D-Amino Acids in the Nervous and Endocrine Systems

Abstract

Amino acids are important components for peptides and proteins and act as signal transmitters. Only L-amino acids have been considered necessary in mammals, including humans. However, diverse D-amino acids, such as D-serine, D-aspartate, D-alanine, and D-cysteine, are found in mammals. Physiological roles of these D-amino acids not only in the nervous system but also in the endocrine system are being gradually revealed. N-Methyl-D-aspartate (NMDA) receptors are associated with learning and memory. D-Serine, D-aspartate, and D-alanine can all bind to NMDA receptors. H₂S generated from D-cysteine reduces disulfide bonds in receptors and potentiates their activity. Aberrant receptor activity is related to diseases of the central nervous system (CNS), such as Alzheimer's disease, amyotrophic lateral sclerosis, and schizophrenia. Furthermore, D-amino acids are detected in parts of the endocrine system, such as the pineal gland, hypothalamus, pituitary gland, pancreas, adrenal gland, and testis. D-Aspartate is being investigated for the regulation of hormone release from various endocrine organs. Here we focused on recent findings regarding the synthesis and physiological functions of D-amino acids in the nervous and endocrine systems.

Figure 1

The synthesis of D-serine in the central nervous systems (CNS). D-Serine is synthesized by serine racemase (SR). SR is inhibited by its translocation from the cytosol to a membrane, such as the endoplasmic reticulum (ER) or plasma membranes, all of which contain phosphatidylinositol 4,5-bisphosphate (PIP₂). F-box only protein 22 (FBXO22) interacts with SR and activates SR by preventing it from binding to the ER membrane. In astrocytes, glutamate receptor interacting protein 1 (GRIP1) binds to the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor and GRIP1 is then released from the AMPA receptor following stimulation with L-glutamate. Released GRIP1 activates SR. Protein interacting with C-kinase (PICK1) binds to erythropoietin-producing hepatocellular receptor (Eph)B3 or EphA4 in the astrocytes. PICK1 is released after ephrinB3 on the neurons interacts with the EphB3 or EphA4 receptor and then activates SR. Stargazin forms a complex with the AMPA receptor, postsynaptic density protein 95 (PSD-95), and SR and inhibits the activity of SR by promoting membrane localization in neurons. After the AMPA receptor is activated, SR is released from the plasma membrane, resulting in the activation of SR. The N-methyl-D-aspartate (NMDA) receptor is activated by glutamate and D-serine.

Figure 2

Activation of the N-methyl-D-aspartate (NMDA) receptor by D-cysteine. D-Cysteine is one of the sources of H₂S in the brain. D-Cysteine is converted to 3-mercaptopyruvate (3MP) by D-amino acid oxidase (DAO). 3MP is then degraded by 3-mercaptopyruvate sulfurtransferase (3MST) to generate H₂S in the neurons. Hydrogen polysulfides (H₂S_n; n = 2–5) are also generated by 3MST from 3MP. H₂S reduces the disulfide bonds in the NMDA receptor and increases the activity of the NMDA receptor. H₂S_n also activates the transient receptor potential (TRP) A1 channel. Activated TRPA1 channel induces Ca²⁺ influx, leading to D-serine release in astrocytes, and D-serine then activates the NMDA receptor.