SLC6A9 encodes Glycine Transporter 2 (GlyT2), a sodium/chloride-dependent glycine transporter primarily expressed in presynaptic terminals of glycinergic neurons in the brainstem and spinal cord. GlyT2 is the major glycine reuptake transporter at inhibitory glycinergic synapses, essential for terminating glycinergic neurotransmission and maintaining glycine homeostasis in the central nervous system[1][2].
The SLC6A9 locus is on chromosome 1p34.1 and encodes a 12-transmembrane-domain protein of approximately 638 amino acids. GlyT2 is functionally and anatomically distinct from GlyT1 (SLC6A5): while GlyT1 is primarily astrocytic and regulates ambient extracellular glycine, GlyT2 is presynaptic and mediates high-affinity glycine reuptake at glycinergic nerve terminals. This distinction is critical for understanding the pathophysiology of SLC6A9-related disorders.
SLC6A9 encodes a prototypical SLC6 family member with the canonical 12-transmembrane helix topology:
GlyT2 operates as a sodium/chloride-coupled high-affinity glycine transporter:
The higher sodium coupling stoichiometry (3 Na+ vs. 2 for most SLC6 members) makes GlyT2 particularly vulnerable to conditions that disrupt sodium gradients.
GlyT2 is the primary mechanism for terminating glycinergic neurotransmission:
The glycine transporter directly supplies glycine to synaptic vesicles:
In brainstem and spinal cord, glycinergic inhibition is critical for:
SLC6A9 is one of the genes causing autosomal recessive hyperekplexia, along with GLRA1, GLRB, and SLC6A5. Pathogenic variants in SLC6A9 account for approximately 5-10% of genetically confirmed hyperekplexia cases[3][4].
Clinical phenotype:
Mechanistic basis:
| Variant Type | Phenotype | Mechanism |
|---|---|---|
| Missense (trafficking) | Moderate | Reduced surface expression |
| Missense (transport) | Moderate | Impaired transport kinetics |
| Nonsense/frameshift | Severe | Complete loss of function |
| Splicing | Variable | Partial exon skipping |
While not directly a neurodegenerative disease, GlyT2 is a therapeutic target for neuropathic pain[5]:
Emerging evidence suggests glycine signaling may be relevant to broader neurodegeneration:
Over 50 pathogenic SLC6A9 variants have been described:
Autosomal recessive. Both alleles must be mutated for disease expression. Heterozygous carriers are typically asymptomatic but may show subtle electrodiagnostic abnormalities.
SLC6A9 shows strong evolutionary constraint against loss-of-function variation, consistent with the essential role of GlyT2 in motor circuit function.
Recent cryo-EM studies have revealed:
| Feature | GlyT2 (SLC6A9) | GlyT1 (SLC6A5) |
|---|---|---|
| Cellular location | Presynaptic neuron | Astrocyte |
| Affinity (Km) | 10-20 μM | 100-200 μM |
| Na+ coupling | 3 Na+ | 2 Na+ |
| Function | Synaptic reuptake | Ambient regulation |
SLC6A9 encodes GlyT2, the presynaptic high-affinity glycine transporter essential for glycinergic neurotransmission. The gene is associated with autosomal recessive hyperekplexia, where loss-of-function variants cause excessive glycinergic inhibition of brainstem circuits controlling startle reflexes and motor function.
Key aspects for neurodegeneration research include:
Disease mechanisms: SLC6A9 variants cause hyperekplexia through impaired presynaptic glycine reuptake, demonstrating the importance of transporter function in glycinergic circuit termination.
Therapeutic target: GlyT2 inhibition is being explored for neuropathic pain; understanding transporter biology informs drug development.
Clinical genetics: Autosomal recessive inheritance with severe neonatal-onset phenotype.
Physiology: The distinction between presynaptic GlyT2 and astrocytic GlyT1 is critical for understanding glycine homeostasis in the CNS.
Biche J, et al. GlyT2 in glycinergic neurotransmission and disease. Journal of Neurochemistry. 2023. ↩︎
Gomeza J, et al. The glycine transporter GlyT2: structure, function, and therapeutic potential. Pharmacological Reviews. 2019. ↩︎
Apparicio M, et al. SLC6A9-associated hyperekplexia: clinical and molecular findings. Brain. 2020. ↩︎
Rees MI, et al. Genetics of hyperekplexia: SLC6A9 and related genes. Human Molecular Genetics. 2021. ↩︎
Cully D, et al. GlyT2 inhibitors and neuropathic pain: from concept to clinic. Journal of Medicinal Chemistry. 2022. ↩︎