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)

Injection of small volumes of N-methyl-D-aspartate (NMDA) or Sin-1 molsidomine (a nitric oxide releasing agent) onto the dendrites of granule cells in the hippocampal dentate gyrus leads to changes in the level of expression of a number of genes. There is a fall in prodynorphin mRNA levels with a corresponding increase in proenkephalin mRNA levels. Similar changes in opioid gene expression occur following the induction of long-term potentiation (LTP). We report here that at short time periods (1-6 h) after injections of NMDA or sin-1 molsidomine, there is an increase in the levels of the mRNA encoding the alpha subunit of Ca2+/calmodulin-dependent protein kinase II (CaMKII alpha), consistent with a report of elevated CaMKII alpha mRNA in postsynaptic neurons in the CA1 region of the hippocampus following LTP induction [54]. However, we also report that 24 h after injection of NMDA or sin-1, there is a dramatic decrease in CaMKII alpha mRNA levels in the vicinity of the injection. This effect is specific for CaMKII alpha mRNA, in that many other mRNA species are not affected, and occurs in the dendritic population of CaMKII alpha mRNA as well as in the pool of mRNA in the granule cell bodies. The effect is blocked by an inhibitor of cGMP-dependent protein kinase. The biphasic regulation of CaMKII alpha mRNA may be of considerable functional importance for the long-term response of granule cells to local stimulation of NMDA receptors or NO release.
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PMID:N-methyl-D-aspartate and nitric oxide regulate the expression of calcium/calmodulin-dependent kinase II in the hippocampal dentate gyrus. 747 22

Phospholamban (PLB), the regulator of the cardiac sarcoplasmic reticulum (SR) Ca2+ pump is specifically phosphorylated at Ser16 and Thr17 by cAMP-dependent protein kinase (PKA) and Ca2+/calmodulin-dependent protein kinase (CaMK), respectively. The regulation of this dual-site phosphorylation of amino acid residues in direct proximity is only poorly understood. In order to study the site-specific phosphorylation of PLB, we used a synthetic peptide (PLB-24) corresponding to the cytosolic part of the PLB monomer with the phosphorylation sites as a model substrate. PLB-24 possesses substrate properties as the native PLB as demonstrated by phosphorylation with exogenous, purified PKA, cGMP-dependent protein kinase (PKG) and a type II CaMK (CaMKII). In isolated vesicles of cardiac SR there was a rapid phosphorylation of the peptide by the endogenous PKA (SR-PKA) and CaMK (SR-CaMK), but not under conditions that activate PKG. Both SR-PKA and SR-CaMK incorporated the same amount of 32P into PLB-24, 0.60 +/- 0.01 nmol 32P/mg SR protein and 0.61 +/- 0.03 nmol 32P/mg SR protein, respectively. Phosphorylation by SR-PKA was abolished by the specific PKA inhibitor (IC50 = 0.2 microM), whereas SR-CaMK phosphorylation was inhibited by calmidazolium (IC50 = 1.6 microM) and a CaMKII-specific inhibitor peptide (IC50 = 2.5 microM). Phosphorylation by SR-PKA was exclusively at Ser, whereas SR-CaMK phosphorylated only Thr. After simultaneous activation of both SR-kinases 32P incorporation into PLB-24 was additive and occurred at Ser as well as at Thr. Sequential activation of SR-PKA and SR-CaMK also caused the additive phosphorylation of PLB-24 independently of which kinase was activated first. Thus, at the monomeric level of PLB the respective phosphorylation site appears to be accessible to its related SR protein kinase in vitro even when the adjacent site is phosphorylated.
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PMID:Site-specific phosphorylation of a phospholamban peptide by cyclic nucleotide- and Ca2+/calmodulin-dependent protein kinases of cardiac sarcoplasmic reticulum. 920 42

The unitary postsynaptic mechanism of plasticity in striatum, neocortex, hippocampus and cerebellum involves the LTP/LTD excitation as result of AMPA and NMDA receptor phosphorylation/dephosphorylation, while the LTP/LTD of inhibition is the result of the GABA receptor phosphorylation/dephosphorylation. It follows from this mechanism that when NMDA channels are closed, the determinant role in receptor phosphorylation is played by the PKG. When the NMDA channels are open, the determinant role in receptor phosphorylation is played by the PKC and CaMKII.
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PMID:[Unified postsynaptic mechanism of plasticity in the striatum, neocortex, hippocampus, and cerebellum]. 1088 14

It is pointed out that Ca(2+)-dependent modification rules for NMDA-dependent (NMDA-independent) synaptic plasticity in the striatum are similar to those in the neocortex and hippocampus (cerebellum). A unitary postsynaptic mechanism of synaptic modification is proposed. It is based on the assumption that, in diverse central nervous system structures, long-term potentiation/depression (LTP/LTD) of excitatory transmission (depression/potentiation of inhibitory transmission, LTDi/LTPi) is the result of an increasing/decreasing the number of phosphorylated AMPA and NMDA (GABA(A)) receptors. According to the suggested mechanism, Ca(2+)/calmodulin-dependent protein kinase II and protein kinase C, whose activity is positively correlated with Ca(2+) enlargement, together with cAMP-dependent protein kinase A (cGMP-dependent protein kinase G, whose activity is negatively correlated with Ca(2+) rise) mainly phosphorylate ionotropic striatal receptors, if NMDA channels are opened (closed). Therefore, the positive/negative post-tetanic Ca(2+) shift in relation to a previous Ca(2+) rise must cause NMDA-dependent LTP+LTDi/LTD+LTPi or NMDA-independent LTD+LTPi/LTP+LTDi. Dopamine D(1)/D(2) or adenosine A(2A)/A(1) receptor activation must facilitate LTP+LTDi/LTD+LTPi due to an augmenting/lowering PKA activity. Activation of muscarinic M(1)/M(4) receptors must enhance LTP+LTDi/LTD+LTPi as a consequence of an increase/decrease in the activity of protein kinase C/A. The proposed mechanism is in agreement with known experimental data.
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PMID:The cortico-basal ganglia-thalamocortical circuit with synaptic plasticity. I. Modification rules for excitatory and inhibitory synapses in the striatum. 1108 40

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. While a growing body of literature indicates that postsynaptic GABA receptors are regulated by phosphorylation, there is discrepancy as to the specific effects of phosphorylation on GABA receptor function. Here, we have identified phosphorylation sites on the human rho1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP-dependent protein kinase (PKA); calmodulin-dependent kinase (CaMKII); casein kinase (CKII); mitogen-activated protein kinase (MAPK); and cGMP-dependent protein kinase (PKG). We demonstrate that in nearly all cases, the consensus sites and actual phosphorylation sites do not agree supporting the risk of relying on a sequence analysis to identify potential phosphorylation sites. In addition, of the six kinases examined, only CKII phosphorylated the human rho2 subunit. Site-directed mutagenesis of the phosphorylation sites, or activation/inhibition of select kinase pathways, did not alter the receptor sensitivity or maximal GABA-activated current of the rho1 GABA receptor expressed in Xenopus laevis oocytes suggesting phosphorylation of rho1 does not directly alter receptor properties. This study is a first and necessary step towards elucidating the regulation of rho1 GABA receptors by phosphorylation.
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PMID:Phosphorylation of the recombinant rho1 GABA receptor. 1217 59

The regulation of adenosine kinase (AK) activity has the potential to control intracellular and interstitial adenosine (Ado) concentrations. In an effort to study the role of AK in Ado homeostasis in the central nervous system, two isoforms of the enzyme were cloned from a mouse brain cDNA library. Following overexpression in bacterial cells, the corresponding proteins were purified to homogeneity. Both isoforms were enzymatically active and found to possess K(m) and V(max) values in agreement with kinetic parameters described for other forms of AK. The distribution of AK in discrete brain regions and various peripheral tissues was defined. To investigate the possibility that AK activity is regulated by protein phosphorylation, a panel of protein kinases was screened for ability to phosphorylate recombinant mouse AK. Data from these in vitro phosphorylation studies suggest that AK is most likely not an efficient substrate for PKA, PKG, CaMKII, CK1, CK2, MAPK, Cdk1, or Cdk5. PKC was found to phosphorylate recombinant AK efficiently in vitro. Further analysis revealed, however, that this PKC-dependent phosphorylation occurred at one or more serine residues associated with the N-terminal affinity tag used for protein purification.
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PMID:Molecular characterization of recombinant mouse adenosine kinase and evaluation as a target for protein phosphorylation. 1531 90

Hexahydro-1-(isoquinoline-5-sulfonyl)-1H-1,4-diazepine, HA-1077, is a known selective inhibitor of Rho-kinase. Although its IC(50) value against Rho-kinase is more than 10 times lower than those for kinases such as PKA, PKB, PKC, PKG, MLCK, CaMKII and others, the molecule still retains relative potent inhibition activities against these kinases. In order to produce highly specific Rho-kinase inhibitors, several HA-1077 analogs were synthesized and their kinase inhibition properties evaluated. (S)-Hexahydro-1-(4-ethenylisoquinoline-5-sulfonyl)-2-methyl-1H-1,4-diazepine was found to be a potent Rho-kinase inhibitor. The IC50 value against Rho-kinase was 6 nM, while those against other kinases remained at almost the same level as that of HA-1077. Furthermore, we designed HA-1077 analogs on the basis of the complex structure of PKA and HA-1077. Amongst these, (S)-hexahydro-4-glycyl-2-methyl-1-(4-methylisoquinoline-5-sulfonyl)-1H-1,4-diazepine and other glycine derivatives were found to be highly specific Rho-kinase inhibitors. These Rho-kinase specific inhibitors were applied to rabbit ocular hypertensive models and were shown to reduce intraocular pressure. These results demonstrate that the new 5-isoquinolinesulfonylamides are not only potent ROCK selective compounds, but are also useful compounds for clinical applications.
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PMID:Development of specific Rho-kinase inhibitors and their clinical application. 1621 95

Phosphorylation of the dopamine transporter (DAT) on N-terminal serines and unidentified threonines occurs concomitantly with protein kinase C (PKC)- and substrate-induced alterations in transporter activity, subcellular distribution, and dopamine efflux, but the residues phosphorylated and identities of protein kinases and phosphatases involved are not known. As one approach to investigating these issues, we recombinantly expressed the N-terminal tail of rat DAT (NDAT) and examined its phosphorylation and dephosphorylation properties in vitro. We found that NDAT could be phosphorylated to significant levels by PKCalpha, PKA, PKG, and CaMKII, which catalyzed serine phosphorylation, and ERK1, JNK, and p38, which catalyzed threonine phosphorylation. We identified Thr53, present in a membrane proximal proline-directed kinase motif as the NDAT site phosphorylated in vitro by ERK1, JNK and p38, and confirmed by peptide mapping and mutagenesis that Thr53 is phosphorylated in vivo. Dephosphorylation studies showed that protein phosphatase 1 catalyzed near-complete in vitro dephosphorylation of PKCalpha-phosphorylated NDAT, similar to its in vivo and in vitro effects on native DAT. These findings demonstrate the ability of multiple enzymes to directly recognize the DAT N-terminal domain and for kinases to act at multiple distinct sites. The strong correspondence between NDAT and rDAT phosphorylation characteristics suggests the potential for the enzymes that are active on NDAT in vitro to act on DAT in vivo and indicates the usefulness of NDAT for guiding future DAT phosphorylation analyses.
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PMID:Proline-directed phosphorylation of the dopamine transporter N-terminal domain. 1914 7

Cardiac atrial natriuretic peptide (ANP) locally counteracts cardiac hypertrophy via the guanylyl cyclase-A (GC-A) receptor and cGMP production, but the downstream signalling pathways are unknown. Here, we examined the influence of ANP on beta-adrenergic versus Angiotensin II (Ang II)-dependent (G(s) vs. G(alphaq) mediated) modulation of Ca(2+) (i)-handling in cardiomyocytes and of hypertrophy in intact hearts. L-type Ca(2+) currents and Ca(2+) (i) transients in adult isolated murine ventricular myocytes were studied by voltage-clamp recordings and fluorescence microscopy. ANP suppressed Ang II-stimulated Ca(2+) currents and transients, but had no effect on isoproterenol stimulation. Ang II suppression by ANP was abolished in cardiomyocytes of mice deficient in GC-A, in cyclic GMP-dependent protein kinase I (PKG I) or in the regulator of G protein signalling (RGS) 2, a target of PKG I. Cardiac hypertrophy in response to exogenous Ang II was significantly exacerbated in mice with conditional, cardiomyocyte-restricted GC-A deletion (CM GC-A KO). This was concomitant to increased activation of the Ca(2+)/calmodulin-dependent prohypertrophic signal transducer CaMKII. In contrast, beta-adrenoreceptor-induced hypertrophy was not enhanced in CM GC-A KO mice. Lastly, while the stimulatory effects of Ang II on Ca(2+)-handling were absent in myocytes of mice deficient in TRPC3/TRPC6, the effects of isoproterenol were unchanged. Our data demonstrate a direct myocardial role for ANP/GC-A/cGMP to antagonize the Ca(2+) (i)-dependent hypertrophic growth response to Ang II, but not to beta-adrenergic stimulation. The selectivity of this interaction is determined by PKG I and RGS2-dependent modulation of Ang II/AT(1) signalling. Furthermore, they strengthen published observations in neonatal cardiomyocytes showing that TRPC3/TRPC6 channels are essential for Ang II, but not for beta-adrenergic Ca(2+) (i)-stimulation in adult myocytes.
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PMID:Novel insights into the mechanisms mediating the local antihypertrophic effects of cardiac atrial natriuretic peptide: role of cGMP-dependent protein kinase and RGS2. 2035 35

In vertebrate models of synaptic plasticity, signaling via the putative "retrograde messenger" nitric oxide (NO) has been hypothesized to serve as a critical link between functional and structural alterations at pre- and postsynaptic sites. In the present study, we show that auditory Pavlovian fear conditioning is associated with significant and long-lasting increases in the expression of the postsynaptically-localized protein GluR1 and the presynaptically-localized proteins synaptophysin and synapsin in the lateral amygdala (LA) within 24 hrs following training. Further, we show that rats given intra-LA infusion of either the NR2B-selective antagonist Ifenprodil, the NOS inhibitor 7-Ni, or the PKG inhibitor Rp-8-Br-PET-cGMPS exhibit significant decreases in training-induced expression of GluR1, synaptophysin, and synapsin immunoreactivity in the LA, while those rats infused with the PKG activator 8-Br-cGMP exhibit a significant increase in these proteins in the LA. In contrast, rats given intra-LA infusion of the NO scavenger c-PTIO exhibit a significant decrease in synapsin and synaptophysin expression in the LA, but no significant impairment in the expression of GluR1. Finally, we show that intra-LA infusions of the ROCK inhibitor Y-27632 or the CaMKII inhibitor KN-93 impair training-induced expression of GluR1, synapsin, and synaptophysin in the LA. These findings suggest that the NO-cGMP-PKG, Rho/ROCK, and CaMKII signaling pathways regulate fear memory consolidation, in part, by promoting both pre- and post-synaptic alterations at LA synapses. They further suggest that synaptic plasticity in the LA during auditory fear conditioning promotes alterations at presynaptic sites via NO-driven "retrograde signaling".
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PMID:Synaptic plasticity and NO-cGMP-PKG signaling regulate pre- and postsynaptic alterations at rat lateral amygdala synapses following fear conditioning. 2057 37


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