title: D-serine-induced inactivation of NMDA receptors in cultured rat hippocampal neurons expressing NR2A subunits is Ca2+-dependent.
abstract: OBJECTIVE
  Our previous studies indicate that glycine can inhibit N-methyl-D-aspartate receptor (NMDAR) responses induced by high concentrations of NMDA in rat hippocampal neurons. The present study was designed to observe whether D-serine induces inactivation of NMDARs in cultured rat hippocampal neurons and to investigate the underlying mechanisms of this effect.
  
  
  METHODS
  Cell culture, whole-cell patch-clamp electrophysiology, Ca(2+) imaging, immunohistochemistry, and Western blot analysis were used.
  
  
  RESULTS
  We found that the peak current and Ca(2+) influx evoked by 30 μM NMDA were increased by co-application of D-serine, but those evoked by 300 μM NMDA were reduced dose-dependently by co-application of D-serine. However, the inhibitory effect of D-serine on NMDAR responses was reversed by ZnCl2 (30 nM), an inhibitor of the NR2A subunit, but was less influenced by ifenprodil (10 μM), an NR2B inhibitor. In addition, the inhibitory effect of D-serine was not detected in young hippocampal neurons that expressed less of the NR2A subunits and reversed in the presence of 10 mM BAPTA.
  
  
  CONCLUSIONS
  D-serine can also induce inactivation of NMDARs, the NR2A subunit is required for the induction of this effect, and this inactivation is Ca(2+)-dependent in nature. This action of D-serine is hypothesized to play a neuroprotective role upon a sustained large glutamate insult to the brain.
authors.affiliation: Department of Neuropharmacology, Institute of Nautical Medicine, Nantong University, Jiangsu, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Zhang
authors.forename: Zhao-Qin
authors.initials: ZQ
authors.lastname: Chen
authors.forename: Zheng-Lin
authors.initials: ZL
authors.lastname: Jiang
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Xu
authors.forename: Yao
authors.initials: Y
authors.lastname: Yang
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012694:Serine / Q000494:pharmacology*
chemical_list: D002118:Calcium; D002121:Calcium Channel Blockers; D002614:Chelating Agents; D004533:Egtazic Acid; D018690:Excitatory Amino Acid Agonists; D016202:N-Methylaspartate; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C010739:ifenprodil
keywords: D-serine; Glycine-dependent inactivation; Hippocampal neurons; N-methyl-D-aspartate; NMDA receptors; Neuroprotection