Affinage

SLC6A5

Sodium- and chloride-dependent glycine transporter 2 · UniProt Q9Y345

Length
797 aa
Mass
87.4 kDa
Annotated
2026-06-10
11 papers in source corpus 6 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC6A5 encodes GlyT2, a presynaptic Na+/Cl--dependent glycine transporter that recycles glycine from the synaptic cleft back into presynaptic terminals to sustain glycinergic inhibitory neurotransmission in the caudal CNS (PMID:16751771, PMID:16884688). Its expression is restricted to neurons, predominantly inhibitory neurons of caudal brain regions, distinguishing it from the more broadly distributed glial/neuronal GlyT1 (PMID:41703440). Transport depends on coupled Na+ and Cl- binding: loss-of-function mutations cause defective subcellular localization, reduced glycine uptake, or protein truncation, and operate through disrupted Cl- binding residues, conformational changes in extracellular loop 4, cation-π interactions, and—for the A275T variant—a voltage-sensitive transport defect arising from lowered Na+ affinity (PMID:16751771, PMID:16884688, PMID:22700964). Such loss-of-function mutations cause hereditary hyperekplexia, and genetic ablation of GlyT2 in mice produces handling-induced spasms, accelerated neuromuscular synapse elimination and AChR subunit switching, and early lethality, consistent with loss of glycinergic inhibition and increased motor neuron activity (PMID:16751771, PMID:16884688, PMID:22272310). At the spinal level, selective pharmacological blockade of GlyT2 controls glycine availability for inhibitory neurotransmission relevant to pain processing (PMID:20173309).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2006 High

    Established that SLC6A5/GlyT2 is a presynaptic component of glycinergic transmission by showing that patient mutations disrupt glycine recycling, linking the transporter to a human disease.

    Evidence Human patient mutation analysis with glycine uptake assays and subcellular localization of mutant GlyT2 constructs

    PMID:16751771 PMID:16884688

    Open questions at the time
    • Did not resolve atomic-level ion-binding mechanism
    • Genotype-phenotype severity relationships not fully mapped
  2. 2010 Medium

    Addressed whether spinal GlyT2 activity gates inhibitory tone in pain, showing selective GlyT2 (not GlyT1) blockade suppresses mechanical allodynia.

    Evidence Intrathecal selective inhibitor ALX1393 in mouse herpetic/postherpetic pain models with behavioral allodynia testing

    PMID:20173309

    Open questions at the time
    • Single lab using pharmacology and behavior only
    • Did not establish molecular site of inhibitor action on GlyT2
  3. 2012 High

    Defined the in vivo consequence of complete GlyT2 loss, demonstrating motor spasms, lethality, and accelerated NMJ maturation consistent with disinhibition of motor neurons.

    Evidence Slc6a5 null mouse knockout with immunoblot confirmation, NMJ morphology, and AChR subunit expression analysis

    PMID:22272310

    Open questions at the time
    • Mechanism linking glycinergic loss to NMJ remodeling not dissected
    • No rescue experiment reported
  4. 2012 High

    Resolved the molecular basis of transport defects across many variants, identifying Cl- binding residues, loop 4 conformation, cation-π interactions, and Na+-affinity-dependent voltage sensitivity as pathogenic mechanisms.

    Evidence Glycine uptake assays for 16 mutations plus voltage-clamp electrophysiology of A275T to measure Na+ affinity

    PMID:22700964

    Open questions at the time
    • No structural model accompanying mutagenesis
    • Single-lab functional data
  5. 2026 Medium

    Clarified the cellular expression boundary of GlyT2, establishing its restriction to neurons (predominantly inhibitory) in caudal brain regions versus the broader glial/neuronal distribution of GlyT1.

    Evidence Single-cell RNA-seq re-analysis, quantitative RT-PCR, and RNAscope across mouse brain regions and peripheral organs

    PMID:41703440

    Open questions at the time
    • Expression mapping not linked to a functional consequence in this study
    • Human cell-type distribution not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GlyT2 transport activity is dynamically regulated (trafficking, post-translational modification, partner proteins) at presynaptic terminals remains uncharacterized in this corpus.
  • No interacting partners or regulatory proteins identified
  • No structural model of human GlyT2
  • Regulation of surface localization unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 2
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-112316 Neuronal System 2 R-HSA-382551 Transport of small molecules 2

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Missense, nonsense, and frameshift mutations in SLC6A5 (GlyT2) cause hereditary hyperekplexia by resulting in defective subcellular GlyT2 localization, decreased glycine uptake, or both; selected mutations affect predicted glycine and Na+ binding sites, establishing GlyT2 as a presynaptic component of glycinergic transmission whose loss disrupts glycine recycling. Human patient mutation analysis combined with functional assays of glycine uptake and subcellular localization studies of mutant GlyT2 constructs Nature genetics High 16751771 16884688
2012 Systematic functional analysis of 16 novel SLC6A5 mutations confirmed all were defective in glycine transport; pathogenic mechanisms include protein truncation, splice site disruption, missense mutations affecting Cl- binding residues, conformational changes mediated by extracellular loop 4, and cation-π interactions. Electrophysiology of mutation A275T specifically showed a voltage-sensitive decrease in glycine transport caused by lower Na+ affinity. Glycine uptake assays for 16 mutations; detailed electrophysiology (voltage-clamp) of A275T mutant to measure Na+ affinity and transport kinetics The Journal of biological chemistry High 22700964
2012 In mice, homozygous loss of GlyT2 (Slc6a5 null allele via MusD retrotransposon insertion) results in undetectable GlyT2 protein, handling-induced spasms by day 5, and death within two weeks; at the neuromuscular junction, synapse elimination and the embryonic-to-adult acetylcholine receptor subunit switch are hastened, consistent with increased motor neuron activity due to loss of glycinergic inhibition. Mouse knockout model (null allele); immunoblot to confirm absence of GlyT2 protein; neuromuscular junction morphology and AChR subunit expression analysis PloS one High 22272310
2010 Intrathecal blockade of GlyT2 (but not GlyT1) with ALX1393 suppresses both dynamic and static mechanical allodynia in herpetic and postherpetic pain in mice, and also suppresses allodynia induced by intrathecal strychnine and NMDA, demonstrating that GlyT2 activity at the spinal level controls glycine availability for inhibitory neurotransmission relevant to pain processing. Intrathecal pharmacological inhibition with selective GlyT2 inhibitor ALX1393 and GlyT1 inhibitor sarcosine in mouse pain models; behavioral testing for mechanical allodynia Journal of pharmacological sciences Medium 20173309
2026 Slc6a5 mRNA is restricted to neurons (predominantly inhibitory neurons) in caudal brain regions in mice, whereas Slc6a9 (GlyT1) is distributed in both glial cells and neurons across broader brain regions; this cellular specificity was established using single-cell RNA sequencing, quantitative RT-PCR, and RNAscope. Single-cell RNA sequencing re-analysis, quantitative RT-PCR, and RNAscope in situ hybridization across mouse brain regions and peripheral organs BMC neuroscience Medium 41703440

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nature genetics 182 16751771
2012 Mutations in the GlyT2 gene (SLC6A5) are a second major cause of startle disease. The Journal of biological chemistry 70 22700964
2006 Mutations within the human GLYT2 (SLC6A5) gene associated with hyperekplexia. Biochemical and biophysical research communications 63 16884688
2010 Blockade of glycine transporter (GlyT) 2, but not GlyT1, ameliorates dynamic and static mechanical allodynia in mice with herpetic or postherpetic pain. Journal of pharmacological sciences 32 20173309
2008 Association study of polymorphisms in the neutral amino acid transporter genes SLC1A4, SLC1A5 and the glycine transporter genes SLC6A5, SLC6A9 with schizophrenia. BMC psychiatry 22 18638388
2012 A MusD retrotransposon insertion in the mouse Slc6a5 gene causes alterations in neuromuscular junction maturation and behavioral phenotypes. PloS one 17 22272310
2019 A glycine transporter SLC6A5 frameshift mutation causes startle disease in Spanish greyhounds. Human genetics 8 30847549
2020 Case report of a PRDM5 linked brittle cornea syndrome type 2 in association with a novel SLC6A5 mutation. Indian journal of ophthalmology 4 33120686
2025 A frameshift variant in the SLC6A5 gene is associated with startle disease in a family of Old English Sheepdogs. Animal genetics 2 40012122
2025 Familial Hyperekplexia Caused by a Novel Homozygous SLC6A5 Variant: A Case Report. Molecular syndromology 1 41064056
2026 Slc6a9 is distributed in glial cells and neurons across several nervous system regions, whereas Slc6a5 is more restricted to neurons in the caudal brain. BMC neuroscience 0 41703440

Missed literature

Know a paper Affinage missed for SLC6A5? Flag it for the maintainers and the community.

No submissions yet.