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:2.7.11.11 (AMPK)
12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the striatum, stimulation of dopamine D2 receptors results in attenuation of glutamate responses. This effect is exerted in large part via negative regulation of AMPA glutamate receptors. Phosphorylation of the GluR1 subunit of the AMPA receptor has been proposed to play a critical role in the modulation of glutamate transmission, in striatal medium spiny neurons. Here, we have examined the effects of blockade of dopamine D2-like receptors on the phosphorylation of GluR1 at the cAMP-dependent protein kinase (PKA) site, Ser845, and at the protein kinase C and calcium/calmodulin-dependent protein kinase II site, Ser831. Administration of haloperidol, an antipsychotic drug with dopamine D2 receptor antagonistic properties, increases the phosphorylation of GluR1 at Ser845, without affecting phosphorylation at Ser831. The same effect is observed using eticlopride, a selective dopamine D2 receptor antagonist. In contrast, administration of the dopamine D2-like agonist, quinpirole, decreases GluR1 phosphorylation at Ser845. The increase in Ser845 phosphorylation produced by haloperidol is abolished in dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) knockout mice, or in mice in which the PKA phosphorylation site on DARPP-32 (i.e. Thr34) has been mutated (Thr34-->Ala mutant mice), and requires tonic activation of adenosine A2A receptors. These results demonstrate that dopamine D2 antagonists increase GluR1 phosphorylation at Ser845 by removing the inhibitory tone exerted by dopamine D2 receptors on the PKA/DARPP-32 cascade.
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PMID:Regulation of phosphorylation of the GluR1 AMPA receptor by dopamine D2 receptors. 1633 34

Cellular function involves the concerted action of signal transduction enzymes. Restriction of enzyme location contributes to the fidelity of each cellular response. A kinase-anchoring proteins (AKAPs) target the cAMP-dependent protein kinase and other signalling enzymes to defined subcellular locations. We have developed a new strategy that combines RNA interference of the endogenous protein and replacement with AKAP79/150 forms unable to anchor selected binding partners. Using this approach we show that AKAP79/150 coordinates different enzyme combinations to modulate the activity of two distinct neuronal ion channels: AMPA-type glutamate receptors and M-type potassium channels. Utilization of distinct enzyme combinations in this manner provides a means to expand the repertoire of cellular events that the same AKAP modulates.
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PMID:Contextual utilization of enzymes in discrete AKAP79/150 signalling complexes. 1646 Aug 36

Central to organization of signaling pathways are scaffolding, anchoring and adaptor proteins that mediate localized assembly of multi-protein complexes containing receptors, second messenger-generating enzymes, kinases, phosphatases, and substrates. At the postsynaptic density (PSD) of excitatory synapses, AMPA (AMPAR) and NMDA (NMDAR) glutamate receptors are linked to signaling proteins, the actin cytoskeleton, and synaptic adhesion molecules on dendritic spines through a network of scaffolding proteins that may play important roles regulating synaptic structure and receptor functions in synaptic plasticity underlying learning and memory. AMPARs are rapidly recruited to dendritic spines through NMDAR activation during induction of long-term potentiation (LTP) through pathways that also increase the size and F-actin content of spines. Phosphorylation of AMPAR-GluR1 subunits by the cAMP-dependent protein kinase (PKA) helps stabilize AMPARs recruited during LTP. In contrast, induction of long-term depression (LTD) leads to rapid calcineurin-protein phosphatase 2B (CaN) mediated dephosphorylation of PKA-phosphorylated GluR1 receptors, endocytic removal of AMPAR from synapses, and a reduction in spine size. However, mechanisms for coordinately regulating AMPAR localization, phosphorylation, and synaptic structure by PKA and CaN are not well understood. A kinase-anchoring protein (AKAP) 79/150 is a PKA- and CaN-anchoring protein that is linked to NMDARs and AMPARs through PSD-95 and SAP97 membrane-associated guanylate kinase (MAGUK) scaffolds. Importantly, disruption of PKA-anchoring in neurons and functional analysis of GluR1-MAGUK-AKAP79 complexes in heterologous cells suggests that AKAP79/150-anchored PKA and CaN may regulate AMPARs in LTD. In the work presented at the "First International Meeting on Anchored cAMP Signaling Pathways" (Berlin-Buch, Germany, October 15-16, 2005), we demonstrate that AKAP79/150 is targeted to dendritic spines by an N-terminal basic region that binds phosphatidylinositol-4,5-bisphosphate (PIP(2)), F-actin, and actin-linked cadherin adhesion molecules. Thus, anchoring of PKA and CaN as well as physical linkage of the AKAP to both cadherin-cytoskeletal and MAGUK-receptor complexes could play roles in coordinating changes in synaptic structure and receptor signaling functions underlying plasticity. Importantly, we provide evidence showing that NMDAR-CaN signaling pathways implicated in AMPAR regulation during LTD lead to a disruption of AKAP79/150 interactions with actin, MAGUKs, and cadherins and lead to a loss of the AKAP and anchored PKA from postsynapses. Our studies thus far indicate that this AKAP79/150 translocation depends on activation of CaN, F-actin reorganization, and possibly Ca(2+)-CaM binding to the N-terminal basic regions. Importantly, this tranlocation of the AKAP79/150-PKA complex from spines may shift the balance of PKA kinase and CaN/PP1 phosphatase activity at the postsynapse in favor of the phosphatases. This loss of PKA could then promote actions of CaN and PP1 during induction of LTD including maintaining AMPAR dephosphorylation, promoting AMPAR endocytosis, and preventing AMPAR recycling. Overall, these findings challenge the accepted notion that AKAPs are static anchors that position signaling proteins near fixed target substrates and instead suggest that AKAPs can function in more dynamic manners to regulate local signaling events.
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PMID:Regulation of neuronal PKA signaling through AKAP targeting dynamics. 1650 38

Inhibitor-1 becomes a potent inhibitor of protein phosphatase 1 when phosphorylated by cAMP-dependent protein kinase at Thr(35). Moreover, Ser(67) of inhibitor-1 serves as a substrate for cyclin-dependent kinase 5 in the brain. Here, we report that dephosphoinhibitor-1 but not phospho-Ser(67) inhibitor-1 was efficiently phosphorylated by protein kinase C at Ser(65) in vitro. In contrast, Ser(67) phosphorylation by cyclin-dependent kinase 5 was unaffected by phospho-Ser(65). Protein kinase C activation in striatal tissue resulted in the concomitant phosphorylation of inhibitor-1 at Ser(65) and Ser(67), but not Ser(65) alone. Selective pharmacological inhibition of protein phosphatase activity suggested that phospho-Ser(65) inhibitor-1 is dephosphorylated by protein phosphatase 1 in the striatum. In vitro studies confirmed these findings and suggested that phospho-Ser(67) protects phospho-Ser(65) inhibitor-1 from dephosphorylation by protein phosphatase 1 in vivo. Activation of group I metabotropic glutamate receptors resulted in the up-regulation of diphospho-Ser(65)/Ser(67) inhibitor-1 in this tissue. In contrast, the activation of N-methyl-d-aspartate-type ionotropic glutamate receptors opposed increases in striatal diphospho-Ser(65)/Ser(67) inhibitor-1 levels. Phosphomimetic mutation of Ser(65) and/or Ser(67) did not convert inhibitor-1 into a protein phosphatase 1 inhibitor. On the other hand, in vitro and in vivo studies suggested that diphospho-Ser(65)/Ser(67) inhibitor-1 is a poor substrate for cAMP-dependent protein kinase. These observations extend earlier studies regarding the function of phospho-Ser(67) and underscore the possibility that phosphorylation in this region of inhibitor-1 by multiple protein kinases may serve as an integrative signaling mechanism that governs the responsiveness of inhibitor-1 to cAMP-dependent protein kinase activation.
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PMID:Phosphorylation of protein phosphatase inhibitor-1 by protein kinase C. 1677 99

Integration of neurotransmitter and neuromodulator signals in the striatum plays a central role in the functions and dysfunctions of the basal ganglia. DARPP-32 is a key actor of this integration in the GABAergic medium-size spiny neurons, in particular in response to dopamine and glutamate. When phosphorylated by cAMP-dependent protein kinase (PKA), DARPP-32 inhibits protein phosphatase-1 (PP1), whereas when phosphorylated by cyclin-dependent kinase 5 (CDK5) it inhibits PKA. DARPP-32 is also regulated by casein kinases and by several protein phosphatases. These complex and intricate regulations make simple predictions of DARPP-32 dynamic behaviour virtually impossible. We used detailed quantitative modelling of the regulation of DARPP-32 phosphorylation to improve our understanding of its function. The models included all the combinations of the three best-characterized phosphorylation sites of DARPP-32, their regulation by kinases and phosphatases, and the regulation of those enzymes by cAMP and Ca(2+) signals. Dynamic simulations allowed us to observe the temporal relationships between cAMP and Ca(2+) signals. We confirmed that the proposed regulation of protein phosphatase-2A (PP2A) by calcium can account for the observed decrease of Threonine 75 phosphorylation upon glutamate receptor activation. DARPP-32 is not simply a switch between PP1-inhibiting and PKA-inhibiting states. Sensitivity analysis showed that CDK5 activity is a major regulator of the response, as previously suggested. Conversely, the strength of the regulation of PP2A by PKA or by calcium had little effect on the PP1-inhibiting function of DARPP-32 in these conditions. The simulations showed that DARPP-32 is not only a robust signal integrator, but that its response also depends on the delay between cAMP and calcium signals affecting the response to the latter. This integration did not depend on the concentration of DARPP-32, while the absolute effect on PP1 varied linearly. In silico mutants showed that Ser137 phosphorylation affects the influence of the delay between dopamine and glutamate, and that constitutive phosphorylation in Ser137 transforms DARPP-32 in a quasi-irreversible switch. This work is a first attempt to better understand the complex interactions between cAMP and Ca(2+) regulation of DARPP-32. Progressive inclusion of additional components should lead to a realistic model of signalling networks underlying the function of striatal neurons.
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PMID:DARPP-32 is a robust integrator of dopamine and glutamate signals. 1719 17

Extracellular signal-regulated kinase (ERK) is activated in vivo in a number of brain areas by nicotine and other drugs of abuse. Here we show that nicotine stimulation of cultured mouse cortical neurons leads to a robust induction of ERK phosphorylation that is dependent on nicotine concentration and duration of exposure. Calcium/calmodulin-dependent protein kinase II activity is necessary for nicotine-induced ERK phosphorylation and neither cAMP-dependent protein kinase or protein kinase C appear to be involved. Activity of glutamate receptors, L-type voltage-gated calcium channels, and voltage-gated sodium channels are also required for nicotine-induced ERK phosphorylation. Nicotine-induced ERK phosphorylation was inhibited by high concentrations of mecamylamine, however it was not blocked by other broad nicotinic acetylcholine receptor (nAChR) inhibitors (including hexamethonium and chlorisondamine) or nAChR subtype selective inhibitors (such as methyllycaconitine, alpha-bungarotoxin, dihydro-beta-erythroidine, and alpha-conotoxin Au1B). In accord with these pharmacological results, nicotine-induced ERK phosphorylation was normal in primary cultures made from beta2 or alpha7 nAChR subunit knockout mice. The alpha3/beta4 nAChR agonist cytisine did not induce ERK phosphorylation suggesting that alpha3/beta4 nAChRs were not involved in this process. Taken together, these data define a necessary role for glutamatergic signaling and calcium/calmodulin-dependent protein kinase II in nicotine-induced ERK phosphorylation in cortical neurons and do not provide evidence for the involvement of classical nAChRs.
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PMID:Nicotine-induced phosphorylation of ERK in mouse primary cortical neurons: evidence for involvement of glutamatergic signaling and CaMKII. 1766 46

We investigated the role of endogenous protein kinase activity on synaptic transmission in the rat nucleus accumbens slice. The isoquinolinesulfonamide H-7 (50muM), a non-selective serine/threonine protein kinase inhibitor, had no effect on pharmacologically isolated glutamatergic EPSCs. However, it reduced GABA release in a dose-dependent manner. This effect of H-7 was not mimicked by the selective cAMP-dependent protein kinase inhibitor H-89, the PKC inhibitor Bisindolylmaleimide-1, or the cGMP-dependent protein kinase inhibitor KT5823. However, bath application of the myosin light chain kinase (MLCK) inhibitor, ML-7, significantly reduced IPSC amplitudes and partially occluded the reduction in IPSCs observed following bath application of H-7. These results suggest that endogenous protein kinase activity, specifically MLCK activity, regulates GABA, but not glutamate release, onto medium spiny neurons in the nucleus accumbens.
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PMID:Protein kinase inhibitors reduce GABA but not glutamate release in the nucleus accumbens. 1796 9

Norepinephrine exerts an important influence on prefrontal cortical functions. The physiological effects of beta-adrenoceptors (beta-ARs) have been examined in other brain regions. However, little is known about beta-AR regulation of synaptic transmission in the prefrontal cortex (PFC). The present study investigated beta-AR modulation of glutamate synaptic transmission in layer V/VI pyramidal cells of the medial PFC (mPFC) of rats. Our results show that 1) isoproterenol (ISO), a selective beta-AR agonist, increased the frequency of spontaneous and miniature excitatory postsynaptic currents (EPSC's); 2) ISO enhancement of miniature EPSC's (mEPSC's) frequency no longer appeared in the presence of the voltage-gated Ca(2+) channel blocker cadmium; 3) ISO enhanced the evoked excitatory postsynaptic currents (eEPSC's) mediated by non-N-methyl-D-aspartic acid receptors (non-NMDA-Rs) and NMDA-Rs. The ISO facilitation of non-NMDA-R eEPSC was blocked by the membrane-permeable cyclic adenosine monophosphate (cAMP) inhibitor Rp-adenosine 3',5'-cyclic monophosphorothioate triethylammonium salt (Rp-cAMPS); 4) ISO enhanced NMDA-induced current, with no effect on glutamate-induced non-NMDA-R current; 5) ISO enhancement of NMDA-R eEPSC and NMDA-induced current was blocked by intracellular application of Rp-cAMPS or the cAMP-dependent protein kinase (PKA) inhibitor PKI(5-24); and 6) ISO suppressed the paired-pulse facilitation of non-NMDA-R and NMDA-R eEPSC's. Taken together, these results provide the first electrophysiological demonstration that beta-AR activation facilitates excitatory synaptic transmission in mPFC pyramidal cells through pre- and postsynaptic mechanisms, probably via cAMP or cAMP/PKA signaling.
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PMID:Pre- and postsynaptic beta-adrenergic activation enhances excitatory synaptic transmission in layer V/VI pyramidal neurons of the medial prefrontal cortex of rats. 1796 26

N-Methyl-D-aspartate receptor (NMDAR)-mediated synaptic responses in hippocampal CA1 pyramidal cells are depressed during NMDAR-dependent long-term depression (LTD) due to mechanisms, in part, distinct from those underlying LTD of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic responses. The mechanisms underlying dedepression of synaptic NMDARs, however, are not known. We find that dedepression of NMDAR-mediated synaptic responses in the CA1 region of the rat hippocampus is input specific and does not require synaptic stimulation to be maintained. The induction of dedepression does not require activation of metabotropic glutamate receptors, L-type Ca(2+) channels, or release of Ca(2+) from intracellular stores. It does, however, rely on activation of NMDARs. In contrast to the dedepression of AMPAR-mediated synaptic responses, dedepression of NMDAR-mediated synaptic responses does not depend on activation of calcium/calmodulin-dependent protein kinase II, protein kinase C, cAMP-dependent protein kinase, or Src kinases. However, dedepression of synaptic NMDARs is significantly impaired by inhibitors of mitogen-activated protein kinase signaling. Specifically, inhibitors of extracellular signal-regulated kinase 1/2 prevented normal dedepression of synaptic NMDARs by a mechanism that did not require protein synthesis. These results provide further evidence that synaptic NMDARs can be bidirectionally modified by activity but by mechanisms distinct from those responsible for the activity-dependent, bidirectional modulation of synaptic AMPARs.
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PMID:Mechanisms underlying dedepression of synaptic NMDA receptors in the hippocampus. 1798 41

Dihydropyrimidinase-like 3 (DPYSL3) is believed to play a role in neuronal differentiation, axonal outgrowth and neuronal regeneration, as well as cytoskeleton organization. Recently we have shown that glutamate excitotoxicity and oxidative stress result in calpain-dependent cleavage of DPYSL3, and that NOS plays a role in this process [R. Kowara, Q. Chen, M. Milliken, B. Chakravarthy, Calpain-mediated truncation of dihydropyrimidinase-like 3 protein (DPYSL3) in response to NMDA and H2O2 toxicity, J. Neurochem. 95 (2005) 466-474; R. Kowara, K.L. Moraleja, B. Chakravarthy, Involvement of nitric oxide synthase and ROS-mediated activation of L-type voltage-gated Ca(2+) channels in NMDA-induced DPYSL3 degradation, Brain Res. 1119 (2006) 40-49]. The present study investigates the involvement of PLA(2) signaling in NMDA-induced DPYSL3 degradation. Exposure of rat primary cortical neurons (PCN) to PLA(2) and COX-2 inhibitors significantly prevented NMDA-induced DPYSL3 degradation. Since the metabolic product of PLA(2) signaling, PGE(2), which augments toxic effect of NMDA, is known to stimulate cAMP, the effect of adenyl cyclase activator (forskolin plus IBMX) and inhibitor (MDL12,300) on NMDA-induced DPYSL3 degradation was tested. Our data indicate that the activation of adenyl cyclase contributes to NMDA-induced DPYSL3 degradation. Furthermore, cAMP-dependent protein kinase (PKA) inhibitor PKI (14-22) provided additional evidence of PKA involvement in NMDA-induced DPYSL3 degradation. In summary, the obtained data show the contribution of PLA(2) signaling to NMDA-induced calpain activation and subsequent degradation of synaptic protein DPYSL3.
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PMID:PLA(2) signaling is involved in calpain-mediated degradation of synaptic dihydropyrimidinase-like 3 protein in response to NMDA excitotoxicity. 1805 48


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