Central nervous system neurons have traditionally been thought to express exclusively membrane transporters and/or vesicular transporters for their transmitter. Three vesicular glutamate transporters (VGLUTs) have recently been cloned: BNPI/VGLUT1 (a brain-specific sodium dependent inorganic phosphate (P_i) transporter), and its homologs DNPI/VGLUT2 (differentiation-associated sodium-dependent P_i transporter) and VGLUT3¹. These transporters mediate glutamate uptake inside presynaptic vesicles and are anatomical and functional markers of glutamatergic excitatory transmission².

VGLUT 1-3 are very similar in structure and function, but are used by different neuronal populations. VGLUT3 is a glycosylated transmembrane protein with ten putative transmembrane domains (TMD I–X) and both amino- and carboxyl-termini located in the cytosol³.

VGLUT3 is localized in a limited number of glutamatergic neurons in multiple brain regions: neocortex, hippocampus, olfactory bulb, hypothalamus, substania nigra and raphe nuclei. Additionally, VGLUT3 is expressed in a population of symmetrical synapses. It is detected in hippocampal and cortical GABAergic neurons, cholinergic neurons in the striatum and serotonergic neurons in the raphe nuclei⁴.

Mice lacking VGLUT3 are congenitally deaf due to loss of glutamate release at the inner hair cell afferent synapse⁵. In addition loss of VGLUT3 specifically impairs mechanical pain sensation⁶.