A key glycolytic enzyme plays a dual role in GABAergic neurotransmission and in human epilepsy.
We have previously described a new endogenous phosphorylation mechanism that maintains ionotropic gamma-aminobutyric acid receptor (GABAAR) function and have shown that the kinase involved is the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). This enzyme is closely associated with the receptor and phosphorylates the alpha1 subunit of the receptor. In a wealth of studies, a reduction in GABAergic neurotransmission has been suggested as a pathophysiological mechanism for human epilepsy. In this paper, we present evidence showing both reduced efficacy of this glycolysis-dependent GABAAR phosphorylation mechanism and of GABAergic inhibition in epileptogenic cortical tissue samples obtained during curative surgery of patients with partial seizures, as compared to non-epileptogenic human cortical tissue. This feature is not due to a reduction in the density of GABAAR alpha1 subunits in the epileptogenic tissue as evidenced by photoaffinity labeling. Maintaining the receptor in a phosphorylated state either by favoring the endogenous phosphorylation or by inhibiting a membrane-bound phosphatase sustains the GABAAR responses in the human epileptogenic cortex. The deficiency in endogenous phosphorylation and the associated decreased GABAAR function can account for transient failures of GABAergic inhibition and may favor seizure initiation and propagation. These findings suggest a functional link between epileptic pathology and the regional cerebral glucose hypometabolism observed in patients with partial epilepsies, since the dysfunction of the GABAergic mechanism is dependent on locally produced glycolytic ATP. They also point to new targets for developing molecules active in drug-resistant epilepsies.
Pumain
René
R
INSERM U573, Centre Paul Broca, Paris, France. rpumain@broca.inserm.fr
Laschet
Jacques
J
D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D004827:Epilepsy / Q000201:enzymology* / Q000503:physiopathology; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D009433:Neural Inhibition / Q000502:physiology; D010766:Phosphorylation; D011963:Receptors, GABA-A / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+)