Glutamathomeostase

Glutamathomeostase, commonly referred to as glutamate homeostasis, is the regulation of extracellular glutamate levels in the central nervous system to support proper synaptic signaling while preventing excitotoxic damage. After release at excitatory synapses, glutamate is rapidly cleared from the extracellular space by high-affinity transporters primarily on astrocytes, and to a lesser extent on neurons. The major astrocytic transporters are EAAT1 (GLAST) and EAAT2 (GLT-1); neuronal uptake involves EAAT3 (EAAC1) among others. In astrocytes, glutamate is mainly converted to glutamine by the enzyme glutamine synthetase. Glutamine is then transported back to neurons, where it is converted again to glutamate by glutaminase, forming the glutamate–glutamine cycle that sustains neurotransmitter supply.

Vesicular glutamate transporters (VGLUT1-3) mediate loading of glutamate into synaptic vesicles and its activity is modulated by various receptors, including metabotropic glutamate receptors that influence release and uptake dynamics. Regulation of glutamate homeostasis also involves gene expression and function of transporters, metabolic enzymes, and astrocyte–neuron coupling, as well as extracellular conditions such as pH and redox state.

Disruptions of this balance can contribute to excitotoxicity and neuronal injury, implicated in ischemia, traumatic brain injury, epilepsy, and neurodegenerative diseases such as ALS and Alzheimer's disease. Genetic mutations or acquired factors that impair transporter activity or glutamine synthetase can elevate extracellular glutamate, highlighting the importance of tight regulation of the glutamate–glutamine cycle for neural health.