A-kinase anchoring protein 79/150 facilitates the phosphorylation of GABA(A) receptors by cAMP-dependent protein kinase via selective interaction with receptor beta subunits.
GABA(A) receptors, the key mediators of fast synaptic inhibition in the brain, are predominantly constructed from alpha(1-6), beta(1-3), gamma(1-3), and delta subunit classes. Phosphorylation by cAMP-dependent protein kinase (PKA) differentially regulates receptor function dependent upon beta subunit identity, but how this kinase is selectively targeted to GABA(A) receptor subtypes remains unresolved. Here we establish that the A-kinase anchoring protein 150 (AKAP150), directly binds to the receptor beta1 and beta3, but not to alpha1, alpha2, alpha3, alpha6, beta2, gamma2, or delta subunits. Furthermore, AKAP79/150 is critical for PKA-mediated phosphorylation of the receptor beta3 subunit. Together, our observations suggest a mechanism for the selective targeting of PKA to GABA(A) receptor subtypes containing the beta1 or beta3 subunits dependent upon AKAP150. Therefore, the selective interaction of beta subunits with AKAP150 may facilitate GABA(A) receptor subtype-specific functional modulation by PKA activity which may have profound local effects on neuronal excitation.
Brandon
Nicholas J
NJ
MRC Laboratory for Molecular Cell Biology and Department of Pharmacology, University College London, Gower Street, London WCIE 6BT, UK.
Jovanovic
Jasmina N
JN
Colledge
Marcie
M
Kittler
Josef T
JT
Brandon
Julia M
JM
Scott
John D
JD
Moss
Stephen J
SJ
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000201:enzymology*; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005333:Fetus; D006624:Hippocampus / Q000201:enzymology; D046911:Macromolecular Substances; D009154:Mutation / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology; D010766:Phosphorylation; D017434:Protein Structure, Tertiary / Q000502:physiology; D021122:Protein Subunits / Q000378:metabolism*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D013569:Synapses / Q000201:enzymology*; D013570:Synaptic Membranes / Q000201:enzymology; D009435:Synaptic Transmission / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; C415703:Akap5 protein, rat; D002352:Carrier Proteins; D046911:Macromolecular Substances; D021122:Protein Subunits; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D017868:Cyclic AMP-Dependent Protein Kinases