d-Aspartate modulates melatonin synthesis in rat pinealocytes

doi:10.1016/S0304-3940(98)00414-5

Neuroscience Letters

Volume 249, Issues 2–3, 19 June 1998, Pages 143-146

https://doi.org/10.1016/S0304-3940(98)00414-5 Get rights and content

Abstract

It has been known that pinealocytes contain the highest level of d-aspartate among various neuroendocrine cells in the rat. Here, we report that exogenous d-aspartate strongly inhibited norepinephrine-dependent melatonin synthesis in the rat pineal gland, the concentration required for 50% inhibition being 75 μM. This inhibition was due at least partly to decreased norepinephrine-dependent serotonin N-acetyltransferase activity. Upon incubation, d-aspartate was gradually released from pinealocytes and accumulated in the incubation medium as determined by high-performance liquid chromatography on a Pirkle-type chiral column. These results suggest that d-aspartate acts as a negative regulator for melatonin synthesis in the pineal gland.

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Acknowledgements

H.Y. and S.Y. were supported by Research Fellowship of the Japan Society from Promotion of Science for Young Scientists. This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan, the Terumo Science Foundation, the Chiba-Geigy Foundation (Japan) for the Promotion of Science, and the Salt Science Research Foundation.

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Glutamate can also inhibit AANAT mRNA expression by combination with metabotropic glutamate receptor type 3 (mGluR3) (Villela et al., 2013; Govitrapong and Ebadi, 1988). Moreover, d-aspartate, another excitatory amino acid, can reduce cAMP levels in the pineal gland in vitro, thus inhibiting AANAT mRNA levels (Ishio et al., 1998). However, miR-375-3p overexpression and OGD/R in pinealocytes induing stronger inhibition on the secretion of melatonin compared to cells only under OGD/R may speak of certain synergism, i.e. the presence of factors other than miR-375-3p involved in the OGD/R effect.
The functional roles of microRNAs (miRNAs) have been studied in various diseases, including hypoxic-ischemic brain damage (HIBD). However, changes in the expression of miRNAs and the underlying mechanisms in the pineal gland during HIBD remain unknown. Based on the previous study by microRNA array, hundreds of miRNAs showed altered expression patterns in the pineal gland in a rat model of HIBD. MiR-375-3p was found to be significantly upregulated and abundant in the pineal gland. Further investigation in an in vitro HI model of pinealocytes showed that miRNA-375 exacerbated the damage to pineal function. After oxygen-glucose deprivation / reoxygenation (OGD/R), miR-375-3p expression increased, while aralkylamine N-acetyltransferase (AANAT) expression and melatonin (MT) secretion decreased. Overexpression of miRNA-375 in pinealocytes aggravated the influence of OGD/R on AANAT expression and MT secretion. Because miRNA-375 overexpression in pinealocytes induced decreased rasd1 mRNA and protein expression, rasd1 may mediate the effect of miR-375-3p on pineal function. Furthermore, miR-375-3p aggravated the cognitive impairment caused by HIBD in rats, as observed by Morris water maze test, and also affected emotion and circadian rhythm in HIBD-treated rats. Thus, miR-375-3p may be a key regulatory molecule in the pineal gland following HIBD, and targeting of miR-375-3p may represent a new strategy for the treatment of HIBD.
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Although d-amino acids are less prevalent in nature, they have been detected in mammals (including humans) and it is widely accepted that they might play important physiological roles. While an analytical method for chiral amino acid profiling is strongly required, it has not been well-established because of the difficulties associated with analysis. A high-sensitivity and high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method was recently reported by our group for chiral amino acids; however, it lacked sufficient repeatability for several d-amino acids. Thus, the aim of this research was to reduce the experimental variation of chiral amino acid analysis. By installing an automatic switching valve system in LC-MS/MS, it was possible to reduce the relative standard deviations of d-amino acid ratios (d/(d+l)) in rat urine obtained from three technical replicates. The results indicated that the automatic switching valve system was effective in minimizing the variation of d-amino acid ratios, and could be applied for profiling d-amino acids because of its high repeatability.
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d-Ser is found in the brain, especially in the cerebral cortex and hippocampus, where it modulates neurotransmission upon binding as a coagonist to the Gly site of the N-methyl-d-aspartate (NMDA) receptor, a subtype of the ionotropic glutamate receptor [4,5]. The d-Asp concentration is maintained at high levels in the brain, pineal gland, pituitary gland and testis, and is associated with the regulation of hormonal secretion and steroidogenesis [6–15]. It was recently reported that d-glutamate (d-Glu) is metabolized in the mammalian heart by d-glutamate cyclase that converts d-Glu to 5-oxo-d-proline (5-oxo-d-Pro), although the physiological significance remains unclear at present [16].
Biomolecular homochirality refers to the assumption that amino acids in all living organisms were believed to be of the l-configuration. However, free d-amino acids are present in a wide variety of organisms and d-amino acid residues are also found in various peptides and proteins, being generated by enzymatic or non-enzymatic isomerization. In mammals, peptides and proteins containing d-amino acids have been linked to various diseases, and they act as novel disease biomarkers. Analytical methods capable of precisely detecting and quantifying d-amino acids in peptides and proteins are therefore important and useful, albeit their difficulty and complexity. Herein, we reviewed conventional analytical methods, especially 0 h extrapolating method, and the problems of this method. For the solution of these problems, we furthermore described our recently developed, sensitive method, deuterium-hydrogen exchange method, to detect innate d-amino acid residues in peptides and proteins, and its applications to sample ovalbumin. This article is part of a Special Issue entitled: d-Amino acids: biology in the mirror, edited by Dr. Loredano Pollegioni, Dr. Jean-Pierre Mothet and Dr. Molla Gianluca.
Simultaneous analysis of D-alanine, D-aspartic acid, and D-serine using chiral high-performance liquid chromatography-tandem mass spectrometry and its application to the rat plasma and tissues
2015, Journal of Pharmaceutical and Biomedical Analysis
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The concentrations of d-Ala were consistent with our previous results (86.4 ± 9.9 nmol/g for anterior pituitary gland, 14.7 ± 2.5 nmol/g for intermediate and posterior pituitary gland, 29.2 ± 5.0 nmol/g for pancreas) [18]. Concerning d-Asp, it was reported to control the synthesis of melatonin in the pineal gland, and promote the secretion of prolactin in the pituitary gland [13–16], and the amounts of d-Asp found in the present paper also agreed with a previous report (3524 ± 263 nmol/g for pineal gland and 80.5 ± 9.0 nmol/g for pituitary gland) [2]. The localization of d-Ser in the brain was first reported by Hashimoto and Nishikawa in 1992 [37] and the functions and the mechanisms to control the d-Ser amounts in the brain have been progressively clarified [38–40].
A highly sensitive and selective chiral LC-MS/MS method for d-alanine, d-aspartic acid and d-serine has been developed using the precolumn derivatization reagents, 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AccQ-Tag) or p-N,N,N-trimethylammonioanilyl N'-hydroxysuccinimidyl carbamate iodide (TAHS). The thus N-tagged enantiomers of the derivatized amino acids were nicely separated within 20 min using the cinchona alkaloid-based zwittterionic ion-exchange type enantioselective column, Chiralpak ZWIX(+). The selected reaction monitoring was applied for detecting the target d-amino acids in biological matrices. By using the present chiral LC-MS/MS method, the three d-amino acids and their l-forms could be simultaneously determined in the range of 0.1–500 nmol/mL. Finally, the technique was successfully applied to rat plasma and tissue samples.

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d-Aspartate modulates melatonin synthesis in rat pinealocytes

Abstract

Section snippets

Acknowledgements

Neuron

Life Sci.

Biochim. Biophys. Acta

Prog. Neurobiol.

Biochem. Biophys. Res. Commun.

FEBS Lett.

J. Biol. Chem.

J. Chromatogr.

Anal. Biochem.