A Role for Endothelial NO Synthase in LTP Revealed by Adenovirus-Mediated Inhibition and Rescue

Kantor, David; Lanzrein, Markus; Stary, Susanne; Sandoval, Gisela M.; Smith, W. Bryan; Sullivan, Brian M.; Davidson, Norman; Schuman, Erin M.

doi:10.1126/science.274.5293.1744

Cited by 239 publications

(109 citation statements)

References 19 publications

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“…Our studies suggest that uninjured iNOS -/-mice perform normally in motor and spatial memory acquisition tasks compared with wild-type mice. This argues against an essential role for iNOS in the events involved in completing these behavioral tasks, as was seen for eNOS in long-term potentiation (46)(47)(48), and argues strongly against a nonspecific functional deficit in our mutant mice (49).…”

Section: Figurementioning

confidence: 91%

Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice

et al. 1999

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Section: Figurementioning

confidence: 91%

Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice

et al. 1999

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“…lial NOS (eNOS) is localized to the membrane by myristolation (Busconi and Michel, 1993), whereas neural NOS (nNOS) can be linked to the NMDA receptor by postsynaptic density-95 (Brenman et al, 1996). Previous studies have implicated both eNOS (Kantor et al, 1996;Haul et al, 1999) and nNOS (Son et al, 1996) in LTP. Recent evidence from cultured hippocampal cells has also shown that NO may have both presynaptic and postsynaptic effects (Wang et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

The Role of Nitric Oxide and GluR1 in Presynaptic and Postsynaptic Components of Neocortical Potentiation

2006

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In this study, we investigated the mechanisms underlying synaptic plasticity at the layer IV to II/III pathway in barrel cortex of mice aged 6 -13 weeks. This pathway is one of the likely candidates for expression of experience-dependent plasticity in the barrel cortex and may serve as a model for other IV to II/III synapses in the neocortex. We found that postsynaptic autocamtide-2-inhibitory peptide is sufficient to block long-term potentiation (LTP) (IC 50 of 500 nM), implicating postsynaptic calcium/calmodulin-dependent kinase II in LTP induction. AMPA receptor subunit 1 (GluR1) knock-out mice also showed LTP in this pathway, but potentiation was predominantly presynaptic in origin as determined by paired-pulse analysis, coefficient of variation analysis, and quantal analysis, whereas wild types showed a mixed presynaptic and postsynaptic locus. Quantal analysis at this synapse was validated by measuring uniquantal events in the presence of strontium. The predominantly presynaptic LTP in the GluR1 knock-outs was blocked by postsynaptic antagonism of nitric oxide synthase (NOS), either with intracellular N--nitro-L-arginine methyl ester or N-nitro-L-arginine, providing the first evidence for a retrograde transmitter role for NO at this synapse. Antagonism of NOS in wild types significantly reduced but did not eliminate LTP (group average reduction of 50%). The residual LTP formed a variable proportion of the total LTP in each cell and was found to be postsynaptic in origin. We found no evidence for silent synapses in this pathway at this age. Finally, application of NO via a donor induced potentiation in layer II/III cells and caused an increase in frequency but not amplitude of miniature EPSPs, again implicating NO in presynaptic plasticity.

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“…To facilitate purification of the protein using glutathione-Sepharose affinity chromatography, we used the bacterial expression vector pGEX-3X (Pharmacia) to construct a recombinant plasmid encoding a fusion protein between eNOS and GST. The fusion protein was designed such that the GST is located at the eNOS N terminus; this site was chosen because previously characterized eNOS fusion proteins involving the enzyme's N terminus appear to retain full activity (20). Indeed, the specific activity of the purified bacterially expressed GST-eNOS fusion protein averaged 50 nmol/min/mg protein (see Fig.…”

Section: Bacterial Expression Of Recombinant Enos and Inhibition Of Tmentioning

confidence: 99%

Caveolin versus Calmodulin

Michel¹,

Féron²,

Sase

et al. 1997

Journal of Biological Chemistry

277

105

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Nitric oxide is synthesized in diverse mammalian tissues by a family of calmodulin-dependent nitric oxide synthases. The endothelial isoform of nitric oxide synthase (eNOS) is targeted to the specialized signal-transducing membrane domains termed plasmalemmal caveolae. Caveolin, the principal structural protein in caveolae, interacts with eNOS and leads to enzyme inhibition in a reversible process modulated by Ca 2؉ -calmodulin (Michel, J. B., Feron, O., Sacks, D., and Michel, T. (1997) J. Biol. Chem. 272, 15583-15586). Caveolin also interacts with other structurally distinct signaling proteins via a specific region identified within the caveolin sequence (amino acids 82-101) that appears to subserve the role of a "scaffolding domain." We now report that the co-immunoprecipitation of eNOS with caveolin is completely and specifically blocked by an oligopeptide corresponding to the caveolin scaffolding domain. Peptides corresponding to this domain markedly inhibit nitric oxide synthase activity in endothelial membranes and interact directly with the enzyme to inhibit activity of purified recombinant eNOS expressed in Escherichia coli. The inhibition of purified eNOS by the caveolin scaffolding domain peptide is competitive and completely reversed by Ca 2؉ -calmodulin. These studies establish that caveolin, via its scaffolding domain, directly forms an inhibitory complex with eNOS and suggest that caveolin inhibits eNOS by abrogating the enzyme's activation by calmodulin.The mammalian nitric oxide (NO) 1 synthases comprise a family of three related proteins and modulate diverse biological processes ranging from neurotransmission to vascular homeostasis to immunological surveillance (1, 2). These homodimeric proteins share similar overall catalytic schemes to produce NO by the NADPH-, heme-, and O 2 -dependent oxidation of L-arginine in a complex reaction involving numerous redox cofactors, and are absolutely dependent on the ability of the enzymes to be allosterically activated by Ca 2ϩ -calmodulin. The roles of calmodulin in NOS catalysis have been extensively studied, and the binding of calmodulin appears to facilitate interdomain electron transfer for all three enzyme isoforms. However, the NOS isoforms differ in important aspects of their Ca 2ϩ -dependence for enzyme activation by calmodulin. For the endothelial and neuronal nitric oxide synthase isoforms (termed eNOS and nNOS, respectively), transient changes in intracellular Ca 2ϩ promote calmodulin binding and enzyme activation; eNOS and nNOS are characteristically activated as a short-term response to receptor-dependent calcium transients. By contrast, the inflammation-related NOS (iNOS) binds calmodulin avidly and appears to be fully active even at low ambient intracellular calcium levels in immunostimulated cells.The different NOS isoforms may also be distinguished by their subcellular distribution. eNOS is unique among the NOS isoforms in being targeted to the signal-transducing membrane microdomains termed plasmalemmal caveolae (3). Plasmalemmal caveola...

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A Role for Endothelial NO Synthase in LTP Revealed by Adenovirus-Mediated Inhibition and Rescue

Cited by 239 publications

References 19 publications

Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice

Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice

The Role of Nitric Oxide and GluR1 in Presynaptic and Postsynaptic Components of Neocortical Potentiation

Caveolin versus Calmodulin

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