Possible neurotransmitter-linked metabolic mechanisms in brain for sensing dietary protein quality and quantity

Compartmentation of Enzymes of Glucose, Glutamate, and Branched Chain Amino
Acid Metabolism in the CNS.
Susan M. Hutson, Ph.D.
Department of Biochemistry, Wake Forest University Health Sciences, Winston-Salem,
North Carolina, USA
Glutamate is the major excitatory neurotransmitter in mammalian brain. Detoxification and
repletion of glutamate released by neurons is achieved by glutamate/glutamine cycle (GGC)
and complex metabolic processes in astrocytes. Glutamate is transported into astrocytes
where some is converted to glutamine; the rest is converted to pyruvate. Glutamine is
transported back to the neurons completing the glutamate/lglutamine cycle (GGC). The GGC
replenishes part, but not all, of the neuronal glutamate. Re-synthesis of glutamate in the glia,
to make up the remaining deficit, requires de novo glutamate synthesis via pyruvate
carboxylation. In the retina, increases in GGC activity resulted in increased de novo
glutamate synthesis and surprisingly increased retina glycolysis but not glucose oxidation.
De novo glutamate synthesis requires a nitrogen source Branched chain amino acids
(BCAAs) are a major source of this nitrogen in reactions catalyzed by the branched chain
aminotransferase isozymes (BCATs), mitochondrial BCATm and cytosolic BCATc.
Compartmentalization of the BCAT isozymes (BCATc in neurons and BCATm in astrocytes)
is thought to facilitate the GGC by providing a cyclic mechanism for shuttling of nitrogen
between neurons and glia. We used immunohistochemistry to examine the distribution of
BCAT isozymes and a key transporter (aspartate/glutamate carrier, AGC) of the redox shuttle
required for glucose oxidation in the retina. In the retina, BCATc immunoreactivity was in
the photoreceptor inner segments and in the outer plexiform layer. More diffuse labeling for
BCATc was found in the inner plexiform layer. Ganglion cells were immunoreactive, as was
the nerve fiber layer. The labeling pattern for BCATm was characteristic of staining of the
Müller glial cells i.e., it co-localizes with vimentin. The pattern of expression of AGC was
similar to the retinal localization of BCATc. We found no carrier protein in Müller cells, but
abundant expression in the photoreceptor cells and inner plexiform layer. In adult rat brain,
BCATc is expressed selected populations of glutamatergic and GABAergic neurons. For
example in glutamatergic granule cells of the dentate gyrus in the hippocampus, BCATc was
present in axons and nerve terminals whereas BCATc was concentrated in the cell bodies of
GABAergic hippocampal pyramidal basket cells. There was strong expression of BCATc in
the mossy fiber projection (granule cell axons) and in the zone of synaptic varicosities
formed between the mossy fibers and target pyramidal cells in field CA3. BCATm was in
astrocytes in the hippocampus. In brain Ramos et al. (Ramos, 2003) have shown AGC
expression is neuronal. In hippocampus AGC mRNA was found in neurons that express
BCATc. Our results suggest that BCATc has access to neurotransmitter pool of glu in
glutamatergic neurons and metabolic pool in GABA neurons and may colocalize with AGC.
Furthermore, the pattern of AGC expression provides a biochemical basis for the Magistretti
hypothesis (Magistretti, 1999) and the high rate of glycolysis in Müller cells and glia.
(Support NIH NS 13924)

Source: http://www.jsnfs-chubu.jp/mt-img/file/49-2.pdf