Phospho-dependent functional modulation of GABA(B) receptors by the metabolic sensor AMP-dependent protein kinase.
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.
Kuramoto
Nobuyuki
N
Department of Neuroscience, University of Pennsylvania, Philadelphia, PA 19104, USA.
Wilkins
Megan E
ME
Fairfax
Benjamin P
BP
Revilla-Sanchez
Raquel
R
Terunuma
Miho
M
Tamaki
Keisuke
K
Iemata
Mika
M
Warren
Noel
N
Couve
Andrés
A
Calver
Andrew
A
Horvath
Zsolt
Z
Freeman
Katie
K
Carling
David
D
Huang
Lan
L
Gonzales
Cathleen
C
Cooper
Edward
E
Smart
Trevor G
TG
Pangalos
Menelas N
MN
Moss
Stephen J
SJ
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*
D007106:Immune Sera; D024661:Potassium Channels, Inwardly Rectifying; D020033:Protein Isoforms; D018080:Receptors, GABA-B; D000249:Adenosine Monophosphate; D017868:Cyclic AMP-Dependent Protein Kinases