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000010474 0247_ $$2DOI$$a10.1111/j.1528-1167.2010.02562.x
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000010474 084__ $$2WoS$$aClinical Neurology
000010474 1001_ $$0P:(DE-Juel1)VDB71164$$aCremer, C.M.$$b0$$uFZJ
000010474 245__ $$aInhibition of glutamate/glutamine cycle in vivo results in decreased benzodiazepine binding and differentially regulated GABAergic subunit expression in the rat brain
000010474 260__ $$aOxford [u.a.]$$bWiley-Blackwell$$c2010
000010474 300__ $$a1446 - 1455
000010474 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article
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000010474 3367_ $$2BibTeX$$aARTICLE
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000010474 440_0 $$012861$$aEpilepsia$$v51$$x0013-9580$$y8
000010474 500__ $$aThis 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.
000010474 520__ $$aThe astrocytic enzyme glutamine synthetase (GS) is a key regulator of glutamate and γ-aminobutyric acid (GABA) metabolism in the glutamate/glutamine cycle (GGC). Inhibition of GS results in changes of neurotransmitter release and recycling. However, little is known about the influence of GGC on neurotransmitter receptor expression. In the pentylenetetrazole model of epilepsy, GS becomes nitrated and partially inhibited, and we demonstrated alterations of neurotransmitter receptor expression in the same model. Therefore, we hypothesized similar changes of neurotransmitter receptor expression when GS is inhibited in vivo.Rats were treated with a single dose (100 mg/kg bodyweight) of l-methionine sulfoximine (MSO), an irreversible inhibitor of GS. We used ³H-receptor autoradiography to measure glutamatergic [α-amino-3-hydroxy-5-methyl-4-isoxazol-propionic acid (AMPA), kainate, N-methyl-D-aspartate (NMDA)], GABAergic (GABA(A) , GABA(B) and GABA(A) -associated benzodiazepine (BZ) binding sites], dopamine D₁, and adenosine A₁ receptor subtypes. In addition, we performed saturation analysis of BZ binding sites on cerebral membrane homogenates and investigated the expression of GABA(A) α₁ and γ₂ subunits (which primarily mediate BZ binding) by western blot analysis.We demonstrated a significant reduction of BZ binding in the somatosensory, piriform, and entorhinal cortices and in the amygdala, 24 and 72 h after MSO treatment. Saturation analysis revealed decreased BZ binding (B(max)) on cerebral membrane homogenates 72 h after MSO treatment, without changes in binding site affinity (K(D)). Furthermore, we found differential changes of α₁ , γ₂ , and phosphorylated γ₂ subunits following MSO treatment.On the basis of our findings, we conclude that the glutamate/glutamine cycle directly influences GABAergic neurotransmission by regulating GABA(A) subunit composition, thereby affecting its modulation by endogenous benzodiazepines.
000010474 536__ $$0G:(DE-Juel1)FUEK409$$2G:(DE-HGF)$$aFunktion und Dysfunktion des Nervensystems (FUEK409)$$cFUEK409$$x0
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000010474 588__ $$aDataset connected to Web of Science, Pubmed
000010474 650_2 $$2MeSH$$aAnimals
000010474 650_2 $$2MeSH$$aAutoradiography: methods
000010474 650_2 $$2MeSH$$aBenzodiazepines: metabolism
000010474 650_2 $$2MeSH$$aBinding Sites: drug effects
000010474 650_2 $$2MeSH$$aBrain: anatomy & histology
000010474 650_2 $$2MeSH$$aBrain: drug effects
000010474 650_2 $$2MeSH$$aBrain: metabolism
000010474 650_2 $$2MeSH$$aDrug Interactions
000010474 650_2 $$2MeSH$$aEnzyme Inhibitors: pharmacology
000010474 650_2 $$2MeSH$$aExcitatory Amino Acid Antagonists: pharmacology
000010474 650_2 $$2MeSH$$aGlutamate-Ammonia Ligase: metabolism
000010474 650_2 $$2MeSH$$aGlutamic Acid: metabolism
000010474 650_2 $$2MeSH$$aGlutamine: metabolism
000010474 650_2 $$2MeSH$$aMale
000010474 650_2 $$2MeSH$$aMethionine Sulfoximine: pharmacology
000010474 650_2 $$2MeSH$$aProtein Binding: drug effects
000010474 650_2 $$2MeSH$$aProtein Subunits: genetics
000010474 650_2 $$2MeSH$$aProtein Subunits: metabolism
000010474 650_2 $$2MeSH$$aRNA, Messenger: metabolism
000010474 650_2 $$2MeSH$$aRats
000010474 650_2 $$2MeSH$$aRats, Wistar
000010474 650_2 $$2MeSH$$aReceptors, GABA: genetics
000010474 650_2 $$2MeSH$$aReceptors, GABA: metabolism
000010474 650_2 $$2MeSH$$aTime Factors
000010474 650_2 $$2MeSH$$aTritium: metabolism
000010474 650_7 $$00$$2NLM Chemicals$$aEnzyme Inhibitors
000010474 650_7 $$00$$2NLM Chemicals$$aExcitatory Amino Acid Antagonists
000010474 650_7 $$00$$2NLM Chemicals$$aProtein Subunits
000010474 650_7 $$00$$2NLM Chemicals$$aRNA, Messenger
000010474 650_7 $$00$$2NLM Chemicals$$aReceptors, GABA
000010474 650_7 $$010028-17-8$$2NLM Chemicals$$aTritium
000010474 650_7 $$012794-10-4$$2NLM Chemicals$$aBenzodiazepines
000010474 650_7 $$01982-67-8$$2NLM Chemicals$$aMethionine Sulfoximine
000010474 650_7 $$056-85-9$$2NLM Chemicals$$aGlutamine
000010474 650_7 $$056-86-0$$2NLM Chemicals$$aGlutamic Acid
000010474 650_7 $$0EC 6.3.1.2$$2NLM Chemicals$$aGlutamate-Ammonia Ligase
000010474 650_7 $$2WoSType$$aJ
000010474 65320 $$2Author$$al-Methionine sulfoximine
000010474 65320 $$2Author$$aNeurotransmitter receptors
000010474 65320 $$2Author$$aGABA(A)
000010474 65320 $$2Author$$aBenzodiazepine binding
000010474 65320 $$2Author$$aAutoradiography
000010474 65320 $$2Author$$aIn situ hybridization
000010474 7001_ $$0P:(DE-HGF)0$$aBidmon, H.-J.$$b1
000010474 7001_ $$0P:(DE-HGF)0$$aGörg, B.$$b2
000010474 7001_ $$0P:(DE-Juel1)VDB1208$$aPalomero-Gallagher, N.$$b3$$uFZJ
000010474 7001_ $$0P:(DE-Juel1)VDB89117$$aLopez Escobar, J.$$b4$$uFZJ
000010474 7001_ $$0P:(DE-HGF)0$$aSpeckmann, E.-J.$$b5
000010474 7001_ $$0P:(DE-Juel1)131714$$aZilles, K.$$b6$$uFZJ
000010474 773__ $$0PERI:(DE-600)2002194-X$$a10.1111/j.1528-1167.2010.02562.x$$gVol. 51, p. 1446 - 1455$$p1446 - 1455$$q51<1446 - 1455$$tEpilepsia$$v51$$x0013-9580$$y2010
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