Decreased Serum Levels of D-Serine in Patients With Schizophrenia

Hashimoto, Kenji; Fukushima, Takeshi; Shimizu, Eiji; Komatsu, Naoya; Watanabe, Hiroyuki; Shinoda, Naoyuki; Nakazato, Michiko; Kumakiri, Chikara; Okada, Shinichi; Hasegawa, H.; Imai, Kazuhiro; Iyo, Masaomi

doi:10.1001/archpsyc.60.6.572

Cited by 462 publications

(143 citation statements)

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“…116 Moreover, there is evidence that Dserine levels are reduced in the brain and blood of patients with schizophrenia. 117,118 Chumakov et al therefore speculated that the G72/DAO associations support the long-standing hypothesis of abnormal glutamatergic transmission in schizophrenia.…”

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The molecular genetics of schizophrenia: new findings promise new insights

2003

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The high heritability of schizophrenia has stimulated much work aimed at identifying susceptibility genes using positional genetics. However, difficulties in obtaining clear replicated linkages have led to the scepticism that such approaches would ever be successful. Fortunately, there are now signs of real progress. Several strong and well-established linkages have emerged. Three of the best-supported regions are 6p24-22, 1q21-22 and 13q32-34. In these cases, single studies achieved genome-wide significance at Po0.05 and suggestive positive findings have also been reported in other samples. The other promising regions include 8p21-22, 6q21-25, 22q11-12, 5q21-q33, 10p15-p11 and 1q42. The study of chromosomal abnormalities in schizophrenia has also added to the evidence for susceptibility loci at 22q11 and 1q42. Recently, evidence implicating individual genes within some of the linked regions has been reported and more importantly replicated. The weight of evidence now favours NRG1 and DTNBP1 as susceptibility loci, though work remains before we understand precisely how genetic variation at each locus confers susceptibility and protection. The evidence for catechol-O-methyl transferase, RGS4 and G72 is promising but not yet persuasive. While further replications remain the top priority, the respective contributions of each gene, relationships with aspects of the phenotype, the possibility of epistatic interactions between genes and functional interactions between the gene products will all need investigation. The ability of positional genetics to implicate novel genes and pathways will open up new vistas for neurobiological research, and all the signs are that it is now poised to deliver crucial insights into the nature of schizophrenia.

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confidence: 90%

The molecular genetics of schizophrenia: new findings promise new insights

2003

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“…10) In addition, we previously reported that the serum D-serine concentration was signiˆcantly reduced in patients with schizophrenia. 11) In 1998, Tsai et al reported that co-administration of D-serine with atypical antipsychotic drugs improved the symptoms of patients with schizophrenia. 12) Considering these reports together, DAAO inhibition by an exogenous drug could be eŠective for the treatment of schizophrenia.…”

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Inhibition of D-Amino Acid Oxidase Activity by Antipsychotic Drugs Evaluated by a Fluorometric Assay Using D-Kynurenine as Substrate

et al. 2011

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A facile ‰uorometric assay using D-kynurenine as a substrate was utilized for evaluating the inhibition of D-amino acid oxidase (DAAO), which is one of the products of a susceptibility gene for schizophrenia, by commercial antipsychotic drugs, namely, chlorpromazine (CPZ), carbamazepine, sulpiride, quetiapine, and imipramine. CPZ inhibited DAAO (65.8±13.2 mM, n＝3) as reported previously, and other drugs also inhibited DAAO activity. Among these, quetiapine had the smallest IC 50 value (19.5±2.60 mM, n＝3). The proposed assay can be useful for the evaluation or screening of DAAO-inhibitory drugs.

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“…We have performed multiple molecular dynamics simulations ( N-Methyl-D-aspartate (NMDA) 4 receptors are ligand-gated ion channels that play a major role in learning and memory (1). They have also been implicated in a number of injury or disease states including for example, schizophrenia (2)(3)(4)(5). NMDA receptors are a distinct subtype of ionotropic glutamate receptor (6) in that they require both glutamate and glycine for activation and membrane depolarization (7).…”

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Molecular Dynamics Simulations of the Ligand-binding Domain of an N-Methyl-d-aspartate Receptor

Kaye¹,

Sansom²,

Biggin³

2006

Journal of Biological Chemistry

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The mechanism of partial agonism at N-methyl-D-aspartate receptors is an unresolved issue, especially with respect to the role of protein dynamics. We have performed multiple molecular dynamics simulations (7 ؋ 20 ns) to examine the behavior of the ligand-binding core of the NR1 subunit with a series of ligands. Our results show that water plays an important role in stabilizing different conformations of the core and how a closed cleft conformation of the protein might be stabilized in the absence of ligands. In the case of ligand-bound simulations with both full and partial agonists, we observed that ligands within the binding cleft may undergo distinct conformational changes, without grossly influencing the degree of cleft closure within the ligand-binding domain. In agreement with recently published crystallographic data, we also observe similar changes in backbone torsions corresponding to the hinge region between the two lobes for the partial agonist, D-cycloserine. This observation rationalizes the classification of D-cycloserine as a partial agonist and should provide a basis with which to predict partial agonism in this class of receptor by analyzing the behavior of these torsions with other potential ligands. N-Methyl-D-aspartate (NMDA)4 receptors are ligand-gated ion channels that play a major role in learning and memory (1). They have also been implicated in a number of injury or disease states including for example, schizophrenia (2-5). NMDA receptors are a distinct subtype of ionotropic glutamate receptor (6) in that they require both glutamate and glycine for activation and membrane depolarization (7). The receptor is a heterotetrameric cation channel typically comprised of two NR1 subunits that contain the glycine-binding site along with two NR2A-D glutamate-binding sites. The heterogeneity of the complex is further extended if the third subtype (NR3), which also binds glycine, is also taken into account.The architecture of each subunit of NMDA receptors is similar to that of non-NMDA receptors. Each subunit is comprised of an aminoterminal binding domain that shows homology to the LIVBP (leucineisoleucine-valine-binding protein) (8), three transmembrane helices (M1, M2, and M3), a re-entrant P-loop, and a ligand-binding domain that is comprised of two discontinuous polypeptide chains, S1 and S2, that form two distinct lobes or subdomains, D1 and D2 (Fig. 1A). An isolated D1D2 ligand-binding core has been shown to bind ligands with similar affinity as wild-type receptors (9, 10).Recently, the crystal structure of the ligand-binding domain of the NR1 subunit has been solved by x-ray diffraction with both full (9) and partial (10) agonists. The overall fold and structure (Fig. 1B) is very similar to those observed for crystal structures of the ligand-binding domains for the (non-NMDA) GluR2 (11-13), GluR5 (14,15), and GluR6 receptors (Refs. 15 and 16; for recent reviews see Refs. 17-19). The major difference is an insertion of 30 residues into loop 1, which also contains two disulfide bridges. Inter...

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Decreased Serum Levels of D-Serine in Patients With Schizophrenia

Abstract: Reduced levels of D-serine may play a role in the pathophysiology of schizophrenia, and serum D- and L-serine levels might provide a measurable biological marker for schizophrenia.

Cited by 462 publications

References 24 publications

The molecular genetics of schizophrenia: new findings promise new insights

The molecular genetics of schizophrenia: new findings promise new insights

Inhibition of D-Amino Acid Oxidase Activity by Antipsychotic Drugs Evaluated by a Fluorometric Assay Using D-Kynurenine as Substrate

Molecular Dynamics Simulations of the Ligand-binding Domain of an N-Methyl-d-aspartate Receptor

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