UniProt: Q9H936 (GHC1_HUMAN). HGNC:19954. Gene = SLC25A22, synonym GC1.
SLC25A22 is a member of the mitochondrial carrier family (SLC25 / TC 2.A.29). It is a
multi-pass integral protein of the mitochondrial inner membrane with the canonical
tripartite mitochondrial-carrier architecture (three Solcar repeats, six transmembrane
helices) [file:human/SLC25A22/SLC25A22-uniprot.txt "Belongs to the mitochondrial carrier
(TC 2.A.29) family"; six TRANSMEM features; three REPEAT ... Solcar features].
Its function is a glutamate/H+ symporter: it imports L-glutamate from the cytosol into
the matrix together with a proton (electroneutral H+/glutamate symport, i.e. glutamate
co-transported with H+ or exchanged for OH-).
Primary experimental characterization: Fiermonte et al. 2002 (PMID:11897791). The two human
glutamate carrier isoforms (GC1 = SLC25A22, GC2 = SLC25A18) were bacterially expressed,
reconstituted into liposomes, and shown to be glutamate/H+ symporters
PMID:11897791 and
PMID:11897791. KM ~4.85 mM for glutamate [file:...SLC25A22-uniprot.txt
"KM=4.85 mM for glutamate"]. This is the source of the IDA MF/BP/CC annotations
(GO:0005313 L-glutamate transmembrane transporter activity; GO:0005280 amino acid:proton
symporter activity; GO:0015813 L-glutamate transmembrane transport; GO:0005743
mitochondrial inner membrane).
The paper notes the two ESTs are related to the aspartate-glutamate carrier
PMID:11897791, but the demonstrated activity is glutamate/H+ symport, not aspartate transport.
GC1 is a glutamate-specific (glutamate/H+) symporter. The aspartate transporter/transport
annotations (GO:0015183 L-aspartate transmembrane transporter activity IBA; GO:0015810
aspartate transmembrane transport IBA; GO:0070778 L-aspartate transmembrane transport IEA)
arise from phylogenetic (IBA) propagation across the broader mitochondrial-carrier /
aspartate-glutamate-carrier clade and inter-ontology inference, not from measured aspartate
transport by SLC25A22. Neither the UniProt FUNCTION/CATALYTIC ACTIVITY nor the Fiermonte
primary paper attributes aspartate transport to GC1; UniProt records only the glutamate/H+
reaction. Marked as over-annotated (aspartate transport belongs to the aspartate-glutamate
carriers SLC25A12/SLC25A13, not to the glutamate carriers).
GC1 participates in the malate-aspartate shuttle indirectly by carrying the glutamate/H+
import leg. Reactome's MAS description makes this the glutamate coimport step
[R-HSA-9856872 "aspartate (L-Asp) gets exported and transaminated to glutamate (L-Glu),
which subsequently gets coimported with a proton and transaminated back"]. Kept as a
non-core downstream/pathway process (the core molecular activity is glutamate/H+ symport).
GO:0006836 (neurotransmitter transport, TAS Reactome:R-HSA-442660) is an over-annotation.
The Reactome node R-HSA-442660 is about the SLC6 family plasma-membrane neurotransmitter
transporters [R-HSA-442660 "The SLC6 gene family encodes proteins that mediate
neurotransmitter uptake thus terminating a synaptic signal"], a different process from
SLC25A22's mitochondrial inner-membrane glutamate/H+ symport. GC1 handles glutamate as a
mitochondrial metabolite, not as a synaptic neurotransmitter being cleared from the cleft.
Mitochondrion inner membrane [file:human/SLC25A22/SLC25A22-uniprot.txt "SUBCELLULAR
LOCATION: Mitochondrion inner membrane"], multi-pass. Supported by IDA (PMID:11897791),
ISS, IEA, Reactome TAS, and HTP mitochondrial-proteome mass-spec (PMID:34800366, HTP =>
mitochondrion). GO:0005743 (mitochondrial inner membrane) is the specific, core location;
GO:0005739 (mitochondrion) is the less-specific HTP location.
No dedicated "glutamate:proton symporter activity" GO term exists (checked OLS), so the pair
GO:0005280 + GO:0005313 is the most specific available representation. No catalytic/enzymatic
MF is assigned — SLC25A22 is a transporter.