Unconventional transmitters and neurodegeneration

Proposed model of ASCT1 function in the serine shuttle. Astrocytic ASCT1 releases L-Ser, which is subsequently taken up by neurons to fuel the synthesis of D-serine by the serine racemase (SR). D-serine released by neurons via plasma membrane transporters (e.g., Asc-1) is taken up by the ASCT1 in astrocytes for storage or degradation by the D-amino acid oxidase (DAO) enzyme. L-Alanine produced in neurons by the alanine aminotransferase (ALT) along with extracellular L-threonine and D-serine serve as extracellular substrates that trigger the L-serine export via ASCT1 by heteroexchange. Deletion of ASCT1 decreases L-serine export and D-serine synthesis while impairing the astrocytic metabolism of L-alanine and L-threonine and promoting their accumulation. Lower release of astrocytic L-serine in ASCT1-KO mice will lead to its conversion to glycine by the serine hydroxymethyltransferase (SHMT) enzyme. When the serine shuttle is impaired, glycine taken up by neurons (dashed arrow) may provide a compensatory pathway for supplying L-serine to neurons that can be generated by SHMT. For details see Kaplan et al, 2018