CNS glutamate handling — neuronal release after synaptic firing, astrocyte uptake via EAAT1/EAAT2, conversion to glutamine via glutamine synthetase (avoids excitotoxicity), glutamine shuttle back to neuron, conversion back to glutamate via glutaminase. Also peripheral glutamate involvement in TCA anaplerosis (α-KG ↔ glutamate via glutamate dehydrogenase or aminotransferases). Glutamate is the dominant CNS excitatory transmitter; NMDA + AMPA + kainate ionotropic + 8 mGluR metabotropic. Ketamine + memantine = NMDA antagonists; perampanel = AMPA antagonist; tiagabine GAT-1 transporter is downstream into GABA (the inhibitory mirror). Hepatic encephalopathy = ammonia rises because hepatic glutamine synthetase fails; lactulose + rifaximin shift gut microbiome to reduce NH3 production.
Organ Systems
nervous
Pathway Steps
glutamate → glutamine — via glutamine synthetase (GS, astrocyte) — incorporates NH4+. Astrocytic glutamine synthetase fixes ammonia onto glutamate, both detoxifying NH4⁺ and recycling the glutamate taken up after synaptic release. This astrocyte–neuron glutamate–glutamine cycle refills releasable transmitter while clearing brain ammonia.
glutamine → glutamate — via glutaminase (GLS, neuronal) — releases NH4+. Neuronal glutaminase regenerates transmitter glutamate (releasing ammonia). Tumors also upregulate glutaminase for “glutamine addiction” (anaplerosis), the rationale for glutaminase-inhibitor oncology drugs.
alpha-ketoglutarate → glutamate — via glutamate dehydrogenase (GDH) — TCA anaplerosis. Glutamate dehydrogenase reversibly links the TCA cycle (α-ketoglutarate) to amino-acid nitrogen, providing anaplerosis and nitrogen disposal; activating GDH mutations cause the hyperinsulinism–hyperammonemia syndrome.
Known Modulators
l glutamine (substrate) — glutamine pool (gut enterocyte fuel + nitrogen carrier). L-glutamine; gut + immune cell fuel; supplementation for intestinal recovery + sickle cell (Endari)