Neurobiology through the looking-glass: D-serine as a new glial-derived transmitter.
D-Amino acids have been known to be present in bacteria for more than 50 years, but only recently they were identified in mammals. The occurrence of D-amino acids in mammals challenge classic concepts in biology in which only L-amino acids would be present or thought to play important roles. Recent discoveries uncovered a role of endogenous D-serine as a putative glial-derived transmitter that regulates glutamatergic neurotransmission in mammalian brain. Free D-serine levels in the brain are about one third of L-serine values and its extracellular concentration is higher than many common L-amino acids. D-Serine occurs in protoplasmic astrocytes, a class of glial cells that ensheath the synapses and modulate neuronal activity. Biochemical and electrophysiological studies suggest that endogenous D-serine is a physiological modulator at the co-agonist site of NMDA-type of glutamate receptors. We previously showed that D-serine is synthesized by a glial serine racemase, a novel enzyme converting L- to D-serine in mammalian brain. The enzyme requires pyridoxal 5'-phosphate and it was the first racemase to be cloned from eucaryotes. Inhibitors of serine racemase have therapeutic implications for pathological processes in which over-stimulation of NMDA receptors takes place, such as stroke and neurodegenerative diseases. Here, we review the role of endogenous D-serine in modulating NMDA neurotransmission, its biosynthetic apparatus and the potential usefulness of serine racemase inhibitors as a novel neuroprotective strategy to decrease glutamate/NMDA excitotoxicity.
Wolosker
Herman
H
Department of Biochemistry, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, P.O. Box 9649, Bat Galim, 31096, Haifa, Israel. hwolosker@tx.technion.ac.il
Panizzutti
Rogerio
R
De Miranda
Joari
J
D000818:Animals; D006801:Humans; D009457:Neuroglia / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000502:physiology*; D019998:Racemases and Epimerases / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D012559:Schizophrenia / Q000503:physiopathology; D012694:Serine / Q000502:physiology*; D000099300:Serine Racemase
D018377:Neurotransmitter Agents; D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D000099300:Serine Racemase