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The Journal of Neuroscience, September 1, 2004, 24(35):7614-7622; doi:10.1523/JNEUROSCI.0868-04.2004

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Cellular/Molecular
Glyceraldehyde-3-Phosphate Dehydrogenase Is a GABA_A Receptor Kinase Linking Glycolysis to Neuronal Inhibition

Jacques J. Laschet,^1,2 Frédéric Minier,² Irène Kurcewicz,¹ Michel H. Bureau,² Suzanne Trottier,¹ Freddy Jeanneteau,¹ Nathalie Griffon,¹ Bart Samyn,³ Jozef Van Beeumen,³ Jacques Louvel,¹ Pierre Sokoloff,¹ and René Pumain¹

¹Laboratory of Molecular Neurobiology and Pharmacology, Institut National de la Santé et de la Recherche Médicale Unité 573, F-75014 Paris, France, ²Laboratory of Neurosciences, University of Rennes 1, F-35000 Rennes, France, and ³Laboratory of Protein Biochemistry and Protein Engineering, University of Ghent, B-9000 Ghent, Belgium

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 1 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 1 subunit at identified serine and threonine residues. GAPDH and the 1 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 1 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 Mg²⁺-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.

Key words: GABA_A receptor phosphorylation; response rundown; receptor-associated kinase; GAPDH; glycolysis; ATP

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Received March 10, 2004; revised June 29, 2004; accepted July 1, 2004.

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				F. Jarczowski, G. Jahreis, F. Erdmann, A. Schierhorn, G. Fischer, and F. Edlich FKBP36 Is an Inherent Multifunctional Glyceraldehyde-3-phosphate Dehydrogenase Inhibitor J. Biol. Chem., January 9, 2009; 284(2): 766 - 773. [Abstract] [Full Text] [PDF]

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