TY  - JOUR
AU  - Cremer, C.M.
AU  - Bidmon, H.-J.
AU  - Görg, B.
AU  - Palomero-Gallagher, N.
AU  - Lopez Escobar, J.
AU  - Speckmann, E.-J.
AU  - Zilles, K.
TI  - Inhibition of glutamate/glutamine cycle in vivo results in decreased benzodiazepine binding and differentially regulated GABAergic subunit expression in the rat brain
JO  - Epilepsia
VL  - 51
SN  - 0013-9580
CY  - Oxford [u.a.]
PB  - Wiley-Blackwell
M1  - PreJuSER-10474
SP  - 1446 - 1455
PY  - 2010
N1  - 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.
AB  - 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.
KW  - Animals
KW  - Autoradiography: methods
KW  - Benzodiazepines: metabolism
KW  - Binding Sites: drug effects
KW  - Brain: anatomy & histology
KW  - Brain: drug effects
KW  - Brain: metabolism
KW  - Drug Interactions
KW  - Enzyme Inhibitors: pharmacology
KW  - Excitatory Amino Acid Antagonists: pharmacology
KW  - Glutamate-Ammonia Ligase: metabolism
KW  - Glutamic Acid: metabolism
KW  - Glutamine: metabolism
KW  - Male
KW  - Methionine Sulfoximine: pharmacology
KW  - Protein Binding: drug effects
KW  - Protein Subunits: genetics
KW  - Protein Subunits: metabolism
KW  - RNA, Messenger: metabolism
KW  - Rats
KW  - Rats, Wistar
KW  - Receptors, GABA: genetics
KW  - Receptors, GABA: metabolism
KW  - Time Factors
KW  - Tritium: metabolism
KW  - Enzyme Inhibitors (NLM Chemicals)
KW  - Excitatory Amino Acid Antagonists (NLM Chemicals)
KW  - Protein Subunits (NLM Chemicals)
KW  - RNA, Messenger (NLM Chemicals)
KW  - Receptors, GABA (NLM Chemicals)
KW  - Tritium (NLM Chemicals)
KW  - Benzodiazepines (NLM Chemicals)
KW  - Methionine Sulfoximine (NLM Chemicals)
KW  - Glutamine (NLM Chemicals)
KW  - Glutamic Acid (NLM Chemicals)
KW  - Glutamate-Ammonia Ligase (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:20384720
UR  - <Go to ISI:>//WOS:000280669600013
DO  - DOI:10.1111/j.1528-1167.2010.02562.x
UR  - https://juser.fz-juelich.de/record/10474
ER  -