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Concentrations of intracellular D-serine and L-serine in wild type (WT) and serine racemase–knockout (SR-KO) keratinocytes (KCs) cultured in medium with and without the addition of L-serine. (a) Concentrations of intracellular D-serine and L-serine in extracts of KCs cultured in medium without addition of L-serine. (b) Concentrations of intracellular D-serine and L-serine in extracts of KCs cultured in medium with addition of 10 mM L-serine. Data are presented as mean±SEM (n=7). *P<0.05; ***P<0.001; two-tailed Student’s t-test.Download Power Point slide (226 KB)
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D-Serine is an endogenous coagonist of the N-methyl-D-aspartate (NMDA)-type glutamate receptor in the central nervous system and its synthesis is catalyzed by serine racemase (SR). Recently, the NMDA receptor has been found to be expressed in keratinocytes (KCs) of the skin and involved in the regulation of KC growth and differentiation. However, t...
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... Compared with the C group, the skin tissue contents of L-serine, L-histidine, imidazole-4-acetaldehyde, palmitoyl ethanolamide, and glyoxylic acid were significantly upregulated, whereas the contents of glutamic acid, N-acetylglutamine, panthenol, and dimethyl ethanolamine were significantly downregulated in fine cashmere-producing Tibetan cashmere goats. L-serine (upregulated in the F group) is a neglected amino acid with some potential therapeutic roles, and its supplementation in epidermal keratinocyte proliferation and skin health [29] has been shown to improve glucose homeostasis and mitochondrial function and reduce neuronal death [30]. Palmitoyl CoA and serine, on the other hand, are precursors for sphingolipids, a class of lipid signalling molecules involved in diverse cellular processes. ...
... In addition to its role in the CNS, D-serine is present in the peripheral tissues of both vertebrates and invertebrates (Nagata et al., 2006;Horio et al., 2011;Tanigawa et al., 2016). In mammals, D-serine functions in the differentiation and maintenance of the skin (Inoue et al., 2014). The enzyme serine racemase converts L-serine into D-serine (Wolosker et al., 1999). ...
... For example, SR expression is increased in confluent keratinocyte cultures compared to cultures in the growing phase. 23 P19 murine embryonal carcinoma cells are a widely accepted in vitro model for early neurogenesis. 24 P19 cells express SR when induced to differentiate into neurons or glia with all-trans retinoic acid (RA). ...
... The correlation between elevated SR expression levels and differentiation observed here was consistent with previous reports. 23,25 In particular, the differentiation of P19 cells was previously shown to be coupled with SR expression, but was not affected by the inhibition of D-serine synthesis. 25 Similar to these findings, in our study we demonstrated that addition of D-serine did not rescue the differentiation deficit in SR-knockdown N2A cells. ...
Although the role of serine racemase (SR) in neuropsychiatric disorders has been extensively studied, its role in cell proliferation and differentiation remains unclear. Deletion of Srr, the encoding gene for SR, has been shown to reduce dendritic arborization and dendritic spine density in the brains of adult mice, whereas increased SR levels have been associated with differentiation in cell cultures. Previously, we demonstrated that valproic acid induces differentiation in the N2A neuroblastoma cell line, and that this differentiation is associated with increased SR expression. These observations suggest that SR may have a role in cell proliferation and differentiation. We herein found that both valproic acid and all‐trans retinoic acid induced N2A differentiation. In contrast, knockdown of SR reduced levels of differentiation, increased N2A proliferation, promoted cell cycle entry, and modulated expression of cell cycle‐related proteins. To further evaluate the effects of SR expression on cell proliferation and differentiation, we used an in vivo model of neuroblastoma in nude mice. N2A cells stably expressing scramble shRNA (Srrwt‐N2A) or specific Srr shRNA (Srrkd‐N2A) were subcutaneously injected into nude mice. The weights and volumes of Srrwt‐N2A‐derived tumors were lower than Srrkd‐N2A‐derived tumors. Furthermore, Srrwt‐N2A‐derived tumors were significantly mitigated by intraperitoneal injection of valproic acid, whereas Srrkd‐N2A‐derived tumors were unaffected. Taken together, our findings demonstrate for the first time that alterations in SR expression determine the transition between proliferation and differentiation in neural progenitor cells. Thus, in addition to its well‐established roles in neuropsychiatric disorders, our study has highlighted a novel role for SR in cell proliferation and differentiation.
... Serine racemase (SR) is widely expressed in the peripheral tissues and CNS, with higher expression in the forebrain (Foltyn et al., 2005;Inoue et al., 2014;Wu, Barger, & Sims, 2004). Particularly, neurons contain a higher amount of SR with relatively less amount in astroglia and microglia (Kartvelishvily et al., 2006;Sasabe et al., 2007;Schell et al., 1995;Wu, Bodles, et al., 2004). ...
Dysregulation of insulin signaling in the Alzheimer's disease (AD) brain has been extensively reported. Serine racemase (SR) modulates insulin secretion in pancreatic islets. This study aimed to examine whether SR regulates insulin synthesis and secretion in neurons, thereby modulating insulin signaling in the AD brain. Srr‐knockout (Srr−/−) mice generated with the CRISPR/Cas9 technique were used. Using immunofluorescence and fluorescence in situ hybridization, levels of insulin protein and insulin(ins2) mRNA were significantly increased in the hippocampal but not in hypothalamic sections of Srr−/− mice compared with WT mice. Real‐time quantitative PCR revealed that ins2 mRNA from primary hippocampal neuronal cultures of Srr−/− mice was significantly increased compared with that from cultured neurons of WT mice. Notably, the secretion of proinsulin C‐peptide was increased in Srr−/− neurons relative to WT neurons. By examining membrane fractional proteins with immunoblotting, Srr−/− neurons retained ATP‐dependent potassium channels on plasmalemma and correspondingly contained higher levels of p‐AMPK. After treatment with Aβ42, the phosphorylation levels of insulin receptor substrate at serine 616 636 (p‐IRS1ser616,636) were significantly lower, whereas p‐AKT³⁰⁸ and p‐AKT⁴⁷³ were higher in Srr−/− neurons than in WT neurons, respectively. The phosphorylated form of c‐Jun N‐terminal kinase decreased in the cultured Srr−/− neurons relative to the WT neurons upon Aβ42 treatment. In contrast, phosphorylated protein kinase R remained at the same levels. Further, reactive oxygen species were reduced in cultured Srr−/− neurons under Aβ42 treatment relative to the WT neurons. Collectively, our study indicated that Srr deletion promoted insulin synthesis and secretion of proinsulin C‐peptide, thereby reversing insulin resistance by Aβ42. This study suggests that targeting the neuronal SR may be utilized to enhance insulin signaling which is inhibited at the early stage of the AD brain. image
... Recently, it has been found that a variety of bacteria can produce D-AAs at concentrations up to 1 mM (Cava et al. 2011;Lam et al. 2009). D-AAs also may be generated from the racemization of L-AAs during the alkaline, heat pretreatment and fermentation of the organic matter (Sheykhkarimli et al. 2014;Conrad et al. 2010;Inoue et al., 2014). Additionally, synthetic D-AAs mainly come from pharmaceutical, and agrochemical industry (Elgamoudi et al. 2020;Gao et al. 2015;Chattopadhyay et al. 2014). ...
Amino acids (AAs) are important intermediate metabolites during the anaerobic digestion (AD) of protein-rich organic matter. L (levorotatory, left-handed) AAs are the predominant AAs found in proteolysis process, and can be converted to D (dextrorotatory, right-handed)-AAs. Alkaline, heat pretreatment and fermentation of the organic matter may lead to the transformation of AAs configuration, that is, L-AAs and D-AAs co-exist in the AD system. D-Ala, D-Asp, and D-Glu are the most frequently detected in food waste. D-AAs also widely exist in seeds, leaves and the extracellular biomolecules of bacterial cell walls and can be applied in pharmaceutical industry and agrochemical industry. Compared with L-AAs, D-AAs is not easily decomposed by microorganisms, thus D-AAs accumulate in waste/wastewater or natural environments. Many evidences showed that D-AAs have specific biological functions. AAs and their enantiomers have certain biological characteristics which are closely related to their configuration, which will have different effects on the microorganisms in the anaerobic system, and eventually affect the stability of AD and the yield of biogas. Therefore, this paper mainly reviews the distribution of AAs and enantiomeric function in AD system, analyzes the promoting/inhibitory effect of AAs on AD and the mechanisms, and puts forward some suggestions for future studies of AD of organic matter.
... D-Serine (Ser) has been shown to be a co-agonist of the N-methyl-D-aspartate subtype of the glutamate receptors and modulates the neuro-transmission in the cerebrum and cerebellum [10]. D-Ser has also been reported to have a protecting effect in the skin [11]. Concerning hydroxy amino acids, the D-forms of threonine (Thr) and allo-threonine (aThr) are also found in mammalian brain and physiological fluids [12,13]. ...
A fully-automated two-dimensional (2D) HPLC system for the determination of serine (Ser), threonine (Thr) and allo-threonine (aThr) enantiomers was developed. The system was validated and applied to the determination of the target hydroxy amino acid enantiomers in vinegar samples including the Japanese traditional amber rice vinegar. The Japanese traditional amber rice vinegar is one of the typical natural fermented products containing high levels of D-amino acids, and the clarification of the amounts of hydroxy amino acid enantiomers is expected. For the on-line 2D-HPLC system, a narrowbore ODS column (Singularity RP18, 1.0 x 250 mm) was used in the first dimension, and an originally-designed Pirkle-type chiral stationary phase (Singularity CSP-013S, 1.5 x 250 mm) was utilized in the second dimension. The target hydroxy amino acids were derivatized with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) and detected by their fluorescence (ex. 470 nm, em. 530 nm). The concentrations and the %D values were compared among a grain vinegar, a widely-distributed black vinegar and Japanese traditional amber rice vinegars (fermented/aged 1 or 5 years by microorganisms in an earthenware jar). The amounts of hydroxy amino acid enantiomers were low (0.21-0.38 μmol/mL, only L-forms) in the grain vinegar, and relatively high amounts of the L-forms were observed (1.05-1.61 μmol/mL) in the widely-distributed black vinegar. On the other hand, clear peaks of the D-forms (0.16-0.86 μmol/mL for D-Ser, 0.02-0.11 μmol/mL for D-aThr) as well as high amounts of the L-forms (2.27-2.51 μmol/mL for L-Ser, 1.85-2.10 μmol/mL for L-Thr) were observed in the Japanese traditional amber rice vinegars. The amounts of D-Ser and D-aThr clearly increased with increasing the fermentation/aging period. This is the first report showing the profiles of the hydroxy amino acid enantiomers simultaneously, and further investigations using various fermented food/beverage samples are expected.
... During the bone mineralization of rats, SRR is expressed in the proliferating chondrocytes, and d-serine exposure affects the chondrocytes' maturation in cell culture (13). In mammalian skin, the presence of d-serine is concomitant with the expressions of SRR and GluNs (14,15). Studies in mice showed that d-serine participates in keratinocyte differentiation by acting on proteins such as involucrin, K10, and TGase3 (15). ...
... In mammalian skin, the presence of d-serine is concomitant with the expressions of SRR and GluNs (14,15). Studies in mice showed that d-serine participates in keratinocyte differentiation by acting on proteins such as involucrin, K10, and TGase3 (15). In the case of skin injury, d-serine participates in homeostasis maintenance and recovery; a flux of cations mediated through NMDARs allows lamellar granule exocytosis from the keratinocytes, leading to skin permeabilization (15,16). ...
... Studies in mice showed that d-serine participates in keratinocyte differentiation by acting on proteins such as involucrin, K10, and TGase3 (15). In the case of skin injury, d-serine participates in homeostasis maintenance and recovery; a flux of cations mediated through NMDARs allows lamellar granule exocytosis from the keratinocytes, leading to skin permeabilization (15,16). A misregulation of calcium dynamics in keratinocytes can lead to pathologies such as Darier's disease and Hailey-Hailey disease (17,18), and a better understanding of the functions of d-serine in skin is thus required. ...
d -Serine, a free amino acid synthesized by serine racemase, is a coagonist of N -methyl- d -aspartate–type glutamate receptor (NMDAR). d -Serine in the mammalian central nervous system modulates glutamatergic transmission. Functions of d -serine in mammalian peripheral tissues such as skin have also been described. However, d -serine’s functions in nonmammals are unclear. Here, we characterized d -serine–dependent vesicle release from the epidermis during metamorphosis of the tunicate Ciona . d -Serine leads to the formation of a pocket that facilitates the arrival of migrating tissue during tail regression. NMDAR is the receptor of d -serine in the formation of the epidermal pocket. The epidermal pocket is formed by the release of epidermal vesicles’ content mediated by d -serine/NMDAR. This mechanism is similar to observations of keratinocyte vesicle exocytosis in mammalian skin. Our findings provide a better understanding of the maintenance of epidermal homeostasis in animals and contribute to further evolutionary perspectives of d -amino acid function among metazoans.
... Conversely,SR is increased in differentiated cells or tissues. For example,SR is increased in con uent keratinocyte cultures compared with growing phase of cultures (11). P19 cells,a line of pluripotent embryonal carcinoma,express SR when induced differentiation into neurons or glia by all-trans retinoic acid;this differentiation is not overcome by inhibiting synthesis of D-serine (12). ...
... In combination with the observation that knockdown of SR promoted proliferation and cell cycle entry,we conclude that SR expression mediates N2A differentiation. We indicated that SR expression modulated cell proliferation and differentiation of neuroblastoma cells;the coupling between elevation of SR expression and the differentiation was in coincidence with previous reports (11,12). Particularly,differentiation of P19 cells is coupled with SR expression but is not overcome by inhibiting D-serine synthesis (12). ...
Genetic deletion of serine racemase(SR) causes development disability of neuronal dendrites whereas increased expression of SR is found in differentiated cells in culture. These observations suggest roles of SR in cell proliferation and differentiation. Very recently,we have characterized increased SR expression when a neuroblastoma cell line,N2A,undergoes differentiation. However,whether and how the expression levels of SR determine cell destiny remains unclear. We herein indicated that valproic acid(VPA) or all-trans retinoic acid induced N2A differentiation which was mitigated by knockdown of SR. Knockdown of SR increased N2A proliferation,promoted cell cycle entry,and modulated expression of cell cycle-related proteins in N2A cells. Tumor formation in nude mice was used to further examine the effect of SR expression on cell destiny. N2A cells stably expressing scramble shRNA( Srr wt -N2A) or Srr shRNA ( Srr kd -N2A) were subcutaneously injected into nude mice,respectively. The tumors growing from Srr wt -N2A,significantly mitigated by intraperitoneal injection of VPA,were smaller than the tumors growing from Srr kd -N2A which were not affected by VPA. With R2 program,the levels of SR expression were predicted to be positively correlated with survival probability in neuroblastoma patients. This study unveils that alteration of SR modulated proliferation and differentiation of neuroblastoma cells and the mechanism. The results further suggest that induction of SR expression is a novel strategy to treat neuroblastoma.
... In the pituitary gland and pancreas, the localization of D-alanine (Ala) has been reported, and the relationship with the control of the blood glucose level is suggested [12,13]. The benefits of D-amino acids for beauty and health care, such as the skin barrier function of D-Ser [14], and the antioxidant effect of D-Asp [15], have also been reported, and foods and beverages containing D-amino acids are matters of interest. Furthermore, the alterations of the D-amino acid contents have been observed along with various diseases such as Alzheimer's disease [16,17] and chronic kidney disease [18,19]. ...
A two-dimensional high-performance liquid chromatographic (2D-HPLC) system using the pre-column derivatization with 4-(N,N-dimethylaminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole (DBD-F) has been developed for the determination of alanine (Ala), aspartic acid (Asp) and serine (Ser) enantiomers. For the precise determination of trace amounts of D-amino acids in complex matrices, a highly sensitive and selective method is required. In the present study, amino acids were derivatized with DBD-F for the sensitive fluorescence detection and were analyzed by a selective 2D-HPLC system combining a reversed-phase column (Singularity RP18, 1.0 x 500 mm) and an enantioselective column (Singularity CSP-001S, 1.5 x 250 mm). The established system was successfully applied to the chiral amino acid analyses of Japanese traditional amber rice vinegar, human plasma and human urine samples. In the Japanese traditional amber rice vinegar and human urine, relatively high amounts of all the target D-amino acids were observed (%D=5.8-37.7), while trace amounts of D-Ser and D-Ala were found in human plasma (%D=0.5-2.1).
... NMDAR subunits are expressed in the stratum basale, spinosum, and granulosum of the epidermis (Fischer et al., 2004). Epidermal keratinocytes in the granular and cornified layers expressed SR localization (Inoue et al., 2014), suggesting an autocrine/paracrine effect of D-serine on the NMDAR expressed in the keratinocytes. Despite the detection of NMDAR subunits and SR in epidermal tissue, no activity of DAAO was detected (Jensen and Jacobsen, 1984). ...
... Cultured human keratinocytes treated with MK-801, showed a decrease in the proliferation and an increase in apoptosis (Fuziwara et al., 2003;Morhenn et al., 2004). In the same way, mice lacking serine racemase (SR-KO mice), showed significantly higher expression of filaggrin, involucrin, loricrin, and transglutaminase 3 in keratinocytes compared to control mice (Inoue et al., 2014). This suggests that a hypofunction of NMDAR would decrease the activity of the calcium dependent TGs leading to the accumulation of proteins necessary for the formation of the CE (Figure 2). ...
... The alterations in the epidermis during aging (Yaar and Gilchrest, 1999) and the changes observed by interfering with NMDAR are very similar, suggesting a possible relationship between aging and a hypofunction for NMDAR. Furthermore, because SR and D-serine are required for the differentiation and maintenance of the physiological function of the skin (Inoue et al., 2014), it would be interesting to analyze the potential therapeutic effect of D-serine to overcome the changes in keratinocytes differentiation caused by aging. ...
Glutamatergic transmission through NMDA receptors (NMDARs) is important for the function of peripheral tissues. In the bone, NMDARs and its co-agonist, D-serine participate in all the phases of the remodeling. In the vasculature, NMDARs exerts a tonic vasodilation decreasing blood perfusion in the corpus cavernosum and the filtration rate in the renal glomerulus. NMDARs are relevant for the skin turnover regulating the proliferation and differentiation of keratinocytes and the formation of the cornified envelope (CE). The interference with NMDAR function in the skin leads to a slow turnover and repair. As occurs with the brain and cognitive functions, the manifestations of a hypofunction of NMDARs resembles those observed during aging. This raises the question if the deterioration of the glomerular vasculature, the bone remodeling and the skin turnover associated with age could be related with a hypofunction of NMDARs. Furthermore, the interference of D-serine and the effects of its supplementation on these tissues, suggest that a decrease of D-serine could account for this hypofunction pointing out D-serine as a potential therapeutic target to reduce or even prevent the detriment of the peripheral tissue associated with aging.
