Compartmentation of glutamate metabolism in brain. Evidence for the existence of two different tricarboxylic acid cycles in brain

Abstract

1. 14C from [1−14C]glucose injected intraperitoneally into mice is incorporated into glutamate, aspartate and glutamine in the brain to a much greater extent than 14C from [2−14C]glucose. This difference for [1−14C]glucose and [2−14C]glucose increases with time. The amount of 14C in C-1 of glutamate increases steadily with time with both precursors. It is suggested that a large part of the glutamate and aspartate pools in brain are in close contact with intermediates of a fast-turning tricarboxylic acid cycle. 2. 14C from [1−14C]acetate and [2−14C]acetate is incorporated to a much larger extent into glutamine than into glutamate. An examination of the time-course of 14C incorporated into glutamine and glutamate reveals that glutamine is not formed from the glutamate pool, labelled extensively by glucose, but from a small glutamate pool. This small glutamate pool is not derived from an intermediate of a fast-turning tricarboxylic acid cycle. 3. It is proposed that two different tricarboxylic acid cycles exist in brain.

Stimulation-Induced Increases of Astrocytic Oxidative Metabolism in Rats and Humans Investigated with 1-11C-Acetate

“…Already early studies of brain metabolism using 14 C-labeled precursors such as glucose or acetate led to the concept of two distinct tricarboxylic acid (TCA) cycle compartments, that is, two separate pools for glutamate and glutamine (Berl and Frigyesi, 1969;Cremer, 1970;Minchin and Beart, 1975;Van den Berg et al, 1969). Later histochemical work on the restricted localization of glutamine synthetase to glial cells (Martinez-Hernandez et al, 1977;Norenberg and Martinez-Hernandez, 1979) further supported the idea on the glial and neuronal site of these distinct pools.…”

“…However, these results reflect whole-body metabolism, brain-specific reactions cannot be directly derived from them. In brain, with 1-and 2-labeled acetate there was substantial labeling of amino acids, such as glutamate, glutamine, and aspartate and further TCA cycle intermediates as shown in older and more recent literature (Badar-Goffer et al, 1990;Berl and Frigyesi, 1969;Lebon et al, 2002;Tyce et al, 1981;Tyson et al, 2003;Van den Berg et al, 1969;Van den Berg and Ronda, 1976). However, the static measurement of metabolites at single time points yields only limited information on astrocytic oxidative metabolism.…”

In vivo1H‐[13C]‐NMR spectroscopy of cerebral metabolism

“…12,13 Glutamate in the cytosol of the neuronal synapse is packaged into synaptic vesicles by an Mg 2þ , H þ and ATP-dependent transport process. Vesicular glutamate is released in the extracellular space by exocytosis following an action potential.…”

“…These experiments, in combination with previous knowledge on compartmentalized glutamate metabolism, 12,13 allowed the development of a quantitative, mathematical model of glucose metabolism. 10,14,15 Among other findings these studies have made important contributions to linking neuronal energy production to glutamatergic neurotransmission and establishing the importance of a glutamate-glutamine neurotransmitter cycle between neurons and astroglia.…”

“…Previous in vivo 13 C NMR spectroscopy in combination with intravenous [1][2][3][4][5][6][7][8][9][10][11][12][13] C]-glucose infusion has shown abundant labeling of [4][5][6][7][8][9][10][11][12][13] C]-glutamate and [4][5][6][7][8][9][10][11][12][13] C]-glutamine, both in animal 6,7 and human [8][9][10][11] brain. These experiments, in combination with previous knowledge on compartmentalized glutamate metabolism, 12,13 allowed the development of a quantitative, mathematical model of glucose metabolism.…”