fig3

Figure 3. Homeostasis of glutamate in neurovascular unit. Glutamate is maintained at approximately 1 mM in the brain interstitial and cerebrospinal fluid (CSF); this concentration is more than 100 higher inside brain cells (~10 mM) and synaptic vesicles (~100 mM). This is due to the presence of Na⁺-dependent excitatory amino-acid transporters (EAATs) not only on neuronal (EAAT1) and astroglial cells (EAAT2 and EAAT3) but also on the brain vasculature (EAAT1, EAAT2, EAAT3). In the astrocyte, glutamate enters the tricarboxylic acid (TCA) cycle or is converted to glutamine by the enzyme glutamine synthetase. Glutamine is then released to the presynaptic neuron, where it is converted to glutamate and packaged into vesicles for further release. It seems evident that the uptake of extracellular glutamate into endothelial cells (EC) via EAATs is also an important step in glutamate homeostasis. When the endothelial glutamate concentration becomes higher than the blood glutamate concentration, glutamate is transported into the blood by XG- transporters that exist only on the luminal membrane in a position that facilitates blood excretion of glutamate from the brain. ECs may also utilize glutamate as an energy substrate. EC may catalyze the conversion of glutamate to α-ketoglutarate (α-KG) and enter the TCA cycle in the mitochondria to form pyruvate, which may then be converted to lactate in the cytosol and transported through monocarboxylate transporter 1 (MCT-1) in the luminal membrane to the blood. From Castillo et al., with permission^[129].