PMID- 26152695
OWN - NLM
STAT- MEDLINE
DCOM- 20160418
LR  - 20181113
IS  - 1937-9145 (Electronic)
IS  - 1945-0877 (Linking)
VI  - 8
IP  - 384
DP  - 2015 Jul 7
TI  - Regulation of brain glutamate metabolism by nitric oxide and S-nitrosylation.
PG  - ra68
LID - 10.1126/scisignal.aaa4312 [doi]
AB  - Nitric oxide (NO) is a signaling intermediate during glutamatergic 
      neurotransmission in the central nervous system (CNS). NO signaling is in part 
      accomplished through cysteine S-nitrosylation, a posttranslational modification 
      by which NO regulates protein function and signaling. In our investigation of the 
      protein targets and functional impact of S-nitrosylation in the CNS under 
      physiological conditions, we identified 269 S-nitrosocysteine residues in 136 
      proteins in the wild-type mouse brain. The number of sites was significantly 
      reduced in the brains of mice lacking endothelial nitric oxide synthase 
      (eNOS(-/-)) or neuronal nitric oxide synthase (nNOS(-/-)). In particular, 
      nNOS(-/-) animals showed decreased S-nitrosylation of proteins that participate 
      in the glutamate/glutamine cycle, a metabolic process by which synaptic glutamate 
      is recycled or oxidized to provide energy. (15)N-glutamine-based metabolomic 
      profiling and enzymatic activity assays indicated that brain extracts from 
      nNOS(-/-) mice converted less glutamate to glutamine and oxidized more glutamate 
      than those from mice of the other genotypes. GLT1 [also known as EAAT2 
      (excitatory amino acid transporter 2)], a glutamate transporter in astrocytes, 
      was S-nitrosylated at Cys(373) and Cys(561) in wild-type and eNOS(-/-) mice, but 
      not in nNOS(-/-) mice. A form of rat GLT1 that could not be S-nitrosylated at the 
      equivalent sites had increased glutamate uptake compared to wild-type GLT1 in 
      cells exposed to an S-nitrosylating agent. Thus, NO modulates glutamatergic 
      neurotransmission through the selective, nNOS-dependent S-nitrosylation of 
      proteins that govern glutamate transport and metabolism.
CI  - Copyright (c) 2015, American Association for the Advancement of Science.
FAU - Raju, Karthik
AU  - Raju K
AD  - Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, 
      USA.
FAU - Doulias, Paschalis-Thomas
AU  - Doulias PT
AD  - Division of Neonatology, Department of Pediatrics, Children's Hospital of 
      Philadelphia Research Institute, Philadelphia, PA 19104, USA.
FAU - Evans, Perry
AU  - Evans P
AD  - Department of Biomedical and Health Informatics, Children's Hospital of 
      Philadelphia Research Institute, Philadelphia, PA 19104, USA.
FAU - Krizman, Elizabeth N
AU  - Krizman EN
AD  - Division of Neurology, Department of Pediatrics, Children's Hospital of 
      Philadelphia Research Institute, Philadelphia, PA 19104, USA.
FAU - Jackson, Joshua G
AU  - Jackson JG
AD  - Division of Neurology, Department of Pediatrics, Children's Hospital of 
      Philadelphia Research Institute, Philadelphia, PA 19104, USA.
FAU - Horyn, Oksana
AU  - Horyn O
AD  - Division of Genetic and Metabolic Disease, Department of Pediatrics, Children's 
      Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA.
FAU - Daikhin, Yevgeny
AU  - Daikhin Y
AD  - Division of Genetic and Metabolic Disease, Department of Pediatrics, Children's 
      Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA.
FAU - Nissim, Ilana
AU  - Nissim I
AD  - Division of Genetic and Metabolic Disease, Department of Pediatrics, Children's 
      Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA.
FAU - Yudkoff, Marc
AU  - Yudkoff M
AD  - Division of Genetic and Metabolic Disease, Department of Pediatrics, Children's 
      Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA.
FAU - Nissim, Itzhak
AU  - Nissim I
AD  - Division of Genetic and Metabolic Disease, Department of Pediatrics, Children's 
      Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA. 
      Department of Biochemistry and Biophysics, University of Pennsylvania, 
      Philadelphia, PA 19104, USA.
FAU - Sharp, Kim A
AU  - Sharp KA
AD  - Department of Biochemistry and Biophysics, University of Pennsylvania, 
      Philadelphia, PA 19104, USA.
FAU - Robinson, Michael B
AU  - Robinson MB
AD  - Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, 
      USA. Division of Neurology, Department of Pediatrics, Children's Hospital of 
      Philadelphia Research Institute, Philadelphia, PA 19104, USA. Department of 
      Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, 
      Philadelphia, PA 19104, USA.
FAU - Ischiropoulos, Harry
AU  - Ischiropoulos H
AD  - Neuroscience Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, 
      USA. Division of Neonatology, Department of Pediatrics, Children's Hospital of 
      Philadelphia Research Institute, Philadelphia, PA 19104, USA. Department of 
      Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, 
      Philadelphia, PA 19104, USA. ischirop@mail.med.upenn.edu.
LA  - eng
GR  - R01-HL054926/HL/NHLBI NIH HHS/United States
GR  - DK-053761/DK/NIDDK NIH HHS/United States
GR  - R01-AG13966/AG/NIA NIH HHS/United States
GR  - R01 AG013966/AG/NIA NIH HHS/United States
GR  - P30 HD026979/HD/NICHD NIH HHS/United States
GR  - T32 AG000255/AG/NIA NIH HHS/United States
GR  - T32-AG000255/AG/NIA NIH HHS/United States
GR  - R01-NS077773/NS/NINDS NIH HHS/United States
GR  - R56 DK053761/DK/NIDDK NIH HHS/United States
GR  - T32 NS007413/NS/NINDS NIH HHS/United States
GR  - R01 DK053761/DK/NIDDK NIH HHS/United States
GR  - P30-HD026979/HD/NICHD NIH HHS/United States
GR  - R01 HL054926/HL/NHLBI NIH HHS/United States
GR  - P30 ES013508/ES/NIEHS NIH HHS/United States
GR  - R01 NS077773/NS/NINDS NIH HHS/United States
GR  - T32-NS007413/NS/NINDS NIH HHS/United States
GR  - P30-ES013508/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150707
PL  - United States
TA  - Sci Signal
JT  - Science signaling
JID - 101465400
RN  - 0 (Excitatory Amino Acid Transporter 2)
RN  - 0 (Proteome)
RN  - 0 (S-Nitrosothiols)
RN  - 0RH81L854J (Glutamine)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 926P2322P4 (S-nitrosocysteine)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type I)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - K848JZ4886 (Cysteine)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Blotting, Western
MH  - Brain/*metabolism
MH  - Chromatography, Liquid
MH  - Cysteine/analogs & derivatives/genetics/*metabolism
MH  - Excitatory Amino Acid Transporter 2/genetics/metabolism
MH  - Glutamic Acid/*metabolism
MH  - Glutamine/metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Nitric Oxide/*metabolism
MH  - Nitric Oxide Synthase Type I/genetics/metabolism
MH  - Nitric Oxide Synthase Type III/genetics/metabolism
MH  - Proteome/metabolism
MH  - Proteomics/methods
MH  - Rats
MH  - S-Nitrosothiols/metabolism
MH  - Tandem Mass Spectrometry
PMC - PMC4746709
MID - NIHMS756058
COIS- Competing interests: The authors declare that they have no competing interests.
EDAT- 2015/07/15 06:00
MHDA- 2016/04/19 06:00
PMCR- 2016/02/09
CRDT- 2015/07/09 06:00
PHST- 2015/07/09 06:00 [entrez]
PHST- 2015/07/15 06:00 [pubmed]
PHST- 2016/04/19 06:00 [medline]
PHST- 2016/02/09 00:00 [pmc-release]
AID - 8/384/ra68 [pii]
AID - 10.1126/scisignal.aaa4312 [doi]
PST - epublish
SO  - Sci Signal. 2015 Jul 7;8(384):ra68. doi: 10.1126/scisignal.aaa4312.