Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Proc Natl Acad Sci U S A
2004 Jul 06;10127:10183-8. doi: 10.1073/pnas.0403683101.
Show Gene links
Show Anatomy links
Phosphatase inhibitors remove the run-down of gamma-aminobutyric acid type A receptors in the human epileptic brain.
Palma E
,
Ragozzino DA
,
Di Angelantonio S
,
Spinelli G
,
Trettel F
,
Martinez-Torres A
,
Torchia G
,
Arcella A
,
Di Gennaro G
,
Quarato PP
,
Esposito V
,
Cantore G
,
Miledi R
,
Eusebi F
.
???displayArticle.abstract???
The properties of gamma-aminobutyric acid (GABA) type A receptors (GABA(A) receptors) microtransplanted from the human epileptic brain to the plasma membrane of Xenopus oocytes were compared with those recorded directly from neurons, or glial cells, in human brains slices. Cell membranes isolated from brain specimens, surgically obtained from six patients afflicted with drug-resistant temporal lobe epilepsy (TLE) were injected into frog oocytes. Within a few hours, these oocytes acquired GABA(A) receptors that generated GABA currents with an unusual run-down, which was inhibited by orthovanadate and okadaic acid. In contrast, receptors derived from membranes of a nonepileptic hippocampal uncus, membranes from mouse brain, or recombinant rat alpha 1 beta 2 gamma 2-GABA receptors exhibited a much less pronounced GABA-current run-down. Moreover, the GABA(A) receptors of pyramidal neurons in temporal neocortex slices from the same six epileptic patients exhibited a stronger run-down than the receptors of rat pyramidal neurons. Interestingly, the GABA(A) receptors of neighboring glial cells remained substantially stable after repetitive activation. Therefore, the excessive GABA-current run-down observed in the membrane-injected oocytes recapitulates essentially what occurs in neurons, rather than in glial cells. Quantitative RT-PCR analyses from the same TLE neocortex specimens revealed that GABA(A)-receptor beta 1, beta 2, beta 3, and gamma 2 subunit mRNAs were significantly overexpressed (8- to 33-fold) compared with control autopsy tissues. Our results suggest that an abnormal GABA-receptor subunit transcription in the TLE brain leads to the expression of run-down-enhanced GABA(A) receptors. Blockage of phosphatases stabilizes the TLE GABA(A) receptors and strengthens GABAergic inhibition. It may be that this process can be targeted to develop new treatments for intractable epilepsy.
Ben-Ari,
Kainate, a double agent that generates seizures: two decades of progress.
2000, Pubmed
Ben-Ari,
Kainate, a double agent that generates seizures: two decades of progress.
2000,
Pubmed
Brandon,
GABAA receptor phosphorylation and functional modulation in cortical neurons by a protein kinase C-dependent pathway.
2000,
Pubmed
Brooks-Kayal,
Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy.
1998,
Pubmed
Brown,
Molecular mechanisms of benzodiazepine-induced down-regulation of GABAA receptor alpha 1 subunit protein in rat cerebellar granule cells.
1996,
Pubmed
Celesia,
Are the epilepsies disorders of ion channels?
2003,
Pubmed
Chvátal,
Distinct populations of identified glial cells in the developing rat spinal cord slice: ion channel properties and cell morphology.
1995,
Pubmed
Cohen,
On the origin of interictal activity in human temporal lobe epilepsy in vitro.
2002,
Pubmed
Gibbs,
Differential epilepsy-associated alterations in postsynaptic GABA(A) receptor function in dentate granule and CA1 neurons.
1997,
Pubmed
Hinterkeuser,
Astrocytes in the hippocampus of patients with temporal lobe epilepsy display changes in potassium conductances.
2000,
Pubmed
Huang,
Maintenance of recombinant type A gamma-aminobutyric acid receptor function: role of protein tyrosine phosphorylation and calcineurin.
1998,
Pubmed
Jones-Davis,
GABA(A) receptor function and pharmacology in epilepsy and status epilepticus.
2003,
Pubmed
Jovanovic,
Brain-derived neurotrophic factor modulates fast synaptic inhibition by regulating GABA(A) receptor phosphorylation, activity, and cell-surface stability.
2004,
Pubmed
Kittler,
Modulation of GABAA receptor activity by phosphorylation and receptor trafficking: implications for the efficacy of synaptic inhibition.
2003,
Pubmed
Köhling,
Spontaneous sharp waves in human neocortical slices excised from epileptic patients.
1998,
Pubmed
Lin,
Enhancement of recombinant alpha 1 beta 1 gamma 2L gamma-aminobutyric acidA receptor whole-cell currents by protein kinase C is mediated through phosphorylation of both beta 1 and gamma 2L subunits.
1996,
Pubmed
Loup,
Selective alterations in GABAA receptor subtypes in human temporal lobe epilepsy.
2000,
Pubmed
Marsal,
Incorporation of acetylcholine receptors and Cl- channels in Xenopus oocytes injected with Torpedo electroplaque membranes.
1995,
Pubmed
,
Xenbase
Mathern,
Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy.
1999,
Pubmed
McDonald,
Altered excitatory and inhibitory amino acid receptor binding in hippocampus of patients with temporal lobe epilepsy.
1991,
Pubmed
McKinley,
Cloning, sequence analysis and expression of two forms of mRNA coding for the human beta 2 subunit of the GABAA receptor.
1995,
Pubmed
Miledi,
Expression of functional neurotransmitter receptors in Xenopus oocytes after injection of human brain membranes.
2002,
Pubmed
,
Xenbase
Mueller,
Reduced extrahippocampal NAA in mesial temporal lobe epilepsy.
2002,
Pubmed
Murray,
Altered mRNA expression for brain-derived neurotrophic factor and type II calcium/calmodulin-dependent protein kinase in the hippocampus of patients with intractable temporal lobe epilepsy.
2000,
Pubmed
Noebels,
The biology of epilepsy genes.
2003,
Pubmed
Palma,
Expression of human epileptic temporal lobe neurotransmitter receptors in Xenopus oocytes: An innovative approach to study epilepsy.
2002,
Pubmed
,
Xenbase
Palma,
Threonine-for-leucine mutation within domain M2 of the neuronal alpha(7) nicotinic receptor converts 5-hydroxytryptamine from antagonist to agonist.
1996,
Pubmed
,
Xenbase
Palma,
Microtransplantation of membranes from cultured cells to Xenopus oocytes: a method to study neurotransmitter receptors embedded in native lipids.
2003,
Pubmed
,
Xenbase
Schröder,
Functional and molecular properties of human astrocytes in acute hippocampal slices obtained from patients with temporal lobe epilepsy.
2000,
Pubmed
Tsunashima,
GABA(A) receptor subunits in the rat hippocampus III: altered messenger RNA expression in kainic acid-induced epilepsy.
1997,
Pubmed
Walz,
Electrophysiological properties of glial cells: comparison of brain slices with primary cultures.
1988,
Pubmed
Wan,
Modulation of GABAA receptor function by tyrosine phosphorylation of beta subunits.
1997,
Pubmed
Wyneken,
Epilepsy-induced changes in signaling systems of human and rat postsynaptic densities.
2003,
Pubmed
Zhao,
Reduced expression of gamma-aminobutyric acid type A/benzodiazepine receptor gamma 2 and alpha 5 subunit mRNAs in brain regions of flurazepam-treated rats.
1994,
Pubmed
