The Glutamate/GABA-Glutamine Cycle

Tetsufumi Ueda, Ueda, Tetsufumi

Glutamate is an excitatory neurotransmitter widely used in the vertebrate central nervous systems. The synaptic transmission process is characterized by three steps: (1) presynaptic vesicular transmitter uptake, (2) presynaptic release, and (3) postsynaptic receptor activation. Presynaptic vesicular glutamate uptake plays an initial pivotal role in glutamate transmission by concentrating glutamate in the vesicular lumen prior to its release. This active glutamate transport harnesses energy derived from ATP hydrolysis, and intra- or extravesicular chloride, and is highly specific to glutamate. The uptake system consists of a vesicular glutamate transporter (VGLUT) and v-type proton-pump ATPase, which generates an electrochemical proton gradient, the driving force of the transport. The major source of ATP is likely to be supplied by glycolytic vesicle-bound enzymes, glyceraldehyde 3-phosphate dehydrogenase, and 3-phosphoglycerate kinase, rather than by mitochondrial ATP synthase. The VGLUT substrate glutamate is proposed to be synthesized by vesicle-bound aspartate amino transferase from α-ketoglutarate, not directly from glutamine. VGLUT has three isoforms, and gaged by their distributions they perform different physiological functions. The mechanism and regulation of vesicular glutamate uptake are discussed. The pharmacology of vesicular glutamate uptake is a developing field of inquiry.