Sodium- and chloride-dependent glycine transporter 1 G319S mutant (GlyT1 G319S)

The Glycine transporter 1 (GlyT1) G319S mutant is a functional variant of the SLC6A9 protein, which is a sodium- and chloride-dependent transporter responsible for glycine reuptake in the central nervous system (Vandenberg et al., 2003). GlyT1 is a major therapeutic target for treating the negative and cognitive symptoms of schizophrenia by modulating NMDA receptor activity through increased synaptic glycine levels (Harvey & Yee, 2013). The G319S mutation, located in the sixth transmembrane domain, is a critical research tool that renders the transporter insensitive to sarcosine, a classic GlyT1 inhibitor, thereby mimicking the pharmacological profile of the GlyT2 transporter (Nunes et al., 2005). This specific residue substitution is used to map the binding pockets of various small-molecule inhibitors and to distinguish between different classes of GlyT1 antagonists (Shahsavar et al., 2021). While the G319S mutant itself is not a primary clinical target, it is indispensable for the structure-based drug design of selective GlyT1 inhibitors such as bitopertin (Pinard et al., 2010). Pharmacological studies of this mutant provide insights into the molecular mechanisms of neurotransmitter transport and the development of therapies for neuropsychiatric disorders (Harsing et al., 2006).

Other names

SLC6A9 G319SGlyT1 G319SGlycine transporter 1 G319SSodium- and chloride-dependent glycine transporter 1 G319S

The G319S mutation alters the binding pocket of the GlyT1 transporter, specifically reducing the affinity for sarcosine and sarcosine-derived inhibitors while maintaining the transport of glycine and the binding of non-sarcosine-like inhibitors (Vandenberg et al., 2003; Shahsavar et al., 2021).