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Herman Wolosker, Darrick T Balu, Joseph T Coyle
d-Serine modulates N-methyl d-aspartate receptors (NMDARs) and regulates synaptic plasticity, neurodevelopment, and learning and memory. However, the primary site of d-serine synthesis and release remains controversial, with some arguing that it is a gliotransmitter and others defining it as a neuronal cotransmitter. Results from several laboratories using different strategies now show that the biosynthetic enzyme of d-serine, serine racemase (SR), is expressed almost entirely by neurons, with few astrocytes appearing to contain d-serine...
October 11, 2016: Trends in Neurosciences
Yoshiro Ishimaru, Chisayo Kozuka, Kenichiro Nakajima, Tsutomu Sasaki
At the 93rd annual meeting of the Physiological Society of Japan, a symposium entitled "Expanding frontiers in weight-control research explored by young investigators" was organized. The latest research on weight control was presented by young up-and-coming investigators. The symposium consisted of the following presentations: Gastrointestinal brush cells, immunity, and energy homeostasis; Impact of a brown rice-derived bioactive product on feeding regulation and fuel metabolism; A novel G protein-coupled receptor-regulated neuronal signaling pathway triggers sustained orexigenic effects; and NMDA receptor co-agonist D-serine regulates food preference...
October 11, 2016: Journal of Physiological Sciences: JPS
Seo-Eun Cho, Kyoung-Sae Na, Seong-Jin Cho, Seung Gul Kang
An increasing amount of evidence indicates that d-serine, a potent and selective endogenous coagonist of the N-methyl-d-aspartate receptor (NMDAR), is efficacious in the treatment of schizophrenia. Although the therapeutic efficacy of d-serine supplementation is based on the d-serine deficit and NMDAR hypofunction hypothesis, it has not been confirmed whether d-serine levels are decreased in patients with schizophrenia compared to healthy controls. We searched the following electronic databases: Embase, Ovid Medline, and the Cochrane Library...
October 4, 2016: Neuroscience Letters
Juan A Orellana
The brain performs exceptionally complex and dynamic tasks that depend on the coordinated interaction of neurons, glial cells, endothelial cells, pericytes, smooth muscle cells, ependymal cells, and circulating blood cells. Among these cells, glial cells have emerged as crucial protagonists in the regulation of synaptic transmission and neural function. Indeed, these cells express a wide range of receptors that enable them to sense changes in neuronal activity and the microenvironment by responding locally via the release of bioactive molecules known as gliotransmitters...
2016: Advances in Experimental Medicine and Biology
James P R Connolly, Andrew J Roe
: We recently discovered that exposure of enterohaemorrhagic Escherichia coli (EHEC) to D-serine resulted in accumulation of this unusual amino acid, induction of the SOS regulon and downregulation of type III secretion that is essential for efficient colonization of the host. Here, we have investigated the physiological relevance of this elevated SOS response, which is of particular interest given the presence of Stx-toxin carrying lysogenic prophages on the EHEC chromosome that are activated during the SOS response...
October 3, 2016: Journal of Bacteriology
Akihiro Watanabe, Tsutomu Sasaki, Toshiro Yukami, Hideaki Kanki, Manabu Sakaguchi, Takemori Hiroshi, Kazuo Kitagawa, Hideki Mochizuki
There are no effective neuroprotectant drugs for acute cerebral ischemia. Serine racemase (SR) synthesizes d-serine, which is involved in N-methyl-d-aspartate (NMDA) receptor-induced neurotoxicity. Recently, SR deletion was reported to protect against focal cerebral ischemia. However, regulatory mechanisms controlling SR-activity in the neurovascular unit (NVU) during cerebral ischemia remain to be clarified. We investigated the effects of SR inhibition on neurovascular protection after ischemia. The SR inhibitor phenazine methosulfate (PMS) alleviated neuronal damage in an ex vivo ischemic model (oxygen glucose deprivation [OGD]) using primary neuronal cultures, and in an in vivo mouse model of ischemia (middle cerebral artery occlusion [MCAO])...
September 28, 2016: Neuroscience
Hui-Fei Zheng, Wen-Qiang Wang, Xin-Min Li, Gail Rauw, Glen B Baker
A review of studies on the body fluid levels of neuroactive amino acids, including glutamate, glutamine, taurine, gamma-aminobutyric acid (GABA), glycine, tryptophan, D-serine, and others, in autism spectrum disorders (ASD) is given. The results reported in the literature are generally inconclusive and contradictory, but there has been considerable variation among the previous studies in terms of factors such as age, gender, number of subjects, intelligence quotient, and psychoactive medication being taken...
September 29, 2016: Amino Acids
Ryan M Clanton, Guoyao Wu, Gamal Akabani, Rodolfo Aramayo
Epilepsy is too complex to be considered as a disease; it is more of a syndrome, characterized by seizures, which can be caused by a diverse array of afflictions. As such, drug interventions that target a single biological pathway will only help the specific individuals where that drug's mechanism of action is relevant to their disorder. Most likely, this will not alleviate all forms of epilepsy nor the potential biological pathways causing the seizures, such as glucose/amino acid transport, mitochondrial dysfunction, or neuronal myelination...
September 28, 2016: Amino Acids
A Prior, R C Moldovan, J Crommen, A C Servais, M Fillet, G J de Jong, G W Somsen
The sensitivity of coupled enantioselective capillary electrophoresis-mass spectrometry (CE-MS) of amino acids (AAs) is often hampered by the chiral selectors in the background electrolyte (BGE). A new method is presented in which the use of a chiral selector is circumvented by employing (+)-1-(9-fluorenyl)ethyl chloroformate (FLEC) as chiral AA derivatizing agent and ammonium perfluorooctanoate (APFO) as a volatile pseudostationary phase for separation of the formed diastereomers. Efficient AA derivatization with FLEC was completed within 10 min...
October 12, 2016: Analytica Chimica Acta
Stephanie Robu, Margret Schottelius, Matthias Eiber, Tobias Maurer, Jürgen Gschwend, Markus Schwaiger, Hans-Jürgen Wester
: Initial studies in patients have demonstrated the suitability of (111)In-PSMA-I&T ((111)In-DOTAGA-(3-iodo-y)-f-k-Sub(KuE)) for radioguided surgery (RGS) of small metastatic prostate cancer (PCa) soft tissue lesions. To meet the clinical need for a more cost-effective alternative, the PSMA-I&T-based tracer concept was adapted to (99m)Tc-labeling chemistry. Two PSMA-I&T-derived inhibitors with all-L-serine- (MAS3) and all-D-serine- (mas3) chelating moieties were evaluated in parallel, and a kit procedure for routine (99m)Tc-labeling was developed...
September 15, 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Alo C Basu, Matthew D Puhl, Joseph T Coyle
We have used mutant mice to probe the roles of the endogenous co-agonists of the NMDA receptor (NMDAR), D-serine and glycine, in fear learning and memory. Serine racemase knockout (SR-/-) mice have less than 15% of wild type forebrain levels of D-serine, whereas glycine transporter 1 heterozygous knockout (GlyT1+/-) mice have elevated synaptic glycine. While cued fear was normal in both delay and trace conditioned mice of both mutant genotypes, contextual fear was affected in trace conditioned subjects: SR-/- mice showed decreased contextual freezing, whereas GlyT1+/- mice showed elevated contextual freezing...
September 12, 2016: Neurobiology of Learning and Memory
Robert Zorec, Vladimir Parpura, Alexei Verkhratsky
The neocortex represents one of the largest estates of the human brain. This structure comprises ~30-40 billions of neurones and even more of non-neuronal cells. Astrocytes, highly heterogeneous homoeostatic glial cells, are fundamental for housekeeping of the brain and contribute to information processing in neuronal networks. Gray matter astrocytes tightly enwrap synapses, contact blood vessels and, naturally, are also in contact with the extracellular space, where convection of fluid takes place. Thus astrocytes receive signals from several distinct extracellular domains and can get excited by numerous mechanisms, which regulate cytosolic concentration of second messengers, such as Ca(2+) and cAMP...
September 14, 2016: Neurochemical Research
Yumiko Takano, Yuji Ozeki, Masae Sekine, Kumiko Fujii, Takashi Watanabe, Hiroaki Okayasu, Takahiro Shinozaki, Akiko Aoki, Kazufumi Akiyama, Hiroshi Homma, Kazutaka Shimoda
BACKGROUND: Alterations in one-carbon metabolism (OCM) have been observed in patients with schizophrenia (SZ), but a comprehensive study of OCM has not yet been conducted. A carbon atom is transferred from l-serine to methionine during OCM, but the relationship between l-serine and methionine in SZ is not yet known. We investigated the relationship between l-serine and methionine to obtain a comprehensive understanding of OCM in SZ. METHODS: We recruited forty-five patients with SZ and thirty normal controls (NC)...
2016: Annals of General Psychiatry
Gourango Talukdar, Ran Inoue, Tomoyuki Yoshida, Tetsuya Ishimoto, Keisuke Yaku, Takashi Nakagawa, Hisashi Mori
BACKGROUND: Serine racemase (SR) catalyzes the production of D-serine, a co-agonist of the N-methyl-D-aspartate receptor (NMDAR). A previous report shows the contribution of SR in the NMDAR-mediated neuronal cell death process. METHODS AND RESULTS: To analyze the intrinsic role of SR in the cell death process, we established the epithelial human embryonic kidney 293T (HEK293T) cell lines expressing wild-type SR (SR-WT), catalytically inactive mutant SR (SR-K56G), and catalytically hyperactive mutant SR (SR-Q155D)...
August 29, 2016: Biochimica et Biophysica Acta
Chengyu Zou, Sophie Crux, Stephane Marinesco, Elena Montagna, Carmelo Sgobio, Yuan Shi, Song Shi, Kaichuan Zhu, Mario M Dorostkar, Ulrike C Müller, Jochen Herms
Dynamic synapses facilitate activity-dependent remodeling of neural circuits, thereby providing the structural substrate for adaptive behaviors. However, the mechanisms governing dynamic synapses in adult brain are still largely unknown. Here, we demonstrate that in the cortex of adult amyloid precursor protein knockout (APP-KO) mice, spine formation and elimination were both reduced while overall spine density remained unaltered. When housed under environmental enrichment, APP-KO mice failed to respond with an increase in spine density...
August 29, 2016: EMBO Journal
Shengzhou Wu, Steven W Barger
This Editorial highlights a study by Xia and coworkers in the current issue of the Journal of Neurochemistry, in which the authors reveal a possible mechanistic link between DISC1 (disrupted-in-schizophrenia-1), a genetic risk factor for schizophrenia, and N-methyl-d-aspartate receptor (NMDAR) that is also linked with schizophrenia. The authors show that perturbed communication between DISC1 and NMDARs represents a hidden perpetrator for abnormal dendritic and synaptic maturation. Read the highlighted article 'DISC1, astrocytes and neuronal maturation: a possible mechanistic link with implications for mental disorders' on page 518...
August 2016: Journal of Neurochemistry
Stefano Bruno, Francesco Marchesani, Luca Dellafiora, Marilena Margiotta, Serena Faggiano, Barbara Campanini, Andrea Mozzarelli
Serine racemase catalyzes both the synthesis and the degradation of d-serine, an obligatory co-agonist of the glutamatergic NMDA receptors. It is allosterically controlled by adenosine triphosphate (ATP), which increases its activity around 7-fold through a co-operative binding mechanism. Serine racemase has been proposed as a drug target for the treatment of several neuropathologies but, so far, the search has been directed only toward the active site, with the identification of a few, low-affinity inhibitors...
October 15, 2016: Biochemical Journal
Ursula Staubli, Natalie Rangel-Diaz, Miguel Alcantara, Yong-Xin Li, Jia-Ying Yang, Kai-Ming Zhang, Alan C Foster
The NMDA subtype of glutamate receptor and its co-agonist d-serine play a key role in synaptic function in the central nervous system (CNS), including visual cortex and retina. In retinal diseases such as glaucoma and macular degeneration, a loss of vision arises from malfunction of retinal cells, resulting in a glutamate hypofunctional state along the visual pathway in the affected parts of the visual field. An effective strategy to remedy this loss of function might be to increase extracellular levels of d-serine and thereby boost synaptic NMDA receptor-mediated visual transmission and/or plasticity to compensate for the impairment...
October 2016: Vision Research
Masumi Katane, Yuki Saitoh, Keita Uchiyama, Kazuki Nakayama, Yasuaki Saitoh, Tetsuya Miyamoto, Masae Sekine, Kouji Uda, Hiroshi Homma
Free d-serine (d-Ser) plays a crucial role in regulating brain function in mammals. In various organisms, including mammals, d-Ser is biosynthesized by Ser racemase, a synthetic enzyme that produces d-Ser from l-Ser. Ser racemase also exhibits dehydratase activity toward several hydroxyamino acids. Thus, this enzyme is unique in that it possesses the capability to both synthesize and degrade d-Ser; however, the physiological significance of its degradative activity remains unclear. In contrast to the physiological roles of d-Ser in mammals, little is known about the role of this amino acid in lower organisms, including the nematode Caenorhabditis elegans...
September 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Éva Szökő, István Vincze, Tamás Tábi
It is widely accepted that some of the free d-amino acids play important biological role. d-Aspartate and d-serine formed in the central nervous system of higher vertebrates have neurotransmitter/neuromodulator function. Together with d-alanine they are distributed in various tissues and biological fluids. Studying their physiological and pathological significance requires their sensitive and accurate determination in biological samples. The various separation and detection methods used for their analysis are overviewed in the present paper...
October 25, 2016: Journal of Pharmaceutical and Biomedical Analysis
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