Intracellular D-serine homeostasis

Intracellular D-serine homeostasis refers to the tightly regulated biological process that maintains optimal concentrations of D-serine, a critical endogenous co-agonist of the N-methyl-D-aspartate (NMDA) receptor (Wolosker, 2018). This homeostasis is primarily governed by the synthetic enzyme serine racemase (SRR), which converts L-serine to D-serine, and the degradative enzyme D-amino acid oxidase (DAAO) (Pollegioni et al., 2018). Additionally, transporters such as the alanine-serine-cysteine transporter 1 (Asc-1/SLC7A10) and ASCT1/2 (SLC1A4/5) play vital roles in the cellular uptake and release of D-serine (Rosenberg et al., 2013). Dysregulation of this system is a hallmark of several neurological conditions; for instance, reduced D-serine levels contribute to NMDA receptor hypofunction in schizophrenia, while excessive levels are linked to excitotoxicity in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (Coyle et al., 2003; Sasabe et al., 2007). Therapeutic strategies targeting this pathway include DAAO inhibitors like luvadaxistat (TAK-831) and sodium benzoate, which aim to increase D-serine availability to improve cognitive function (Sacchi et al., 2012). Monitoring D-serine levels or the D-serine/L-serine ratio in cerebrospinal fluid or plasma serves as a key biomarker for evaluating the state of this homeostatic system in clinical settings.

Other names

D-serine metabolismD-serine signaling pathwayD-serine regulationD-serine shuttle

D-amino acid oxidase inhibition, Serine racemase modulation, and NMDA receptor co-agonism