Serine racemase and the serine shuttle between neurons and astrocytes

d-Serine is a brain-enriched d-amino acid that works as a transmitter-like molecule by physiologically activating NMDA receptors. Synthesis of d-serine is carried out by serine racemase (SR), a pyridoxal 5′-phosphate-dependent enzyme. In addition to carry out racemization, SR α,β-eliminates water from l- or d-serine, generating pyruvate and NH4+. Here I review the main mechanisms regulating SR activity and d-serine dynamics in the brain. I propose a role for SR in a novel form of astrocyte-neuron communication—the “serine shuttle”, whereby astrocytes synthesize and export l-serine required for the synthesis of d-serine by the predominantly neuronal SR. d-Serine synthesized and released by neurons can be further taken up by astrocytes for storage and activity-dependent release. I discuss how SR α,β-elimination with d-serine itself may limit the achievable intracellular d-serine concentration, providing a mechanistic rationale on why neurons do not store as much d-serine as astrocytes. The higher content of d-serine in astrocytes appears to be related to increased d-serine stability, for their low SR expression will prevent substantial d-serine metabolism via α,β-elimination. SR and the serine shuttle pathway are therapeutic targets in neurodegenerative diseases in which NMDA receptor dysfunction plays pathological roles. This article is part of a Special Issue entitled: Pyridoxal Phospate Enzymology.

Research highlights
► Mechanisms of d-serine synthesis by serine racemase
► Role of serine racemase elimination reaction in limiting the achievable intracellular d-serine concentration and providing a mechanistic rationale on why neurons do not store as much d-serine as astrocytes.
► I propose the serine shuttle model, whereby astrocytes synthesize and export l-serine required for the synthesis of d-serine by the predominantly neuronal serine racemase.
► d-Serine synthesized and released by neurons can be further taken up by astrocytes for storage and activity-dependent release.