2.A.22.2.6
Glycine:Na⁺ transporter, GlyT2b (glycine/3Na⁺/1Cl^- symporter, SLC6A5). GlyT2 and VIAAT cooperate to determine the vesicular glycinergic phenotype (Aubrey et al., 2007). Startle disease in Irish wolfhounds is associated with a microdeletion in the glycine transporter GlyT2 gene (Gill et al., 2011). A dominant hyperekplexia (startle disease) mutation Y705C in humans alters trafficking and the biochemical properties of GlyT2 (Gimenez et al. 2012). Structural determinants of the neuronal glycine transporter 2 for the selective inhibitors ALX1393 and ORG25543 have been determined (Benito-Muñoz et al. 2021).  The efficacy of the analgesic GlyT2 inhibitor, ORG25543, is determined by two connected allosteric sites (Chater et al. 2023).  Hyperekplexia (OMIM 149400), a sensorimotor syndrome of perinatal clinical relevance, causes newborn humans to display an energic startle reflex in response to certain trivial stimuli. This condition can be lethal due to apnea episodes. The disease is caused by a blockade of glycinergic neurotransmission. Glycinergic interneurons preserve their identity by the activity of the surface glycine transporter GlyT2, which supplies glycine to presynaptic terminals to maintain glycine content in synaptic vesicles. Loss-of-function mutations in the GlyT2 gene (SLC6A5) cause a presynaptic form of human hyperekplexia (Sarmiento-Jiménez et al. 2025).  A variant causes a loss of function regarding GlyT2 activity but a gain of function as a cell proteostasis disturber (Sarmiento-Jiménez et al. 2025).