1 mumol) or 8-bromo cyclic GMP (1 mumol) all failed to produce any significant relieving effect on the nociceptive threshold of rodent hind-paws. Concomitant administrations of each agent with a sub-threshold dose (0.1 nmol) of BK induced significant hyperalgesia. 6. Rp-adenosine 3':5'-cyclic monophosphothioate (Rp-cAMPS; 1 nmol), an inhibitor of cyclic AMP-dependent protein kinase, significantly suppressed BK-induced mechanical hyperalgesia. Concomitant administration of forskolin (1 nmol) with 8-bromo cyclic GMP (100 nmol) induced significant hyperalgesia. 7. In the superfusion experiment of a blister base on the instep of rodent hind-paws, intradermally administered BK (3 nmol) significantly increased the outflow of both cyclic GMP and cyclic AMP from the blister base. Concomitant administrations of L-NAME (10 nmol) with BK significantly reduced the BK-induced outflow of cyclic GMP without affecting the cyclic AMP content. 8. These results suggest that the NO-cyclic GMP pathway is involved in the mechanism of BK-induced hyperalgesia, and an activation of both cyclic GMP-and cyclic AMP-second messenger system plays an important role in the production of peripherally induced mechanical hyperalgesia.
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PMID:Involvement of endogenous nitric oxide in the mechanism of bradykinin-induced peripheral hyperalgesia. 882 27

1. While exposure of smooth muscle cells to sodium nitroprusside (SNP) leads to the development of tolerance to soluble guanylate cyclase (sGC) activation, the mechanisms responsible for this phenomenon in intact cells remain unclear. In the present study, possible mechanisms of tolerance were investigated in a cell culture model where sGC activity was estimated from the accumulation of cyclic GMP in response to 10 microM SNP over a 15 min period in the presence of a phosphodiesterase (PDE) inhibitor. 2. Pretreatment of rat aortic smooth muscle cells with 10-500 microM SNP led to a dose-dependent downregulation of cyclic GMP accumulation upon subsequent SNP stimulation. This effect was evident as early as 2 h following incubation with 10 microM SNP, reached a plateau at 4 h and was blocked by co-incubation with 30 microM oxyhaemoglobin. 3. Pretreatment of smooth muscle cells with the PDE inhibitor, zaprinast, resulted in downregulation of the SNP-induced cyclic GMP accumulation in a time- and concentration-dependent manner, that was first evident after 12 h. Moreover, while the zaprinast-induced downregulation of cyclic GMP accumulation was completely inhibited by the protein kinase A (PKA) inhibitor, H89, tolerance to SNP was partially reversed by H89. 4. beta 1 sGC steady state mRNA levels of S-nitroso N-acetylpenicillamine (SNAP)- or 8Br-cyclic GMP-pretreated cells were unchanged, as indicated by Northern blot analysis. However, Western blot analysis revealed that alpha 1 protein levels were decreased in zaprinast, but not in SNP, SNAP or 8Br-cyclic GMP pretreated cells. 5. While thiol depletion did not prevent the development of tolerance, pretreatment of cells with SNP in the presence of reducing agents partially or completely restored the ability of cells to respond to SNP. 6. We conclude that tolerance to SNP results from two distinct mechanisms: an early onset, NO-mediated event that is reversed by reducing agents and a more delayed, PKA-sensitive process that is mediated through increases in cyclic GMP and a decrease in sGC protein levels.
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PMID:Mechanisms of tolerance to sodium nitroprusside in rat cultured aortic smooth muscle cells. 882 56

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

We investigated the vasorelaxant effects of MCI-154, a cardiotonic agent designed to target thin filaments in cardiac muscles in intact and skinned vessels from guinea pigs. In normal Krebs-Henseleit solution, MCI-154 (10(-7)-10(-4) M) inhibited the contractions induced by angiotensin II, (Ang II), endothelin-1 (ET-1), phenylephrine, and phorbol 12-myristate 13-acetate (PMA) in a concentration-dependent manner in guinea pig aorta. In Ca(2+)-free solutions, ET-1 and PMA caused slowly developing and sustained contractions in guinea pig aorta, whereas phenylephrine and caffeine induced transient contractions due to Ca2+ release from the sarcoplasmic reticulum (SR). MCI-154 (10(-7)-10(-4) M) inhibited the contractile responses to ET-1 and PMA. MCI-154 also reduced the contraction induced by Ca2+ release from phenylehrine- and caffeine-sensitive Ca2+ store sites. On the other hand, the relaxation response to MCI-154 was not affected by the presence of methylene blue, a guanylate cyclase inhibitor or by the removal of endothelial cells. MCI-154 decreased the Ca(2+)-activated tension development in saponin-treated skinned fibers from guinea pig femoral arteries. The effects of MCI-154 were not potentiated in the presence of protein kinase A (PKA), whereas those of cyclic AMP were potentiated, possibly because of lack of protein kinase A. The present experiments demonstrate that MCI-154 inhibits vascular contraction when the contractions are produced by any of three mechanisms: protein kinase C (PKC) activation, Ca2+ mobilization from store sites, or sensitization of contractile elements by Ca2+.
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PMID:MCI-154-induced relaxation in vascular smooth muscles of guinea pig. 884 68

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

1. In the retina, as in other regions of the vertebrate central nervous system, glutamate receptors mediate excitatory chemical synaptic transmission and are a critical site for the regulation of cellular communication. In this study, retinal horizontal cells from the hybrid less were dissociated in cell culture, voltage clamped by the whole cell recording technique, and the currents evoked by application of excitatory amino acids recorded. 2. Responses to glutamate and its agonist kainate were reduced by approximately 50% in the presence of the nitric oxide (NO) donors sodium nitroprusside and S-nitroso-N-acetylpenicillamine. The effect of these compounds was blocked by the NO scavenger hemoglobin. 3. This effect of NO donors on kainate currents could be mimicked by the application of a membrane permeable guanosine 3',5'-cyclic monophosphate (cGMP) analogue, 8-Br-cGMP. The NO effect was also blocked by application of the guanylate cyclase inhibitor LY-83583, and by a protein kinase G inhibitor peptide. 4. In H1-type horizontal cells, stimulation of endogenous nitric oxide synthase with L-arginine reduced kainate responses, whereas application of D-arginine had no effect. 5. This receptor modulation mechanism may act in concert with other pre- and postsynaptic mechanisms to modify horizontal cell synaptic function according to the adaptational state of the retina and also may protect horizontal cells from glutamate excitotoxicity.
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PMID:Nitric oxide and cGMP modulate retinal glutamate receptors. 889 5

The photoreceptor membrane guanylate cyclase is a member of a family of proteins with a set of four structural motifs: an extracellular ligand binding domain, a transmembrane domain, an intracellular protein kinase-like domain, and an intracellular catalytic domain. Purified preparations of the photoreceptor guanylate cyclase have allowed us to explore the function of the protein kinase-like domain. ATP enhances the guanylate cyclase activity 2-fold in membranes stripped of peripheral proteins. The stimulation can be mimicked by ATPgammaS (adenosine 5'-O-(3-thiotriphosphate)), AMPPNP (5'-adenylyl beta,gamma-imidodiphosphate), and ADP, but not AMP. While this effect is lost by solubilizing guanylate cyclase, ATP binds the purified, solubilized enzyme in a site distinct from the catalytic GTP site as shown by specific labeling with 8-N3[alpha-32P]ATP. The enzyme has a protein kinase activity that is Mg2+-dependent and autophosphorylates serine residues. Myelin basic protein serves as a substrate for the kinase and enables further characterization of the kinase properties. The Km for ATP is 81 microM. The kinase activity is unaffected by calcium, cyclic nucleotides, and phorbol 12-myristate 13-acetate/L-alpha-phosphatidylserine/Ca2+ and is inhibited by high concentrations of staurosporine. These properties are distinct from other Ser/Thr kinases identified in rod outer segment preparations including protein kinase A, protein kinase C, and rhodopsin kinase. The observations offer the first biochemical evidence that a member of the receptor guanylate cyclase family has intrinsic protein kinase activity.
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PMID:The photoreceptor guanylate cyclase is an autophosphorylating protein kinase. 890 Jan 99


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