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@ARTICLE{Cremer:10474,
      author       = {Cremer, C.M. and Bidmon, H.-J. and Görg, B. and
                      Palomero-Gallagher, N. and Lopez Escobar, J. and Speckmann,
                      E.-J. and Zilles, K.},
      title        = {{I}nhibition of glutamate/glutamine cycle in vivo results
                      in decreased benzodiazepine binding and differentially
                      regulated {GABA}ergic subunit expression in the rat brain},
      journal      = {Epilepsia},
      volume       = {51},
      issn         = {0013-9580},
      address      = {Oxford [u.a.]},
      publisher    = {Wiley-Blackwell},
      reportid     = {PreJuSER-10474},
      pages        = {1446 - 1455},
      year         = {2010},
      note         = {This study was partially supported by a grant of the
                      Helmholtz Alliance in "Mental Health in an Ageing Society."
                      We thank S. Buller, L. Igdalova, and S. Wilms for their
                      excellent technical assistance.},
      abstract     = {The astrocytic enzyme glutamine synthetase (GS) is a key
                      regulator of glutamate and γ-aminobutyric acid (GABA)
                      metabolism in the glutamate/glutamine cycle (GGC).
                      Inhibition of GS results in changes of neurotransmitter
                      release and recycling. However, little is known about the
                      influence of GGC on neurotransmitter receptor expression. In
                      the pentylenetetrazole model of epilepsy, GS becomes
                      nitrated and partially inhibited, and we demonstrated
                      alterations of neurotransmitter receptor expression in the
                      same model. Therefore, we hypothesized similar changes of
                      neurotransmitter receptor expression when GS is inhibited in
                      vivo.Rats were treated with a single dose (100 mg/kg
                      bodyweight) of l-methionine sulfoximine (MSO), an
                      irreversible inhibitor of GS. We used ³H-receptor
                      autoradiography to measure glutamatergic
                      [α-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid
                      (AMPA), kainate, N-methyl-D-aspartate (NMDA)], GABAergic
                      (GABA(A) , GABA(B) and GABA(A) -associated benzodiazepine
                      (BZ) binding sites], dopamine D₁, and adenosine A₁
                      receptor subtypes. In addition, we performed saturation
                      analysis of BZ binding sites on cerebral membrane
                      homogenates and investigated the expression of GABA(A) α₁
                      and γ₂ subunits (which primarily mediate BZ binding) by
                      western blot analysis.We demonstrated a significant
                      reduction of BZ binding in the somatosensory, piriform, and
                      entorhinal cortices and in the amygdala, 24 and 72 h after
                      MSO treatment. Saturation analysis revealed decreased BZ
                      binding (B(max)) on cerebral membrane homogenates 72 h after
                      MSO treatment, without changes in binding site affinity
                      (K(D)). Furthermore, we found differential changes of α₁
                      , γ₂ , and phosphorylated γ₂ subunits following MSO
                      treatment.On the basis of our findings, we conclude that the
                      glutamate/glutamine cycle directly influences GABAergic
                      neurotransmission by regulating GABA(A) subunit composition,
                      thereby affecting its modulation by endogenous
                      benzodiazepines.},
      keywords     = {Animals / Autoradiography: methods / Benzodiazepines:
                      metabolism / Binding Sites: drug effects / Brain: anatomy
                      $\&$ histology / Brain: drug effects / Brain: metabolism /
                      Drug Interactions / Enzyme Inhibitors: pharmacology /
                      Excitatory Amino Acid Antagonists: pharmacology /
                      Glutamate-Ammonia Ligase: metabolism / Glutamic Acid:
                      metabolism / Glutamine: metabolism / Male / Methionine
                      Sulfoximine: pharmacology / Protein Binding: drug effects /
                      Protein Subunits: genetics / Protein Subunits: metabolism /
                      RNA, Messenger: metabolism / Rats / Rats, Wistar /
                      Receptors, GABA: genetics / Receptors, GABA: metabolism /
                      Time Factors / Tritium: metabolism / Enzyme Inhibitors (NLM
                      Chemicals) / Excitatory Amino Acid Antagonists (NLM
                      Chemicals) / Protein Subunits (NLM Chemicals) / RNA,
                      Messenger (NLM Chemicals) / Receptors, GABA (NLM Chemicals)
                      / Tritium (NLM Chemicals) / Benzodiazepines (NLM Chemicals)
                      / Methionine Sulfoximine (NLM Chemicals) / Glutamine (NLM
                      Chemicals) / Glutamic Acid (NLM Chemicals) /
                      Glutamate-Ammonia Ligase (NLM Chemicals) / J (WoSType)},
      cin          = {INM-2 / JARA-BRAIN},
      ddc          = {610},
      cid          = {I:(DE-Juel1)INM-2-20090406 / $I:(DE-82)080010_20140620$},
      pnm          = {Funktion und Dysfunktion des Nervensystems (FUEK409) /
                      89571 - Connectivity and Activity (POF2-89571)},
      pid          = {G:(DE-Juel1)FUEK409 / G:(DE-HGF)POF2-89571},
      shelfmark    = {Clinical Neurology},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:20384720},
      UT           = {WOS:000280669600013},
      doi          = {10.1111/j.1528-1167.2010.02562.x},
      url          = {https://juser.fz-juelich.de/record/10474},
}