한빛사 논문
Mihyun Bae1†, Junyeop Daniel Roh2†, Youjoung Kim2, Seong Soon Kim3, Hye Min Han4, Esther Yang5, Hyojin Kang6, Suho Lee1, Jin Yong Kim5, Ryeonghwa Kang2, Hwajin Jung1, Taesun Yoo1, Hyosang Kim2, Doyoun Kim1, Heejeong Oh2, Sungwook Han2, Dayeon Kim7, Jinju Han7, Yong Chul Bae4, Hyun Kim5, Sunjoo Ahn3, Andrew M Chan8, Daeyoup Lee2, Jin Woo Kim2 and Eunjoon Kim*,1,2
1Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, Korea
2Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon, Korea
3Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, Korea
4Department of Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, Korea
5Department of Anatomy and Division of Brain Korea 21, Biomedical Science, College of Medicine, Korea University, Seoul, Korea
6Division of National Supercomputing, KISTI, Daejeon, Korea
7Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea
8School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
†These authors contributed equally to this work.
*Corresponding author
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.
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