Glutamate Receptor Agonists Stimulate Nitric Oxide Synthase in Primary Cultures of Cerebellar Granule Cells

Kiedrowski, Lech; Costa, E.; Wroblewski, Jarda T.

doi:10.1111/j.1471-4159.1992.tb09315.x

Cited by 235 publications

(104 citation statements)

References 44 publications

(51 reference statements)

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“…Stimulation of cerebellar granule cells with NMDA leads not only to AP-I induction [18] but also to the activation of NO production [21]. Thus, NO produced intracellularly could cause fine modulation of AP-1 activity in vivo through unknown intermediate carriers, the functions of which might be mimicked by SNP and DTT in vitro.…”

Section: Resultsmentioning

confidence: 99%

Modulation of AP‐1 activity by nitric oxide (NO) in vitro: NO‐mediated modulation of AP‐1

et al. 1994

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To understand the role of nitric oxide (NO) in controlling the specific DNA-binding activities of transcriptional factors, we investigated the in vitro effect of the NO-donor sodium nitroprusside (SNP) on the AP-1 activity of cultured mouse cerebellar granule cells. A gel-mobility assay showed that SNP inhibited AP-1 activity in the presence, but not the absence of dithiothreitol (DTT). This DTT-dependent inhibition of AP-1 activity by SNP corresponded with the activation of the chemical reactivity of SNP with DTT, which can be monitored by the production of nitrite (NO;). In contrast, diamide, a typical sulfhydryl oxidizing agent, inhibited AP-I activity in the absence of DTT and its inhibitory effect was reversed competitively by DTT. Studies using structurally or functionally related analogues of SNP demonstrated that S-nitrosylation of the AP-1 moiety mediated by some NO-carriers but not by free NO, which can be produced by the chemical reaction of SNP with DTT, was responsible for the inhibition of AP-1 activity, suggesting NO-mediated regulation of the AP-1 transcriptional factor.

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Section: Resultsmentioning

confidence: 99%

Modulation of AP‐1 activity by nitric oxide (NO) in vitro: NO‐mediated modulation of AP‐1

et al. 1994

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“…A variety of cell types including endothelial cells [1,2], macropbages [3,4], and neurons [5,6] produce superoxide and nitric oxide. These species are free radical intermediates which react with each other in aqueous solution at an almost diffusion-controlled rate (k = 6.7 x 10 9 M -l"s -1) [7] to yield the peroxynitrite anion (Eqn.…”

Section: Introductionmentioning

confidence: 99%

Peroxynitrite‐mediated oxidation of albumin to the protein‐thiyl free radical

1994

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Nitric oxide reacts with superoxide to produce peroxynitrite, which may be an important mediator of oxidant-induced cellular injury. Here we report that peroxynitrite is able to oxidize a protein, bovine serum albumin (BSA), to the corresponding protein-thiyl free radical as demonstrated by electron pararnagnetic resonance (EPR)-spin-trapping experiments with both et-phenyl-N-tert-butyl nitrone (PBN) and 5,5-dimethyl-l-pyrroline-N-oxide (DMPO). BSA radical adduct yields increased with pH indicating peroxynitrite anion as its main forming agent. Reaction with peroxynitrite may be another aspect of the antioxidant action of albumin in extracellular fluids.

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“…Signaling by the calcium/calmodulin regulated neuronal nitric oxide synthase (nNOS) 1 in cerebellar neurons is activated by calcium influx through N-methyl-D-aspartic acid (NMDA) receptors (1,2), but nNOS is not efficiently stimulated by activation of non-NMDA receptors that also generate calcium influx (3). Therefore, a mechanism must exist to specifically couple NMDA receptor-mediated calcium influx to nNOS.…”

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confidence: 99%

PSD-95 Assembles a Ternary Complex with theN-Methyl-d-aspartic Acid Receptor and a Bivalent Neuronal NO Synthase PDZ Domain

Christopherson

Hillier

Lim

et al. 1999

Journal of Biological Chemistry

514

359

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Nitric oxide (NO) biosynthesis in cerebellum is preferentially activated by calcium influx through N-methyl-D-aspartate (NMDA)-type glutamate receptors, suggesting that there is a specific link between these receptors and neuronal NO synthase (nNOS). Here, we find that PSD-95 assembles a postsynaptic protein complex containing nNOS and NMDA receptors. Formation of this complex is mediated by the PDZ domains of PSD-95, which bind to the COOH termini of specific NMDA receptor subunits. In contrast, nNOS is recruited to this complex by a novel PDZ-PDZ interaction in which PSD-95 recognizes an internal motif adjacent to the consensus nNOS PDZ domain. This internal motif is a structured "pseudo-peptide" extension of the nNOS PDZ that interacts with the peptide-binding pocket of PSD-95 PDZ2. This asymmetric interaction leaves the peptidebinding pocket of the nNOS PDZ domain available to interact with additional COOH-terminal PDZ ligands. Accordingly, we find that the nNOS PDZ domain can bind PSD-95 PDZ2 and a COOH-terminal peptide simultaneously. This bivalent nature of the nNOS PDZ domain further expands the scope for assembly of protein networks by PDZ domains.Efficiency and specificity in cellular signaling cascades is often mediated by assembly of multiprotein transduction networks. Signaling by the calcium/calmodulin regulated neuronal nitric oxide synthase (nNOS) 1 in cerebellar neurons is activated by calcium influx through N-methyl-D-aspartic acid (NMDA) receptors (1, 2), but nNOS is not efficiently stimulated by activation of non-NMDA receptors that also generate calcium influx (3). Therefore, a mechanism must exist to specifically couple NMDA receptor-mediated calcium influx to nNOS.In addition to mediating neuronal functions, nNOS is also found in skeletal muscle, where nNOS localizes to the sarcolemma. Membrane association of nNOS in skeletal muscle is mediated by direct interaction with ␣1-syntrophin, a component of the dystrophin complex. Binding of nNOS to syntrophin occurs through direct interaction of PDZ protein motifs present near the NH 2 termini of both proteins (4). Mice lacking ␣1-syntrophin lose nNOS protein and enzyme activity from muscle membranes (5). Furthermore, patients with Duchenne muscular dystrophy and mdx mice that lack dystrophin evince a selective loss of nNOS from the sarcolemma (6).In neurons, nNOS is also associated with cell membranes. In a detailed ultrastructural analysis of primate visual cortex, nNOS immunoreactivity in spines was concentrated over thick postsynaptic specializations of plasma membranes, often in association with NMDA receptors (7). This synaptic localization of nNOS in brain may be mediated by association with the postsynaptic density protein, PSD-95. Like ␣1-syntrophin, PSD-95 binds directly to nNOS through a PDZ-PDZ interaction that involves the second PDZ domain of PSD-95 (4). Moreover, PSD-95 is a member of a larger family of postsynaptic density proteins (PSD-95/SAP-90, PSD-93/chapsyn-110, and SAP-102) that cluster NMDA receptors and may anchor these...

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Glutamate Receptor Agonists Stimulate Nitric Oxide Synthase in Primary Cultures of Cerebellar Granule Cells

Cited by 235 publications

References 44 publications

Modulation of AP‐1 activity by nitric oxide (NO) in vitro: NO‐mediated modulation of AP‐1

Modulation of AP‐1 activity by nitric oxide (NO) in vitro: NO‐mediated modulation of AP‐1

Peroxynitrite‐mediated oxidation of albumin to the protein‐thiyl free radical

PSD-95 Assembles a Ternary Complex with theN-Methyl-d-aspartic Acid Receptor and a Bivalent Neuronal NO Synthase PDZ Domain

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