The synthesis of ATP by glycolytic enzymes in the postsynaptic density and the effect of endogenously generated nitric oxide

Wu, Kuang‐Chong; Aoki, Chiye; Elste, Alice; Rogalski-Wilk, Adrienne A.; Siekevitz, Philip

doi:10.1073/pnas.94.24.13273

Cited by 109 publications

(95 citation statements)

References 75 publications

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“…glyceraldehyde-3-phosphate dehydrogenase, triosephosphate isomerase, phosphoglycerate mutase-1, and fructose-bisphosphate aldolase A. This is in agreement with a previous study, which demonstrated by immunoelectron microscopy the presence of glyceraldehyde-3-phosphate dehydrogenase in the dendritic spine and PSD (80). It was postulated that these proteins provide immediate availability of glycolytic source of ATP to the synapse.…”

Section: Discussionsupporting

confidence: 81%

Proteomics Analysis of Rat Brain Postsynaptic Density

Hornshaw

Schors

et al. 2004

Journal of Biological Chemistry

235

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The postsynaptic density contains multiple protein complexes that together relay the presynaptic neurotransmitter input to the activation of the postsynaptic neuron. In the present study we took two independent proteome approaches for the characterization of the protein complement of the postsynaptic density, namely 1) two-dimensional gel electrophoresis separation of proteins in conjunction with mass spectrometry to identify the tryptic peptides of the protein spots and 2) isolation of the trypsin-digested sample that was labeled with isotope-coded affinity tag, followed by liquid chromatography-tandem mass spectrometry for the partial separation and identification of the peptides, respectively. Functional grouping of the identified proteins indicates that the postsynaptic density is a structurally and functionally complex organelle that may be involved in a broad range of synaptic activities. These proteins include the receptors and ion channels for glutamate neurotransmission, proteins for maintenance and modulation of synaptic architecture, sorting and trafficking of membrane proteins, generation of anaerobic energy, scaffolding and signaling, local protein synthesis, and correct protein folding and breakdown of synaptic proteins. Together, these results imply that the postsynaptic density may have the ability to function (semi-) autonomously and may direct various cellular functions in order to integrate synaptic physiology.The majority of excitatory neurotransmission in the brain occurs via glutamatergic synapses. In the presynaptic element of the synapse, specialized secretion machinery determines the activity-dependent membrane fusion of glutamate-containing vesicles and the release of transmitter into the synaptic cleft. In the postsynaptic element, glutamate receptors and downstream signal transduction are organized by the protein assembly of the postsynaptic density (PSD). 1 Both the presynaptic release machinery and the PSD are electron-dense assemblies (1, 2), in which proteins are thought to be organized into distinct functional complexes (3-5) that may be dynamically regulated by neuronal activity (6 -8). The modulation of this molecular architecture of the synapse is at the basis of synaptic plasticity (6 -8), and aberrations thereof may underlie neuronal disorders.In view of the importance of the PSD in glutamatergic neurotransmission and its involvement in neuroplasticity, considerable efforts have been made to identify its protein constituents as a prelude to understand the molecular basis of PSD functioning. In the past several years, yeast two-hybrid technology has been extensively used to characterize proteins that interact with the glutamate receptors and may constitute core elements of the PSD involved in the regulation of receptor trafficking and signaling (reviewed in Refs. 9 -11). Based largely on these studies a protein-protein interaction map of the PSD has emerged. In brief, the model posits that the postsynaptic receptor complexes are localized by scaffolding proteins such as the s...

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Section: Discussionsupporting

confidence: 81%

Proteomics Analysis of Rat Brain Postsynaptic Density

Hornshaw

Schors

et al. 2004

Journal of Biological Chemistry

235

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“…It has been suggested (Raffin et al, 1992;Rosenthal and Sick, 1992) that the plasma membrane Na ϩ /K ϩ -ATPase is preferentially fueled by ATP produced from glycolysis (although it is unclear why mitochondrially produced ATP cannot diffuse to plasma membrane Na ϩ pumps, and an increase in glycolytic rate via the Pasteur effect might explain why mitochondrial block has relatively little effect). Consistent with a metabolic compartmentation within cells in which glycolysis powers ion pumping, glycolytic enzymes have been detected in synaptic locations where energy use on ion pumping is high (Wu et al, 1997;Ikemoto et al, 2003). This could explain why fueling glycolysis with glucose while blocking mitochondria prevents an AD; glycolytic ATP might allow the Na ϩ /K ϩ -ATPase to function sufficiently to maintain transmembrane ion gradients.…”

Section: Metabolic Compartmentationmentioning

confidence: 60%

A Preferential Role for Glycolysis in Preventing the Anoxic Depolarization of Rat Hippocampal Area CA1 Pyramidal Cells

Allen

Káradóttir²,

Attwell³

2005

J. Neurosci.

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During brain anoxia or ischemia, a decrease in the level of ATP leads to a sudden decrease in transmembrane ion gradients [anoxic depolarization (AD)]. This releases glutamate by reversing the operation of glutamate transporters, which triggers neuronal death. By whole-cell clamping CA1 pyramidal cells, we investigated the energy stores that delay the occurrence of the AD in hippocampal slices when O 2 and glucose are removed. With glycolytic and mitochondrial ATP production blocked in P12 slices, the AD occurred in ϳ7 min at 33°C, reflecting the time needed for metabolic activity to consume the existing ATP and phosphocreatine, and for subsequent ion gradient decrease. Allowing glycolysis fueled by glycogen, in the absence of glucose, delayed the AD by 5.5 min, whereas superfused glucose prevented the AD for Ͼ1 h. With glycolysis blocked, the latency to the AD was 6.5 min longer when mitochondria were allowed to function, demonstrating that metabolites downstream of glycolysis (pyruvate, citric acid cycle intermediates, and amino acid oxidation) provide a significant energy store for oxidative phosphorylation. With glycolysis blocked but mitochondria functioning, superfusing lactate did not significantly delay the AD, showing that ATP production from lactate is much less than that from endogenous metabolites. These data demonstrate a preferential role for glycolysis in preventing the AD. They also define a hierarchy of pool sizes for hippocampal energy stores and suggest that brain ATP production from glial lactate may not be significant in conditions of energy deprivation.

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“…Taken together, these findings indicate that ND2, but not the entire complex I, is normally present within the PSD. Many enzymes in the PSD may be involved in regulating synaptic function (39), including glycolytic enzymes capable of generating ATP (40). However, without the remaining components of complex I, it is unlikely that ND2 functions catalytically in the PSD.…”

Section: Discussionmentioning

confidence: 99%

Unique domain anchoring of Src to synaptic NMDA receptors via the mitochondrial protein NADH dehydrogenase subunit 2

Gingrich

Pelkey

Fam

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

116

115

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Src is the prototypic protein tyrosine kinase and is critical for controlling diverse cellular functions. Regions in Src define structural and functional domains conserved in many cell signaling proteins. Src also contains a region of low sequence conservation termed the unique domain, the function of which has until now remained enigmatic. Here, we show that the unique domain of Src is a protein–protein interaction region and we identify NADH dehydrogenase subunit 2 (ND2) as a Src unique domain-interacting protein. ND2 is a subunit of complex I in mitochondria, but we find that ND2 interacts with Src outside this organelle at excitatory synapses in the brain. ND2 acts as an adapter protein anchoring Src to the N-methyl-d-aspartate (NMDA) receptor complex, and is crucial for Src regulation of synaptic NMDA receptor activity. By showing an extramitochondrial action for a protein encoded in the mitochondrial genome, we identify a previously unsuspected means by which mitochondria regulate cellular function, suggesting a new paradigm that may be of general relevance for control of Src signaling

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The synthesis of ATP by glycolytic enzymes in the postsynaptic density and the effect of endogenously generated nitric oxide

Cited by 109 publications

References 75 publications

Proteomics Analysis of Rat Brain Postsynaptic Density

Proteomics Analysis of Rat Brain Postsynaptic Density

A Preferential Role for Glycolysis in Preventing the Anoxic Depolarization of Rat Hippocampal Area CA1 Pyramidal Cells

Unique domain anchoring of Src to synaptic NMDA receptors via the mitochondrial protein NADH dehydrogenase subunit 2

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