d‐Amino acids in the brain: d‐serine in neurotransmission and neurodegeneration

Abstract

N-methyl d-aspartate receptors (NMDARs) are key excitatory neurotransmitter receptors in the brain and are involved in many physiological processes, including memory formation, synaptic plasticity and development [1]. The NMDARs are composed of multiple subunits and their activity is regulated by numerous mechanisms, including different ligands and interacting proteins [2]. The NMDARs display high permeability to Ca 2+ , which is known to play a central role in syn-aptic plasticity and many signal transduction mechanisms [1]. NMDAR overstimulation promotes neurotoxicity and is implicated in several pathological conditions, such as stroke and neurodegenerative diseases [3]. The NMDARs are unique in their requirement for more than one agonist to operate. Glutamate, the main NMDAR agonist, does not activate the receptors unless a co-agonist binding site located at the NR1 subunit is occupied [4,5]. d-Serine, an unusual d-amino acid present in mammalian brain, is now recognized as a physiological ligand of the NMDAR co-agonist site, mediating several NMDAR-dependent processes [6-15]. At first, the NMDAR co-agonist site was thought to be occupied by glycine. Hence, the co-agonist site is also generally referred to as the 'glycine site'. In addition, to be essential for NMDAR activity, the co-agonist site exerts neuromodulatory roles. Thus, co-agonist binding increases the receptor's affinity for glutamate [16], decreases its desensitization [17] and promotes NMDAR turnover by internalization [18]. Since its discovery, the role of the co-agonist site in regulating the activity of the NMDAR has been The mammalian brain contains unusually high levels of d-serine, a d-amino acid previously thought to be restricted to some bacteria and insects. In the last few years, studies from several groups have demonstrated that d-serine is a physiological co-agonist of the N-methyl d-aspartate (NMDA) type of glutamate receptor-a key excitatory neurotransmitter receptor in the brain. d-Serine binds with high affinity to a co-agonist site at the NMDA receptors and, along with glutamate, mediates several important physiological and pathological processes, including NMDA receptor transmission, synaptic plasticity and neurotoxicity. In recent years, biosynthetic, degrada-tive and release pathways for d-serine have been identified, indicating that d-serine may function as a transmitter. At first, d-serine was described in astrocytes, a class of glial cells that ensheathes neurons and release several transmitters that modulate neurotransmission. This led to the notion that d-serine is a glia-derived transmitter (or gliotransmitter). However, recent data indicate that serine racemase, the d-serine biosynthetic enzyme, is widely expressed in neurons of the brain, suggesting that d-serine also has a neuronal origin. We now review these findings, focusing on recent questions regarding the roles of glia versus neurons in d-serine signaling. Abbreviations ALS, amyotrophic lateral sclerosis; AMPA, a-amino-3-hydroxy-5-methylisoxazole-4-propionic a...

Crystal Structure of a Zinc-dependent d-Serine Dehydratase from Chicken Kidney

“…In rat brains, the localization of D-amino acid oxidase activity is reciprocal to that of D-serine (8,9), suggesting that D-amino acid oxidase determines the basal levels of D-serine in mammalian brains. However, we have found recently that, in the chicken brain, D-serine is degraded mainly by a D-serine dehydratase (DSD) 4 (10), which catalyzes the ␣,␤-elimination of water from D-serine to form pyruvate and ammonia. In addition, we have found that the chicken DSD (chDSD) has a primary structure similar to those of metal-activated D-threonine aldolases (11)(12)(13), which are fold-type III PLP-dependent enzymes (14), and is distinct from a well known metal-independent bacterial DSD (dsdA) belonging to the foldtype II PLP-dependent enzyme family (14,15).…”

“…The NMDA receptor is a glutamate-gated ion channel (3), and glutamate does not activate the receptor unless a co-agonist binding site is simultaneously occupied by D-serine or glycine (4). Because significant concentrations of D-serine exist in vertebrate brains (5), D-serine is believed to physiologically control the sensitivity of the NMDA receptor to glutamate (6).…”

An in vitro based investigation into the cytotoxic effects of D-amino acids

“…For example, D-serine has been found to modulate the activity of N-methyl-D-aspartate (NMDA) receptor in the brain (6). It is postulated that D-serine binds to the coagonist binding site of the MDA receptor, which is involved in numerous physiological and pathological processes, including synaptic plasticity, learning, memory, neuronal cell migration, and neural diseases (7,8 …”

Study of Amino Acid Composition in a Thalictrum Foetidum L. Herb

“…Furthermore L-Glutamic undergoes the reverse transformation into glutamine under the existence of tissue glutaminase, at the binding ammonia forms. Abovementioned properties of glutamic acid explain its beneficial effect at some central nervous system diseases [7,8]. L-Aspartic plays an important role in the correct function of nervous and endocrine systems and stimulated hormone production (growth hormone, testosterone, progesterone).…”