title: Phospho-dependent functional modulation of GABA(B) receptors by the metabolic sensor AMP-dependent protein kinase.
abstract: GABA(B) receptors are heterodimeric G protein-coupled receptors composed of R1 and R2 subunits that mediate slow synaptic inhibition in the brain by activating inwardly rectifying K(+) channels (GIRKs) and inhibiting Ca(2+) channels. We demonstrate here that GABA(B) receptors are intimately associated with 5'AMP-dependent protein kinase (AMPK). AMPK acts as a metabolic sensor that is potently activated by increases in 5'AMP concentration that are caused by enhanced metabolic activity, anoxia, or ischemia. AMPK binds the R1 subunit and directly phosphorylates S783 in the R2 subunit to enhance GABA(B) receptor activation of GIRKs. Phosphorylation of S783 is evident in many brain regions, and is increased dramatically after ischemic injury. Finally, we also reveal that S783 plays a critical role in enhancing neuronal survival after ischemia. Together our results provide evidence of a neuroprotective mechanism, which, under conditions of metabolic stress or after ischemia, increases GABA(B) receptor function to reduce excitotoxicity and thereby promotes neuronal survival.
authors.affiliation: Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kuramoto
authors.forename: Megan E
authors.initials: ME
authors.lastname: Wilkins
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fairfax
authors.forename: Raquel
authors.initials: R
authors.lastname: Revilla-Sanchez
authors.forename: Miho
authors.initials: M
authors.lastname: Terunuma
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tamaki
authors.forename: Mika
authors.initials: M
authors.lastname: Iemata
authors.forename: Noel
authors.initials: N
authors.lastname: Warren
authors.forename: Andrés
authors.initials: A
authors.lastname: Couve
authors.forename: Andrew
authors.initials: A
authors.lastname: Calver
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Horvath
authors.forename: Katie
authors.initials: K
authors.lastname: Freeman
authors.forename: David
authors.initials: D
authors.lastname: Carling
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
authors.forename: Cathleen
authors.initials: C
authors.lastname: Gonzales
authors.forename: Edward
authors.initials: E
authors.lastname: Cooper
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Smart
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
mesh_terms: D000249:Adenosine Monophosphate / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007106:Immune Sera; D009474:Neurons / Q000378:metabolism; D009994:Osmolar Concentration; D010766:Phosphorylation; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D020033:Protein Isoforms / Q000276:immunology; D051381:Rats; D018080:Receptors, GABA-B / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*
chemical_list: D007106:Immune Sera; D024661:Potassium Channels, Inwardly Rectifying; D020033:Protein Isoforms; D018080:Receptors, GABA-B; D000249:Adenosine Monophosphate; D017868:Cyclic AMP-Dependent Protein Kinases