Meta-Biol

• Pathways

There are two classes of glutamate transporters; the excitatory amino acid transporters (EAATs) which depend on an electrochemical gradient of Na+ ions and vesicular glutamate transporters (VGLUTs) which don't. Together, these transporters uptake and release glutamate to mediate this neurotransmitter's excitatory signal and are part of the glutamate-gluatamine cycle. Three members of the SLC17A gene family (7, 6 and 8) encode VGLUTs 1-3 respectively. This uptake is thought to be coupled to the proton electrochemical gradient generated by the vacuolar type H+-ATPase. They are all expressed in the CNS in neuron-rich areas but SLC17A8 (VGLUT3) is also expressed on astrocytes and in the liver and kidney. Defects in SLC17A8 can cause autosomal dominant deafness 25 (DFNA25; MIM:605583), a form of non-syndromic sensorineural hearing loss. The cochlea expresses SLC17A8 and in mice which lack this transporter are congenitally deaf. Hearing loss is due to the lack of glutamate release by inner hair cells therefore a loss of synaptic transmission at the IHC-afferent nerve synapse.

In two unrelated families, a heterozygous missense mutation, c.632C->T (p.A211V), was found to cause DFNA25. The A211 residue is conserved in VGLUT3 across species and in all human subtypes, suggesting an important functional role (Ruel et al. 2008).