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J. Biol. Chem., Vol. 278, Issue 8, 5929-5940, February 21, 2003

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Glycolysis and Glutamate Accumulation into Synaptic Vesicles
ROLE OF GLYCERALDEHYDE PHOSPHATE DEHYDROGENASE AND 3-PHOSPHOGLYCERATE KINASE^*

Atsushi Ikemoto^§, David G. Bole, and Tetsufumi Ueda^¶**

From the  Mental Health Research Institute, Departments of ^¶ Pharmacology and  Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan 48109-0669

Glucose is the major source of brain energy and is essential for maintaining normal brain and neuronal function. Hypoglycemia causes impaired synaptic transmission. This occurs even before significant reduction in global cellular ATP concentration, and relationships among glycolysis, ATP supply, and synaptic transmission are not well understood. We demonstrate that the glycolytic enzymes glyceraldehyde phosphate dehydrogenase (GAPDH) and 3-phosphoglycerate kinase (3-PGK) are enriched in synaptic vesicles, forming a functional complex, and that synaptic vesicles are capable of accumulating the excitatory neurotransmitter glutamate by harnessing ATP produced by vesicle-bound GAPDH/3-PGK at the expense of their substrates. The GAPDH inhibitor iodoacetate suppressed GAPDH/3-PGK-dependent, but not exogenous ATP-dependent, [³H]glutamate uptake into isolated synaptic vesicles. It also decreased vesicular [³H]glutamate content in the nerve ending preparation synaptosome; this decrease was reflected in reduction of depolarization-induced [³H]glutamate release. In contrast, oligomycin, a mitochondrial ATP synthase inhibitor, had minimal effect on any of these parameters. ADP at concentrations above 0.1 mM inhibited vesicular glutamate and dissipated membrane potential. This suggests that the coupled GAPDH/3-PGK system, which converts ADP to ATP, ensures maximal glutamate accumulation into presynaptic vesicles. Together, these observations provide insight into the essential nature of glycolysis in sustaining normal synaptic transmission.

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