Abstract | PURPOSE: METHODS: 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. RESULTS: 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. CONCLUSION: 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.
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Authors | Christian M Cremer, Hans-Jürgen Bidmon, Boris Görg, Nicola Palomero-Gallagher, Jennifer Lopez Escobar, Erwin-Josef Speckmann, Karl Zilles |
Journal | Epilepsia
(Epilepsia)
Vol. 51
Issue 8
Pg. 1446-55
(Aug 2010)
ISSN: 1528-1167 [Electronic] United States |
PMID | 20384720
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2010 International League Against Epilepsy. |
Chemical References |
- Enzyme Inhibitors
- Excitatory Amino Acid Antagonists
- Protein Subunits
- RNA, Messenger
- Receptors, GABA
- Glutamine
- Tritium
- Benzodiazepines
- Methionine Sulfoximine
- Glutamic Acid
- Glutamate-Ammonia Ligase
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Topics |
- Animals
- Autoradiography
(methods)
- Benzodiazepines
(metabolism)
- Binding Sites
(drug effects)
- Brain
(anatomy & histology, drug effects, 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, metabolism)
- RNA, Messenger
(metabolism)
- Rats
- Rats, Wistar
- Receptors, GABA
(genetics, metabolism)
- Time Factors
- Tritium
(metabolism)
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