Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.2.1.13 (glyceraldehyde-3-phosphate dehydrogenase)
 6,511 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein phosphorylation is crucial for regulating synaptic transmission. We describe a novel mechanism for the phosphorylation of the GABA(A) receptor, which mediates fast inhibition in the brain. A protein copurified and coimmunoprecipitated with the phosphorylated receptor alpha1 subunit; this receptor-associated protein was identified by purification and microsequencing as the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Molecular constructs demonstrated that GAPDH directly phosphorylates the long intracellular loop of GABA(A) receptor alpha1 subunit at identified serine and threonine residues. GAPDH and the alpha1 subunit were found to be colocalized at the neuronal plasma membrane. In keeping with the GAPDH/GABA(A) receptor molecular association, glycolytic ATP produced locally at plasma membranes was consumed for this alpha1 subunit phosphorylation, possibly within a single macrocomplex. The membrane-attached GAPDH is thus a dual-purpose enzyme, a glycolytic dehydrogenase, and a receptor-associated kinase. In acutely dissociated cortical neurons, the rundown of the GABA(A) responses was essentially attributable to a Mg(2+)-dependent phosphatase activity, which was sensitive to vanadate but insensitive to okadaic acid or fluoride. Rundown was significantly reduced by the addition of GAPDH or its reduced cofactor NADH and nearly abolished by the addition of its substrate glyceraldehyde-3-phosphate (G3P). The prevention of rundown by G3P was abolished by iodoacetamide, an inhibitor of the dehydrogenase activity of GAPDH, indicating that the GABA(A) responses are maintained by a glycolysis-dependent phosphorylation. Our results provide a molecular mechanism for the direct involvement of glycolysis in neurotransmission.
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PMID:Glyceraldehyde-3-phosphate dehydrogenase is a GABAA receptor kinase linking glycolysis to neuronal inhibition. 1534 27

We have shown that the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is the kinase involved in the endogenous phosphorylation of the alpha1 subunit of the gamma-aminobutyric acid (GABA)(A) receptor (GABA(A)R), maintaining GABA(A)-R function. GABA(A)R endogenous phosphorylation is opposed by one or several atypical phosphatases. We have shown in addition, using cerebral tissue obtained during epilepsy surgery and control tissue from patients undergoing brain tumor surgery, that both endogenous phosphorylation and GABA(A)R function are significantly reduced in the "epileptogenic" cerebral cortex when compared to control. This dysfunction likely contributes to seizure generation and/or transition from the interictal to the ictal state. The therapeutic challenge is to alleviate the endogenous phosphorylation deficiency of GABA(A)R in the epileptogenic cortical tissue, either through activating the endogenous kinase activity, or inhibiting dephosphorylation of the alpha1 subunit. Following the first trail, we have shown that spermine (the most effective polyamine) increases the GAPDH kinase activity on GABA(A)R and that subsequently such modulation potentiates its function as assessed by rundown studies on isolated neurons. Following the second trail, we have developed methods to identify these atypical membrane-bound phosphatases. Their activities were detected using two synthetic phosphopeptides corresponding to the alpha1 regions of phosphorylation by GAPDH. After purification, the active fractions are submitted to proteomic analysis by nanoLC-Maldi-TOF/TOF for protein identification. Two candidate proteins have been identified, which will be used as targets for high-throughput screening in order to develop original antiepileptic molecules.
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PMID:New therapeutic targets to develop molecules active in drug-resistant epilepsies. 2061 99