Defective SLC17A8 does not exchange cytosolic L-Glu for synaptic vesicle H+

Stable Identifier
Reaction [transition]
Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
18674745 Impairment of SLC17A8 encoding vesicular glutamate transporter-3, VGLUT3, underlies nonsyndromic deafness DFNA25 and inner hair cell dysfunction in null mice

Smith, RJ, El Mestikawy, S, Bersot, T, Nouvian, R, Giros, B, Ruel, J, Emery, S, Delprat, B, Puel, JL, Moser, T, Sivakumaran, TA, Rebillard, G, Lenoir, M, Amilhon, B, Lesperance, MM, Eybalin, M, Van Rybroek, JM

Am. J. Hum. Genet. 2008
Catalyst Activity

L-glutamate transmembrane transporter activity of SLC17A8 A211V [synaptic vesicle membrane]

Normal reaction
Functional status

Loss of function of SLC17A8 A211V [synaptic vesicle membrane]

Name Identifier Synonyms
autosomal dominant nonsyndromic deafness DOID:0050564 autosomal dominant deafness
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