The role of PTEN C-terminus in the regulation of brain glycine homeostasis and NMDA receptor function through SLC6A20A

Abstract

Glycine transporters that regulate the levels of brain glycine –an obligatory coagonist for NMDA receptors –are important therapeutic targets for disorders with altered NMDAR function. While GlyT1 and GlyT2 have filled the role of such candidates, it remains to be discovered whether these two glycine transporters constitute the entirety of glycine homeostasis mechanism in the brain, or whether other transporters also play essential roles. As an answer, we hereby report that SLC6A20A, a transporter originally designated as imino acid transporter of proline, can also regulate glycine levels, and by extension, NMDAR function in the brain. SLC6A20 transcript and protein levels were increased in mutant mice with PTEN lacking the C-terminus through enhanced β-catenin binding to the Slc6a20A gene. These mice displayed reduction of proline and glycine and decreased NMDAR currents. Elevating glycine levels back to normal ranges by antisense-oligonucleotide-induced SLC6A20 knockdown, or the competitive GlyT1 antagonist sarcosine, normalized NMDAR currents and climbing behavior. Conversely, mice lacking SLC6A20A displayed increased extracellular glycine levels and NMDAR currents. Lastly, both mouse and human SLC6A20 mediated proline/glycine transports, and SLC6A20 proteins could be detected in human neurons. Collectively, these results highlight SLC6A20A both as a novel regulator of glycine homeostasis within the brain, and a promising candidate for therapeutic intervention for brain disorders involving NMDAR hypofunction.