GlyT2

Glycine transporter 2 (GlyT2), encoded by SLC6A5, is a presynaptic sodium- and chloride-dependent transporter that recaptures glycine into glycinergic nerve terminals and maintains the intracellular glycine pool required for efficient inhibitory neurotransmission^[1][2]. Mechanistically, GlyT2 preserves vesicular glycine content by supplying substrate for vesicle refilling, thereby sustaining quantal glycinergic signaling in the spinal cord, brainstem, retina, and other glycinergic circuits^[1][3]. GlyT2-mediated transport is characterized by high-affinity glycine uptake coupled to Na⁺ and Cl⁻ gradients, a process that is essential for maintaining presynaptic glycine availability and synaptic inhibitory strength^[2]. Regulation of GlyT2 expression also links glycinergic transmission to broader signaling networks, including Hedgehog pathway activity, which can modulate GlyT2 abundance, transport activity, and glycine homeostasis through ubiquitination-dependent mechanisms^[3]. In disease contexts, loss-of-function mutations in SLC6A5 cause hyperekplexia, and GlyT2-deficient animal models develop severe motor abnormalities, impaired inhibitory transmission, and early postnatal lethality, highlighting the transporter’s critical physiological role^[1][2][3]. Compared with the related isoform GlyT1, which is predominantly associated with glial glycine clearance around synapses, GlyT2 is localized to glycinergic presynaptic terminals and is required for maintaining transmitter stores rather than primarily shaping extracellular glycine levels^[2][4]. For experimental applications, selective GlyT2 inhibitors such as ALX-1393 and ORG25543 are widely used to investigate glycinergic signaling, transporter selectivity, and glycine-dependent modulation of neuronal circuits^[4].