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)

We previously found that the nitric oxide (NO)-cGMP-cGMP-dependent protein kinase (PKG) signaling pathway acts in parallel with the cAMP-cAMP-dependent protein kinase (PKA) pathway to produce protein and RNA synthesis-dependent late-phase long-term potentiation (L-LTP) and cAMP response element-binding protein (CREB) phosphorylation in the CA1 region of mouse hippocampus. We have now investigated the possible involvement of a downstream target of PKG, ryanodine receptors. L-LTP can be induced by either multiple-train tetanization, NO or 8-Br-cGMP paired with one-train tetanization, or the cAMP activator forskolin, and all three types of potentiation are accompanied by an increase in phospho-CREB immunofluorescence in the CA1 cell body area. Both the potentiation and the increase in phospho-CREB immunofluorescence induced by multiple-train tetanization or 8-Br-cGMP paired with one-train tetanization are reduced by prolonged perfusion with ryanodine, which blocks Ca(2+) release from ryanodine-sensitive Ca(2+) stores. By contrast, neither the potentiation nor the increase in immunofluorescence induced by forskolin are reduced by depletion of ryanodine and inositol-1,4,5-triphosphate (IP3)-sensitive Ca(2+) stores. These results suggest that NO, cGMP, and PKG cause release of Ca(2+) from ryanodine-sensitive stores, which in turn causes phosphorylation of CREB in parallel with PKA during the induction of L-LTP.
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PMID:Ryanodine receptors contribute to cGMP-induced late-phase LTP and CREB phosphorylation in the hippocampus. 1220 48

Suramin is a well known antitrypanosomal drug and a novel experimental agent for the treatment of several cancers, yet the molecular mechanisms through which suramin exerts its effects on cell functions are not completely clear. In this study, we investigated the potential of suramin to activate the mitogen-activated protein kinase cascade in cultured Chinese hamster ovary (CHO) cells. The treatment of CHO cells with suramin increased the enzyme activity of extracellular signal-regulated kinases (ERK1/2) approximately 10-fold dose and time dependently. The EC(50) value was approximately 2.4 microM. This activation is inhibited by PD98059 and wortmannin/LY294002, indicating a crucial role for mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3-kinase (PI3K), respectively. Suramin-mediated stimulation of PI3K was confirmed by the observation that suramin stimulates the phosphorylation of protein kinase B (Akt) in a wortmannin-sensitive manner. Furthermore, cAMP response element-binding protein, a transcription factor, was also activated by suramin in a MEK-dependent manner. The suramin-induced phosphorylation of cGMP-dependent protein kinase was also suggested by a solid-phase kinase assay. The suramin effects on CHO cells were shown to have a concomitant increase in DNA synthesis, which was attenuated by PD98059. Similar activation of ERK1/2 activity by suramin was observed in other cell lines such as Chinese hamster lung or PC12 cells, but not in RBL2H3, ECV304, and OVK18 cells, indicating a cell-type specific mechanism for suramin. These results indicate that suramin induces mitogenic activity in several cell lines through the pathway from PI3K to MEK and ERK.
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PMID:Stimulation of extracellular signal-regulated kinase pathway by suramin with concomitant activation of DNA synthesis in cultured cells. 1459 92

Increased expression of CD11b, the beta-integrin marker of microglia, represents microglial activation during neurodegenerative inflammation. However, the molecular mechanism behind increased microglial CD11b expression is poorly understood. The present study was undertaken to explore the role of nitric oxide (NO) in the expression of CD11b in microglial cells. Bacterial lipopolysaccharide (LPS) induced the production of NO and increased the expression of CD11b in mouse BV-2 microglial cells and primary microglia. Either a scavenger of NO (PTIO) or an inhibitor of inducible nitric-oxide synthase (L-NIL) blocked this increase in microglial CD11b expression. Furthermore, co-microinjection of PTIO with LPS was also able to suppress LPS-mediated expression of CD11b and loss of dopaminergic neuronal fibers and neurotransmitters in striatum in vivo. Similarly, other inducers of NO production such as interferon-gamma, interleukin-1beta, human immunodeficiency virus type-1 gp120, and double-stranded RNA (poly(IC)) also increased the expression of CD11b in microglia through NO. The role of NO in the expression of CD11b was corroborated further by the expression of microglial CD11b by GSNO, an NO donor. Because NO transduces many intracellular signals via guanylate cyclase (GC), we investigated the role of GC, cyclic GMP (cGMP), and cGMP-activated protein kinase (PKG) in microglial expression of CD11b. Inhibition of LPS- and GSNO-mediated up-regulation of CD11b either by NS2028 (a specific inhibitor of GC) or by KT5823 and Rp-8-bromo-cGMP (specific inhibitors of PKG), and increase in CD11b expression either by 8-bromo-cGMP or by MY-5445 (a specific inhibitor of cGMP phosphodiesterase) alone suggest that NO increases microglial expression of CD11b via GC-cGMP-PKG. In addition, GSNO induced the activation of cAMP response element-binding protein (CREB) via PKG that was involved in the up-regulation of CD11b. This study illustrates a novel biological role of NO in regulating the expression of CD11b in microglia through GC-cGMP-PKG-CREB pathway that may participate in the pathogenesis of devastating neurodegenerative disorders.
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PMID:Up-regulation of microglial CD11b expression by nitric oxide. 1655 37

Cyclic GMP modulates gene expression in vascular smooth muscle cells (SMCs) in part by stimulating cGMP-dependent protein kinase I (PKGI) and the phosphorylation of transcription factors. In some cells, cGMP increases nuclear translocation of PKGI and PKGI-dependent phosphorylation of transcription regulators; however, these observations have been variable, and the mechanisms mediating nuclear PKGI translocation are incompletely understood. We tested the hypothesis that proteolytic cleavage of PKGI is required for cGMP-stimulated nuclear compartmentation of PKGI and phosphorylation of transcription factors. We detected an NH(2)-terminal PKGI fragment with leucine zipper domain immunoreactivity in the cytosol and endoplasmic reticulum of SMCs, but only a COOH-terminal PKGI fragment containing the catalytic region (now termed PKGIgamma) was observed in the Golgi apparatus (GA) and nucleoplasm. Posttranslational PKGI processing in the GA was critical for nuclear compartmentation of PKGIgamma because GA disruption with nocodazol or brefeldin A inhibited PKGIgamma nuclear localization. PKGIgamma immunoreactivity was particularly abundant in the nucleolus of interphase SMCs where its colocalization with the nucleolar dense fibrillar component protein fibrillarin closely matched the level of nucleolar assembly. Purified nucleolar PKGIgamma enzyme activity was insensitive to cGMP stimulation, which is consistent with its lack of the NH(2)-terminal autoinhibitory domain. Mutation of a putative proteolytic cleavage region in PKGI inhibited cGMP-mediated phosphorylation of cAMP response element-binding protein, cAMP response element-dependent transcription, and nuclear localization of PKGIgamma. These observations suggest that posttranslational modification of PKGI critically influences the nuclear translocation of PKGI and activities of cGMP in SMCs.
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PMID:Proteolytic processing of cGMP-dependent protein kinase I mediates nuclear cGMP signaling in vascular smooth muscle cells. 1853 60