Journal article
Displacing hexokinase from mitochondrial voltage-dependent anion channel impairs GLT-1-mediated glutamate uptake but does not disrupt interactions between GLT-1 and mitochondrial proteins
Journal of neuroscience research, v 93(7), pp 999-1008
Jul 2015
PMID: 25546576
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The glutamate transporter GLT-1 is the major route for the clearance of extracellular glutamate in the forebrain, and most GLT-1 protein is found in astrocytes. This protein is coupled to the Na+ electrochemical gradient, supporting the active intracellular accumulation of glutamate. We recently used a proteomic approach to identify proteins that may interact with GLT-1 in rat cortex, including the Na+/K+-ATPase, most glycolytic enzymes, and several mitochondrial proteins. We also showed that most GLT-1 puncta (approximate to 70%) are overlapped by mitochondria in astroglial processes in organotypic slices. From this analysis, we proposed that the glycolytic enzyme hexokinase (HK)-1 might physically form a scaffold to link GLT-1 and mitochondria because HK1 is known to interact with the outer mitochondrial membrane protein voltage-dependent anion channel (VDAC). The current study validates the interactions among HK-1, VDAC, and GLT-1 by using forward and reverse immunoprecipitations and provides evidence that a subfraction of HK1 colocalizes with GLT-1 in vivo. A peptide known to disrupt the interaction between HK and VDAC did not disrupt interactions between GLT-1 and several mitochondrial proteins. In parallel experiments, displacement of HK from VDAC reduced GLT-1-mediated glutamate uptake. These results suggest that, although HK1 forms coimmunoprecipitatable complexes with both VDAC and GLT-1, it does not physically link GLT-1 to mitochondrial proteins. However, the interaction of HK1 with VDAC supports GLT-1-mediated transport activity. (c) 2014 Wiley Periodicals, Inc.
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Details
- Title
- Displacing hexokinase from mitochondrial voltage-dependent anion channel impairs GLT-1-mediated glutamate uptake but does not disrupt interactions between GLT-1 and mitochondrial proteins
- Creators
- Joshua G. Jackson - Children's Hospital of PhiladelphiaJohn C. O'Donnell - Childrens Hosp Philadelphia, Res Inst, Philadelphia, PA 19104 USAElizabeth Krizman - Children's Hospital of PhiladelphiaMichael B. Robinson - University of Pennsylvania
- Publication Details
- Journal of neuroscience research, v 93(7), pp 999-1008
- Publisher
- Wiley
- Number of pages
- 10
- Grant note
- T32GM008076 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R01NS077773 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) P30 HD26979 / Institutional Intellectual and Developmental Disabilities Research Center RO1 NS077773 / NINDS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) P30HD026979 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) T32 GM008076; F31 NS086255; T32 NS007413 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000354822900003
- Scopus ID
- 2-s2.0-84929656077
- Other Identifier
- 991021900193904721
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- Web of Science research areas
- Neurosciences