D‐Aspartic acid is a novel endogenous neurotransmitter

Abstract

D-aspartic acid (D-Asp) is present in invertebrate and vertebrate neuroendocrine tissues, where it carries out important physiological functions and is implicated in nervous system development. We show here that D-Asp is a novel endogenous neurotransmitter in two distantly related animals, a mammal (Rattus norvegicus) and a mollusk (Loligo vulgaris). Our main findings demonstrate that D-Asp is present in high concentrations in the synaptic vesicles of axon terminals; synthesis for this amino acid occurs in neurons by conversion of L-Asp to D-Asp via D-aspartate racemase; depolarization of nerve endings with K(+) ions evokes an immediate release of D-Asp in a Ca(2+) dependent manner; specific receptors for D-Asp occur at the postsynaptic membrane, as demonstrated by binding assays and by the expansion of squid skin chromatophores; D-aspartate oxidase, the specific enzyme that oxidizes D-Asp, is present in the postsynaptic membranes; and stimulation of nerve endings with D-Asp triggers signal transduction by increasing the second messenger cAMP. Taken together, these data demonstrate that D-Asp fulfills all criteria necessary to be considered a novel endogenous neurotransmitter. Given its known role in neurogenesis, learning, and neuropathologies, our results have important implications for biomedical and clinical research.

MicroRNAs in Schizophrenia: Implications for Synaptic Plasticity and Dopamine–Glutamate Interaction at the Postsynaptic Density. New Avenues for Antipsychotic Treatment Under a Theranostic Perspective

“…More recently, a role of the "noncanonical" aminoacid Daspartate, which stimulates NMDA receptors through its direct binding at the glutamate site of this receptor [131,132], has been suggested in schizophrenia pathophysiology [133]. Intriguingly, increased levels of D-aspartate have been demonstrated to counteract the locomotor effect of amphetamine in D-aspartate oxidase (DDO) deficient animals and therefore to influence indirectly dopaminergic function [134].…”

Discovery of a novel amino acid racemase through exploration of natural variation in Arabidopsis thaliana

“…Bacteria use D-amino acids as paracrine and autocrine effectors by secreting large amounts into their surroundings to trigger population transition to stationary-phase growth and to regulate cell-wall architecture (11). In the mammalian nervous system, D-Asp is involved in development and acts as a neurotransmitter, and in the endocrine system it is an important player in hormone synthesis and release from the hypothalamus, pituitary glands, and gonads (12). D-Ser is a coregulator of NMDA receptors and an important component in excitatory neurotransmission in the cerebral cortex and hippocampus and plays a role in learning, memory, and behavior (13).…”

“…In bacteria, D-amino acids confer cell-wall protease resistance and regulate cell-wall remodeling (9-11). D-amino acids were also found to be involved in signaling mechanisms in animal nervous systems and plant pollination (12,13). Enzymes that catalyze the conversion of L-amino acids to D-amino acids are a class of isomerases known as amino acid racemases (14).…”

Nutritional and medicinal aspects of d-amino acids

“…D-Asp was found to accumulate in the pituitary with concurrent diminished synthesis and levels of pituitary proopiomelanocortin (Huang et al 2006), D-Asp shows potential for pharmacologic use. It was involved in cell-to-cell signaling in neuron-containing ganglia of the California sea slug (Scanlan et al 2010), behaved as a neurotransmitter in the central nervous system of vertebrates and invertebrates (D'Aniello et al 2011;Topo et al 2010b), regulated the growth of nerve cells, learning, and memory , and exhibited neuromodulatory action at glutamatergic synapses that might play a beneficial role in conditions related to mammalian brain pathology (Errico et al 2009). D-Asp also regulated reproductive activity in animals and humans and improved semen quality in rabbit bucks (Macchia et al 2010).…”