Journal article
Regulation of brain glutamate metabolism by nitric oxide and S-nitrosylation
Science signaling, v 8(384), pp ra68-ra68
07 Jul 2015
PMID: 26152695
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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. N-15-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.
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Details
- Title
- Regulation of brain glutamate metabolism by nitric oxide and S-nitrosylation
- Creators
- Karthik Raju - University of PennsylvaniaPaschalis-Thomas Doulias - Childrens Hosp Philadelphia, Res Inst, Dept Pediat, Div Neonatol, Philadelphia, PA 19104 USAPerry Evans - Children's Hospital of PhiladelphiaElizabeth N. Krizman - Children's Hospital of PhiladelphiaJoshua G. Jackson - Children's Hospital of PhiladelphiaOksana Horyn - Children's Hospital of PhiladelphiaYevgeny Daikhin - Children's Hospital of PhiladelphiaIlana Nissim - Children's Hospital of PhiladelphiaMarc Yudkoff - Children's Hospital of PhiladelphiaItzhak Nissim - Children's Hospital of PhiladelphiaKim A. Sharp - University of PennsylvaniaMichael B. Robinson - University of PennsylvaniaHarry Ischiropoulos - University of Pennsylvania
- Publication Details
- Science signaling, v 8(384), pp ra68-ra68
- Publisher
- Amer Assoc Advancement Science
- Number of pages
- 10
- Grant note
- T32-AG000255 / NIA training P30-ES013508 / National Institute of Environmental Health Sciences (NIEHS) Center of Excellence in Environmental Toxicology T32-NS007413 / National Institute of Neurological Disorders and Stroke (NINDS) training R01-NS077773 / NINDS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) DK-053761 / National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) R01-AG13966 / National Institute on Aging (NIA); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) P30-HD026979 / National Institute of Child Health and Human Development (NICHD) Intellectual and Developmental Disabilities Research Center (IDDRC) R01-HL054926 / National Heart, Lung, and Blood Institute (NHLBI); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000357617600002
- Scopus ID
- 2-s2.0-84936869077
- Other Identifier
- 991021900195504721
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- Web of Science research areas
- Biochemistry & Molecular Biology
- Cell Biology