Vesicular glutamate transporter 3 (VGLUT3), encoded by SLC17A8, is a member of the vesicular glutamate transporter family that mediates the uptake of glutamate into synaptic vesicles. Unlike VGLUT1 and VGLUT2, VGLUT3 is expressed in distinct populations of serotonergic, cholinergic, GABAergic and glutamatergic neurons, including neurons in the cortex, hippocampus, striatum and raphe nuclei [1–3]. A co-localization with the acetylcholine transporter VAChT and the monoamine transporter 2 VMaT2 has been reported in distinct neuronal populations, particularly during development [4,5]. VGLUT3 enables glutamate co-transmission in neurons that primarily use other neurotransmitters and can modulate the storage and release of serotonin, acetylcholine and GABA. In particular, VGLUT3 contributes to vesicular synergy in striatal cholinergic interneurons, thereby influencing cholinergic signaling [1,2].
VGLUT3 dysfunction has been associated with several neurological and sensory disorders. In the auditory system, VGLUT3 is essential for glutamate release from cochlear inner hair cells, and pathogenic SLC17A8 variants cause autosomal-dominant nonsyndromic hearing loss (DFNA25) [6]. VGLUT3 has also been implicated in Parkinson’s disease and L-DOPA-induced dyskinesia, as well as pathological pain processing [2].
