Elsevier

Brain Research Reviews

Volume 53, Issue 2, February 2007, Pages 215-234
Brain Research Reviews

Review
d-Aspartic acid: An endogenous amino acid with an important neuroendocrine role

https://doi.org/10.1016/j.brainresrev.2006.08.005Get rights and content

Abstract

d-Aspartic acid (d-Asp), an endogenous amino acid present in vertebrates and invertebrates, plays an important role in the neuroendocrine system, as well as in the development of the nervous system. During the embryonic stage of birds and the early postnatal life of mammals, a transient high concentration of d-Asp takes place in the brain and in the retina. d-Asp also acts as a neurotransmitter/neuromodulator. Indeed, this amino acid has been detected in synaptosomes and in synaptic vesicles, where it is released after chemical (K+ ion, ionomycin) or electric stimuli. Furthermore, d-Asp increases cAMP in neuronal cells and is transported from the synaptic clefts to presynaptic nerve cells through a specific transporter. In the endocrine system, instead, d-Asp is involved in the regulation of hormone synthesis and release. For example, in the rat hypothalamus, it enhances gonadotropin-releasing hormone (GnRH) release and induces oxytocin and vasopressin mRNA synthesis. In the pituitary gland, it stimulates the secretion of the following hormones: prolactin (PRL), luteinizing hormone (LH), and growth hormone (GH) In the testes, it is present in Leydig cells and is involved in testosterone and progesterone release. Thus, a hypothalamus–pituitary–gonads pathway, in which d-Asp is involved, has been formulated. In conclusion, the present work is a summary of previous and current research done on the role of d-Asp in the nervous and endocrine systems of invertebrates and vertebrates, including mammals.

Section snippets

Introduction: stereochemical consideration on d-amino acids

Stereochemical configuration of the α-carbon atom of amino acids is fundamental to all living systems. All the amino acids found in proteins (except for glycine) are optically active and have the same stereochemical configuration as the α-carbon atom. The prefix l attached to these amino acids goes back to half a century ago when Louis Pasteur in 1851 (Pasteur, 1851) observed that asparagine, the first natural amino acid discovered by Vauquelin and Robiquet in 1806 (Vauquelin and Robiquet, 1806

d-Amino acids in peptides and proteins

The first d-amino acids detected in living organisms were discovered in some plants and bacteria about 50 years ago (Corrigan, 1969, Meister et al., 1965). These compounds were either found in a free state or were incorporated in peptides and protein linkages. Indeed, a number of antibiotics (e.g., polymixin, bacitracin, gramicidin, actinomycins, etc.) and bacterial cell walls contain d-amino acid residues in peptides bound to l-amino acids. In the last case, d-amino acids seem to constitute a

d-Amino acids in animal tissues

The principal free d-amino acids found in significant quantities in animal tissues are d-Ala, d-Ser and d-Asp. d-Ala was first discovered in the blood of the milkweed bug Oncopeltus fasciata and in the larva of the monarch butterfly Danaus plexippus (Meister et al., 1965). Later, it was also found in marine crustaceans (Abe et al., 1999, D'Aniello and Giuditta, 1980, Okuma and Abe, 1994), in eggs and embryos of echinoderms (D'Aniello et al., 1990), and in bivalve mollusks (Okuma et al., 1998).

d-Aspartic acid in animal tissues

d-Asp is the mostly widespread amino acid in animal tissues. Back in 1977, we discovered its presence in the brain and optic lobes of the cephalopod mollusk Octopus vulgaris (common octopus) (D'Aniello and Giuditta, 1977). Later, it was found not only in the peripheral nervous system (stellate ganglia and in the axoplasm fluid of the giant axon) of the cephalopods Sepia officinalis (common cuttlefish) and Loligo vulgaris (common squid) (D'Aniello and Giuditta, 1978, D'Aniello et al., 1995b),

d-Aspartic acid in the nervous system: general consideration

Many data suggest that d-Asp promotes the synthesis of proteins involved in the development of the nervous system and acts as a neurotransmitter or neuromodulator at synapses. For instance, it has been observed that in the brain and retina of 13- to 14-day-old chicken embryos, transient high concentrations of d-Asp occur (about 230–260 nmol/g tissue and 550–650 nmol/g tissue, respectively). After this stage, the d-Asp concentrations rapidly decrease to very low levels (about 20–40 nmol/g

d-Aspartic acid in the endocrine system: general considerations

It has been demonstrated that in the nervous system of chicken, rat and human embryos, d-Asp occurs at high concentrations. By contrast, it practically disappears from the nervous tissues of adult animals but increases in endocrine glands (Table 1). The latter phenomenon, clearly highlighting d-Asp involvement in the endocrine activity of the adult animal, and, more generally, in endocrinology, has been substantially supported by the rich array of studies burgeoning in this field in the past

d-Aspartic acid as a precursor for the synthesis of NMDA

Recently, we have demonstrated that N-methyl-d-aspartic acid (NMDA) is a molecule present in the rat neuroendocrine system (D'Aniello et al., 2000a, D'Aniello et al., 2000b), in C. intestinalis (D'Aniello et al., 2003), and in other animal phyla (D'Aniello et al., 2002). Synthetic NMDA is well known for its stimulatory action on the NMDA-type l-glutamate receptor. Then, in addition to having this stimulatory effect, NMDA is also known to induce hormone release in the hypothalamus and

Conclusion on the role of d-aspartic acid and NMDA

In conclusion, the evidence so far accumulated suggests that d-Asp plays a dual role: a role in the nervous system and a role in the endocrine system.

In the nervous system, some studies have pinpointed that in the chicken brain and retina a transient high concentration of d-Asp occurs in the last stage of the animal's embryonic life. The same event occurs in the rat brain and retina during the early postnatal life (Dunlop et al., 1986, Hashimoto et al., 1993b, Neidle and Dunlop, 1990).

d-Aspartate oxidase: the key enzyme for measuring the concentration of d-Asp and NMDA

The last part of the present review contains a brief summary of the methods we developed to detect low quantities of d-Asp and NMDA. Since d-aspartate oxidase constituted the essential tool for the determination of d-Asp and NMDA, we will first describe some of its main characteristics and then each specific method.

d-Aspartate oxidase (d-AspO; EC 1.4.3.1), a peroxysomal enzyme with a molecular weight of about 40 kDa, is a flavoprotein that containing two FAD (flavin–adenin-dinucleotide)

Determination of total d-Asp, d-Glu and NMDA and specific analysis for d-Asp or NMDA

The total amount of d-Asp, d-Glu and NMDA is determined by various colorimetric or fluorimetric methods based on the determination of the α-ketoacid or H2O2 (Gross and Sirer, 1959) developed by the oxidation of one of the above amino acids by d-AspO according to the following reaction:

NH3 is developed if the substrate is d-Asp or d-Glu, whereas CH3-NH2 (methylamine) is developed if the substrate is NMDA (D'Aniello and Giuditta, 1977, D'Aniello et al., 1993a, D'Aniello et al., 1993b, D'Aniello

Future prospects

On the basis of what has been discovered so far on d-Asp and NMDA, it would be of great scientific interest to delve deeper into the molecular mechanisms and signal transduction mechanisms that are elicited by these two amino acids in the nervous and endocrine systems. The theory that d-Asp is involved in the nervous system has been based on the fact that in chickens, during the last embryonic stage (Dunlop et al., 1986), and in rats, during the early neonatal life (Neidle and Dunlop, 1990), a

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