SLC6A20 transporter: a novel regulator of brain glycine homeostasis and NMDAR function

Abstract

Glycine transporters (GlyT1 and GlyT2) that regulate levels of brain glycine, an inhibitory neurotransmitter with co‐agonist activity for NMDA receptors (NMDARs), have been considered to be important targets for the treatment of brain disorders with suppressed NMDAR function such as schizophrenia. However, it remains unclear whether other amino acid transporters expressed in the brain can also regulate brain glycine levels and NMDAR function. Here, we report that SLC6A20A, an amino acid transporter known to transport proline based on in vitro data but is understudied in the brain, regulates proline and glycine levels and NMDAR function in the mouse brain. SLC6A20A transcript and protein levels were abnormally increased in mice carrying a mutant PTEN protein lacking the C terminus through enhanced β‐catenin binding to the Slc6a20a gene. These mice displayed reduced extracellular levels of brain 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 repetitive climbing behavior observed in these mice. Conversely, mice lacking SLC6A20A displayed increased extracellular glycine levels and NMDAR currents. Lastly, both mouse and human SLC6A20 proteins mediated proline and glycine transports, and SLC6A20 proteins could be detected in human neurons. These results suggest that SLC6A20 regulates proline and glycine homeostasis in the brain and that SLC6A20 inhibition has therapeutic potential for brain disorders involving NMDAR hypofunction.

The Multifaceted Roles of Proline in Cell Behavior

“…Mutations of SLC6A19 are associated with Hartnup disease, a complex syndrome involving cerebellar ataxia and psychosis (Seow et al, 2004). SLC6A20 (IMINO) is expressed in human neurons and regulates L-Pro and glycine homeostasis (Bae et al, 2021).…”

NMDARs, Coincidence Detectors of Astrocytic and Neuronal Activities

“…The proline transporter, SLC6A20A [ 172 ], is a novel transporter of glycine in the brain that regulates extracellular glycine and NMDAR function [ 173 ]. SLC6A20A cotransport glycine with Na + and Cl - ions.…”

“…SLC6A20A cotransport glycine with Na + and Cl - ions. SLC6A20A is expressed in glia (astrocytes and microglia) and is less prominent in neurons [ 173 ]. Unlike GlyT1 and GlyT2, which are more strongly expressed in the brain stem [ 40 , 174 , 175 ], SLC6A20A are located in various brain regions, including the hippocampus and cortex [ 173 ].…”

“…So far, only System A appears to accumulate intracellular d -serine in vivo. However, this relied on inhibition by the System A substrate MeAIB [ 176 ], which is also a substrate of the novel glycine transporter, SLC6A20A [ 173 ]; as such, confirmation awaits the development of a specific non-competitive inhibitor.…”

“…GlyT1 has, in principle, the ionic strength/accumulative power needed to reduce [gly] o well below values that saturate the glycine site of NMDAR (40 nM to 1 µM [29,152]). The proline transporter, SLC6A20A [172], is a novel transporter of glycine in the brain that regulates extracellular glycine and NMDAR function [173]. SLC6A20A cotransport glycine with Na + and Clions.…”