Functional and immunocytochemical characterization of D‐serine transporters in cortical neuron and astrocyte cultures

Shao, Zongjun; Kamboj, Amit; Anderson, Christopher M.

doi:10.1002/jnr.22086

Cited by 34 publications

(35 citation statements)

References 55 publications

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“…However, preliminary observations indicate that pyruvate concentration is not increased in apoptotic neurons in the presence of 2 mM of D-serine (not shown), suggesting that ab-elimination activity is not implicated. A more plausible alternative hypothesis should involve D-serine uptake, likely through low-affinity Na+-dependent D-serine uptake (Shao et al, 2009) and D-serine degradation by DAAO. The last is a flavoenzyme that metabolizes certain D-amino acids (D-alanine, D-proline, and D-leucine and D-serine).…”

Section: Discussionmentioning

confidence: 99%

Contribution of serine racemase/d‐serine pathway to neuronal apoptosis

et al. 2012

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SummaryRecent data indicate that age-related N-methyl-D-aspartate receptor (NMDAR) transmission impairment is correlated with the reduction in serine racemase (SR) expression and D-serine content. As apoptosis is associated with several diseases and conditions that generally occur with age, we investigated the modulation of SR ⁄ D-serine pathway during neuronal apoptosis and its impact on survival. We found that in cerebellar granule neurons (CGNs), undergoing apoptosis SR/D-serine pathway is crucially regulated. In the early phase of apoptosis, the expression of SR is reduced, both at the protein and RNA level through pathways, upstream of caspase activation, involving ubiquitin proteasome system (UPS) and c-Jun N-terminal kinases (JNKs). Forced expression of SR, together with treatment with NMDA and D-serine, blocks neuronal death, whereas pharmacological inhibition and Sh-RNA-mediated suppression of endogenous SR exacerbate neuronal death. In the late phase of apoptosis, the increased expression of SR contribute to the last, NMDAR-mediated, wave of cell death. These findings are relevant to our understanding of neuronal apoptosis and NMDAR activity regulation, raising further questions as to the role of SR/D-serine in those neuro-pathophysiological processes, such as aging and neurodegenerative diseases characterized by a convergence of apoptotic mechanisms and NMDAR dysfunction.

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Section: Discussionmentioning

confidence: 99%

Contribution of serine racemase/d‐serine pathway to neuronal apoptosis

et al. 2012

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“…To support this hypothesis, Asc-1 and SRR have been localized to neuronal synapses (43,44). To directly test this hypothesis, rat cerebellar lysates were immunoprecipitated with the anti-BSN antibody, and the immunoprecipitates were probed with Asc-1 and SRR antibodies (supplemental Fig.…”

Section: Dao Colocalizes With Bsn In Cultured Cerebellar Granule Neurmentioning

confidence: 99%

d-Amino Acid Oxidase Activity Is Inhibited by an Interaction with Bassoon Protein at the Presynaptic Active Zone

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Ross

Charych

et al. 2011

Journal of Biological Chemistry

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Schizophrenia is a highly heritable neuropsychiatric disorder affecting ϳ1% of the world's population. Linkage and association studies have identified multiple candidate schizophrenia susceptibility genes whose functions converge on the glutamatergic neurotransmitter system. One such susceptibility gene encoding D-amino acid oxidase (DAO), an enzyme that metabolizes the NMDA receptor (NMDAR) co-agonist D-serine, has the potential to modulate NMDAR function in the context of schizophrenia. To further investigate its cellular regulation, we sought to identify DAO-interacting proteins that participate in its functional regulation in rat cerebellum, where DAO expression is especially high. Immunoprecipitation with DAO-specific antibodies and subsequent mass spectrometric analysis of coprecipitated proteins yielded 24 putative DAO-interacting proteins. The most robust interactions occurred with known components of the presynaptic active zone, such as bassoon (BSN) and piccolo (PCLO). The interaction of DAO with BSN was confirmed through co-immunoprecipitation assays using DAOand BSN-specific antibodies. Moreover, DAO and BSN colocalized with one another in cultured cerebellar granule cells and in synaptic junction membrane protein fractions derived from rat cerebellum. The functional consequences of this interaction were studied through enzyme assay experiments, where DAO enzymatic activity was significantly inhibited as a result of its interaction with BSN. Taking these results together, we hypothesize that synaptic D-serine concentrations may be under tight regulation by a BSN-DAO complex. We therefore predict that this mechanism plays a role in the modulation of glutamatergic signaling through NMDARs. It also furthers our understanding of the biology underlying this potential therapeutic entry point for schizophrenia and other psychiatric disorders.Several lines of evidence, including NMDAR 2 antagonist studies, pharmacological intervention at the glycine modulatory site, postmortem patient brain analysis, and genetic studies, implicate NMDAR hypofunction in schizophrenia etiology (1). One potential approach for restoring NMDAR signaling is to increase the concentration of NMDAR co-agonists, such as D-serine and D-alanine (2-5). Levels of D-serine have been shown to be reduced in the CSF and serum of schizophrenic patients compared with control subjects (6, 7), which may reflect an increase in the activity of D-amino acid oxidase (DAO), the enzyme that catalyzes D-serine and D-alanine degradation (8,9). Supporting this hypothesis are reports of increased DAO activity in schizophrenic patients (10 -12).Genetic association of DAO with schizophrenia has been demonstrated in several (13-17) but not all (18 -21) linkage and association studies (22). Nevertheless, association studies have identified several single-nucleotide polymorphisms (SNPs) within the gene encoding G72, a putative DAO-interacting protein, which are associated with schizophrenia (14,15,17,23).Data from DAO functional knock-out mice provide further s...

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“…A largely glial localization of DAO would seem to contrast with the fact that Asc-1, the primary means of synaptic Dserine transport, 112 is expressed predominantly, if not exclusively, by neurons. [113][114][115] Furthermore, a second D-serine transporter, ASCT2, [116][117][118] believed to be glial, 119 is now also reported to be localized to neurons. 120 These data suggest that a substantial portion of synaptic D-serine is taken up into the neurons, thus indirectly supporting the possibility that DAO is functional in both the neurons and glia.…”

Section: 50mentioning

confidence: 99%

The neurobiology of D-amino acid oxidase and its involvement in schizophrenia

et al. 2009

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D-amino acid oxidase (DAO) is a flavoenzyme that metabolizes certain D-amino acids, notably the endogenous N-methyl D-aspartate receptor (NMDAR) co-agonist, D-serine. As such, it has the potential to modulate the function of NMDAR and to contribute to the widely hypothesized involvement of NMDAR signalling in schizophrenia. Three lines of evidence now provide support for this possibility: DAO shows genetic associations with the disorder in several, although not all, studies; the expression and activity of DAO are increased in schizophrenia; and DAO inactivation in rodents produces behavioural and biochemical effects, suggestive of potential therapeutic benefits. However, several key issues remain unclear. These include the regional, cellular and subcellular localization of DAO, the physiological importance of DAO and its substrates other than D-serine, as well as the causes and consequences of elevated DAO in schizophrenia. Herein, we critically review the neurobiology of DAO, its involvement in schizophrenia, and the therapeutic value of DAO inhibition. This review also highlights issues that have a broader relevance beyond DAO itself: how should we weigh up convergent and cumulatively impressive, but individually inconclusive, pieces of evidence regarding the role that a given gene may have in the aetiology, pathophysiology and pharmacotherapy of schizophrenia? Molecular Psychiatry (2010) 15, 122-137;

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Functional and immunocytochemical characterization of D‐serine transporters in cortical neuron and astrocyte cultures

Cited by 34 publications

References 55 publications

Contribution of serine racemase/d‐serine pathway to neuronal apoptosis

Contribution of serine racemase/d‐serine pathway to neuronal apoptosis

d-Amino Acid Oxidase Activity Is Inhibited by an Interaction with Bassoon Protein at the Presynaptic Active Zone

The neurobiology of D-amino acid oxidase and its involvement in schizophrenia

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