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

1. An inward current (I[in]) was produced by gamma-aminobutyric acid (GABA) and muscimol, but not by baclofen, in an identifiable giant neuron type, v-LCDN (ventral-left cerebral distinct neuron), of an African giant snail (Achatina fulica Ferussac) under voltage clamp. 2. The pharmacological features of the excitatory GABA receptors in this Achatina neuron type, termed the Achatina muscimol II type GABA receptors, were mainly comparable to those of the mammalian GABA(C) receptors. 3. It was demonstrated in the present study that the following inhibitors for intracellular signal transduction systems showed no significant effect on the I(in) produced by GABA in this Achatina neuron type: H-7 [1-(5-isoquinolinyl sulfonyl)-2-methylpiperazine], an inhibitor of cyclic AMP-dependent protein kinase (PKA), cyclic GMP-dependent protein kinase (PKG) and protein kinase C (PKC); H-8 (N-[2-(methylamino)-ethyl]-5-isoquinolinesulfonamide), a PKA and PKG inhibitor; H-9 [N-(2-aminoethyl)-5-isoquinolinesulfonamide], a PKA inhibitor; staurosporine ((9alpha,10beta,11beta,13alpha)-(+)-2,3,10,11,12 ,13-hexahydro-10-methoxy-9-methyl-11-(methylamino)-9,13-epoxy-1H,9H-d iindolo[1,2,3-gh: 3',2',1'-1m]pyrrolo[3,4-j] [1,7]benzodiazonin-1-one), a PKA and PKC inhibitor; KT5823 ((8R,9S, 11S)-9-methoxy-9-methoxycarbonyl-2N,8-dimethyl-2,3,9,10-tetrahydro-8,11- epoxy-1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cycloocta[c,d,e]- trinden-1-one), a PKG inhibitor; W-7 [N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide], a calmodulin inhibitor; ML-9 [1-(5-chloronaphthalene-1-sulfonyl-1H-hexahydro-1,4-diazepine hydrochloride], a myosin light-chain kinase inhibitor; genistein [5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one], a tyrosine protein kinase inhibitor; IBMX (3-isobutyl-1-methylxanthine), a cyclic nucleotide phosphodiesterase (PDE) inhibitor; fluphenazine nitrogen-mustard (2-chloroethyl)-4[3-(2-trifluoromethyl-10-phenothiazinyl)-propyl]p iperazine dihydrochloride), a calmodulin-dependent PDE inhibitor; calyculin A, a type 1 protein phosphatase inhibitor; and okadaic acid (9,10-deepithio-9,10-didehydroacanthifolicin), a type 1, 2A and 2B protein phosphatase inhibitor. 4. With these results, it was proposed that the excitatory Achatina muscimol II type GABA receptors in v-LCDN are not metabotropic but ionotropic.
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PMID:Effects of inhibitors for intracellular signal transduction systems on the inward current produced by GABA in a snail neuron. 950 77

Recently, the CLN3 gene associated with Batten disease (juvenile neuronal ceroid lipofuscinosis, JNCL), a recessively inherited, progressive, neurodegenerative disorder of childhood, has been identified. The CLN3 gene encodes a novel protein (battenin) of a predicted 438 amino acids containing several potential posttranslational modifications. We have expressed a full-length CLN3 protein as a C-terminal fusion with green fluorescent protein (GFP) to evaluate whether CLN3 protein is phosphorylated. By using in vivo labeling with 32P, detection with anti-phosphoamino acid antibodies, and phosphoamino acid analysis, we demonstrate that the CLN3 protein is phosphorylated on both serine and threonine residues. We also demonstrate that CLN3 protein is not modified by mannose 6-phosphate. Furthermore, we show that phosphorylation of CLN3 protein is carried out by protein kinase A (cAMP-dependent protein kinase, PKA), protein kinase G (cGMP-dependent protein kinase, PKG), and casein kinase II and that it is enhanced by inhibition of protein phosphatase 1 (PP 1) or protein phosphatase 2A (PP 2A).
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PMID:Evidence for phosphorylation of CLN3 protein associated with Batten disease. 987 58

G-substrate, a specific substrate of the cGMP-dependent protein kinase, has previously been localized to the Purkinje cells of the cerebellum. We report here the isolation from mouse brain of a cDNA encoding G-substrate. This cDNA was used to localize G-substrate mRNA expression, as well as to produce recombinant protein for the characterization of G-substrate phosphatase inhibitory activity. Brain and eye were the only tissues in which a G-substrate transcript was detected. Within the brain, G-substrate transcripts were restricted almost entirely to the Purkinje cells of the cerebellum, although transcripts were also detected at low levels in the paraventricular region of the hypothalamus and the pons/medulla. Like the native protein, the recombinant protein was preferentially phosphorylated by cGMP-dependent protein kinase (Km = 0.2 microM) over cAMP-dependent protein kinase (Km = 2.0 microM). Phospho-G-substrate inhibited the catalytic subunit of native protein phosphatase-1 with an IC50 of 131 +/- 27 nM. Dephospho-G-substrate was not found to be inhibitory. Both dephospho- and phospho-G-substrate were weak inhibitors of native protein phosphatase-2A1, which dephosphorylated G-substrate 20 times faster than the catalytic subunit of protein phosphatase-1. G-substrate potentiated the action of cAMP-dependent protein kinase on a cAMP-regulated luciferase reporter construct, consistent with an inhibition of cellular phosphatases in vivo. These results provide the first demonstration that G-substrate inhibits protein phosphatase-1 and suggest a novel mechanism by which cGMP-dependent protein kinase I can regulate the activity of the type 1 protein phosphatases.
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PMID:Phosphorylation-dependent inhibition of protein phosphatase-1 by G-substrate. A Purkinje cell substrate of the cyclic GMP-dependent protein kinase. 992 Aug 94

G-substrate, an endogenous substrate for cGMP-dependent protein kinase, exists almost exclusively in cerebellar Purkinje cells, where it is possibly involved in the induction of long-term depression. A G-substrate cDNA was identified by screening expressed sequence tag databases from a human brain library. The deduced amino acid sequence of human G-substrate contained two putative phosphorylation sites (Thr-68 and Thr-119) with amino acid sequences [KPRRKDT(p)PALH] that were identical to those reported for rabbit G-substrate. G-substrate mRNA was expressed almost exclusively in the cerebellum as a single transcript. The human G-substrate gene was mapped to human chromosome 7p15 by radiation hybrid panel analysis. In vitro translation products of the cDNA showed an apparent molecular mass of 24 kDa on SDS/PAGE which was close to that of purified rabbit G-substrate (23 kDa). Bacterially expressed human G-substrate is a heat-stable and acid-soluble protein that cross-reacts with antibodies raised against rabbit G-substrate. Recombinant human G-substrate was phosphorylated efficiently by cGMP-dependent protein kinase exclusively at Thr residues, and it was recognized by antibodies specific for rabbit phospho-G-substrate. The amino acid sequences surrounding the sites of phosphorylation in G-substrate are related to those around Thr-34 and Thr-35 of the dopamine- and cAMP-regulated phosphoprotein DARPP-32 and inhibitor-1, respectively, two potent inhibitors of protein phosphatase 1. However, purified G-substrate phosphorylated by cGMP-dependent protein kinase inhibited protein phosphatase 2A more effectively than protein phosphatase 1, suggesting a distinct role as a protein phosphatase inhibitor.
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PMID:Molecular identification of human G-substrate, a possible downstream component of the cGMP-dependent protein kinase cascade in cerebellar Purkinje cells. 1005 66

We investigated the effect of carbachol (CCh) on L-type Ca2+ current (ICa(L)) enhanced by dialyzed adenosine 3',5'-cyclic monophosphate (cAMP) and/or bath-applied 3-isobutyl-1-methylxanthine (IBMX) in guinea pig isolated ventricular myocytes. At pipette concentrations ([cAMP]pip) from 30 microM to 1 mM, cAMP increased ICa(L) to 25.8 +/- 0.9 microA/cm2 (682 +/- 24.8% increase above control). CCh (100 microM) did not inhibit ICa(L) at any [cAMP]pip. IBMX, a nonselective phosphodiesterase (PDE) inhibitor, increased ICa(L) maximally at 300 microM IBMX (17.9 +/- 0.7 microA/cm2; 449 +/- 20% increase). CCh (100 microM) inhibited ICa(L) by 92 +/- 9.5% at 30 microM IBMX and 78 +/- 4.6% at 100 microM IBMX; this effect was reduced or absent at higher IBMX concentrations (300 and 1,000 microM). Coadministration of cAMP and IBMX also progressively suppressed inhibition by CCh. CCh had a negligible effect on ICa(L) at 750 microM IBMX in the absence of pipette cAMP and at 50 microM IBMX in the presence of 100 microM [cAMP]pip. ACh-activated K+ current (IK(ACh)) was unchanged in atrial myocytes dialyzed with 100 microM cAMP; this excludes a phosphorylation-dependent desensitization of the muscarinic receptor (mAChR) or Gi by cAMP. LY83583 (100 microM), an inhibitor of cyclic guanosine monophosphate (cGMP) production, attenuated inhibition of ICa(L) by CCh in the presence of IBMX. 8-Bromo-cGMP (8-Br-cGMP), an activator of cGMP-dependent protein kinase (PKG), mimicked CCh in its actions on ICa(L) raised by both cAMP (no significant change) and IBMX (49 +/- 5.1% inhibition). Okadaic acid, an inhibitor of type 1 and 2A phosphatases, blocked inhibition of IBMX-stimulated ICa(L) by either CCh or 8-Br-cGMP. Thus the ability of CCh to inhibit ICa(L) appears caused by cGMP/PKG activation of an okadaic acid-sensitive protein phosphatase, and elevated levels of cAMP protect against this action.
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PMID:Elevated cAMP suppresses muscarinic inhibition of L-type calcium current in guinea pig ventricular myocytes. 1044 83

The GABA(A) receptor and the non-NMDA subtype of the ionotropic glutamate receptor were co-expressed in Xenopus oocytes by injection of quail brain mRNA. The oocytes were treated with various protein kinase (PK) and protein phosphatase (PP) activators and inhibitors and the effects on receptor functioning were monitored. Two phorbol esters, 4-beta-phorbol 12-myristate-13-acetate (PMA) and 4-beta-phorbol 12,13-dibutyrate (PDBu); the cGMP-dependent PK activators sodium nitroprusside (SNP) and S-nitrosoglutathione (SNOG); and the PP inhibitor okadaic acid (OA) reduced the amplitude of the GABA-induced currents, whilst the PK inhibitor staurosporine potentiated it. In addition, PMA, PDBu, SNP, and OA reduced the desensitization of the GABA-induced response. Identical treatments generally had similar but less pronounced effects on responses generated by kainate (KA) but the desensitization characteristic of the non-NMDA receptor was not affected. None of the treatments had any effect on the reversal potentials of the induced currents. Immunoblots revealed that the oocytes express endogenous PKG and guanylate cyclase. The results are discussed in terms of the molecular structures of GABA(A) and non-NMDA receptors and the potential functional consequences of phosphorylation/dephosphorylation.
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PMID:Protein kinase and phosphatase modulation of quail brain GABA(A) and non-NMDA receptors co-expressed in Xenopus oocytes. 1067 79

The soluble form of guanylyl cyclase (sGC) plays a pivotal role in the transduction of inter- and intracellular signals conveyed by nitric oxide. Here, a feedback inhibitory mechanism triggered by cyclic guanosine-3',5'-monophosphate (cGMP)-dependent protein kinase (PKG) activation is described. Preincubation of chromaffin cells with C-type natriuretic peptide, which increased cGMP levels and activated PKG, or with cGMP-permeant analogue (which also activates PKG), in the presence of a broad-spectrum phosphodiesterase inhibitor, resulted in a decrease in subsequent sodium nitroprusside (SNP)-dependent cGMP elevations. This inhibitory effect was mimicked by activating a protein phosphatase and counteracted by the selective PKG inhibitor KT-5823 and by different protein phosphatase inhibitors. Immunoprecipitation of sGC from cells submitted to different treatments followed by immunodetection with antiphosphoserine antibodies (clone 4A9) showed changes in phosphorylation levels of the beta subunit of sGC, and these changes correlated well with differences in SNP-elicited cGMP accumulations. Pretreatment of cells with several PKG inhibitors or protein phosphatase inhibitors produced an enhancement of SNP-stimulated cGMP rises without changing the SNP concentration required to produce half-maximal or maximal responses. Taken together, these results indicate that the catalytic activity of sGC is closely coupled to the phosphorylation state of its beta subunit and that the tonic activity of PKG or its stimulation regulates sGC activity through dephosphorylation of the beta subunit.
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PMID:Nitric oxide-sensitive guanylyl cyclase activity inhibition through cyclic GMP-dependent dephosphorylation. 1103 92

A model of plasticity is proposed for the olivocerebellar neural network in which the efficiency of the synaptic inputs to different neurons changes simultaneously and interdependently. This effect is based on the following functional characteristics of the network: simultaneous arrival of an afferent signal via mossy fibers to input granule cells and output neurons in the deep cerebellar nuclei; synchronous arrival of the signal from the inferior olive, via climbing fibers and their collaterals, at cells in the input and output layers, and to Purkinje cells, and the existence of local excitatory, inhibitory, and disinhibitory feedback circuits. Increases (decreases) in post-tetanic Ca2+ concentrations relative to the level evoked by the preceding stimulation in these cells are accompanied by decreases (increases) in the activity of cGMP-dependent protein kinase G, with increases (decreases) in the activity of protein phosphatase I. As a result, dephosphorylation (phosphorylation) of ionotropic receptors is accompanied by simultaneous depression (potentiation) of the excitatory input to a given neuron and potentiation (depression) of the inhibitory input to the same neuron. The depolarizing signal from the inferior olive affects synapse modification in different layers of the network in such a way that its presence (absence) depresses (potentiates) the signal sent from the output cells of the cerebellum to other structures.
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PMID:Interrelated modification of excitatory and inhibitory connections in the olivocerebellar neural network. 1176 93

Mitogenic cell proliferation requires a rapid and transient H2O2 generation, which is blocked by catalase or PKA activators. Previously, we observed that anemic HIV(+) individuals expressed acidic pIs of catalase in RBC with significantly high activities [Mol Cell Biochem 165: 77-81, 1996]. These findings led us to hypothesize that cell signaling molecules regulate catalase to control cell mitogenesis. To test the hypothesis, we determined (i) whether RBC counts correlate with their catalase activities, (ii) whether protein kinases and phosphatases alter catalase activity in vitro, and (iii) whether protein kinase activators increase catalase activity to suppress proliferation of cultured cells. The results indicated that RBC counts inversely correlated with RBC catalase activities in both HIV(+) (r: -0.6769, r2: 0.4582, n: 69 male, p < 0.0001) and HIV(-) (r: -0.3827, r2: 0.1464, n: 177 male, p < 0.0001) populations. Catalytic PKA, PKC and Casein Kinase II, but none of PKG, Ca2+/calmodulin kinase II and p34cdc/cyclinB, rapidly elevated catalase activity in vitro by up to 2-fold. Whereas a major CAT subunit (60 kDa) showed immunoreactive phosphoserine and phosphothreonine, the kinases- and gamma-32P-ATP-dependent phosphorylation occurred with a minor component (110 kDa). Among PKC isozymes examined, PKCzeta was the most effective modulator followed by PKCgamma, and protein phosphatase 1gamma and 2A decreased the catalase activity. PKA and PKCzeta activators of forskolin and okadaic acid increased catalase activity and 110 kDa expression in NIH3T3 cells up to 2.4-fold and suppressed the cell growth, showing an inverse correlation of the indices (r: -0.9286, r2: 0.8622, n: 18, p < 0.0001). Taken together, these results suggest for the first time that catalase is under the regulation of cell signaling molecules and capable of modulating mitogenic cell proliferation.
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PMID:Regulation of catalase enzyme activity by cell signaling molecules. 1248 79

Protein phosphatases play key roles in cellular regulation and are subjected to control by protein inhibitors whose activity is in turn regulated by phosphorylation. Here we investigated the possible regulation of phosphorylation-dependent type-1 protein phosphatase (PP1) inhibitors, CPI-17, PHI-1, and KEPI, by various kinases. Protein kinases A (PKA) and G (PKG) phosphorylated CPI-17 at the inhibitory site (T38), but not PHI-1 (T57). Phosphorylated CPI-17 inhibited the activity of both the PP1 catalytic subunit (PP1c) and the myosin phosphatase holoenzyme (MPH) with IC(50) values of 1-8 nM. PKA predominantly phosphorylated a site distinct from the inhibitory T73 in KEPI, whereas PKG was ineffective. Integrin-linked kinase phosphorylated KEPI (T73) and this dramatically increased inhibition of PP1c (IC(50)=0.1 nM) and MPH (IC(50)=8 nM). These results suggest that the regulatory phosphorylation of CPI-17 and KEPI may involve distinct kinases and signaling pathways.
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PMID:Phosphorylation of protein phosphatase type-1 inhibitory proteins by integrin-linked kinase and cyclic nucleotide-dependent protein kinases. 1280 74


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