Anchoring of protein kinase A is required for modulation of AMPA/kainate receptors on hippocampal neurons.
Phosphorylation of molecules involved in synaptic transmission by multifunctional protein kinases modulates both pre- and post-synaptic events in the central nervous system. The positioning of kinases near their substrates may be an important part of the regulatory mechanism. The A-kinase-anchoring proteins (AKAPs; ref. 3) are known to bind the regulatory subunit of cyclic AMP-dependent protein kinase A with nanomolar affinity. Here we show that anchoring of protein kinase A by AKAPs is required for the modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/kainate channels. Intracellular perfusion of cultured hippocampal neurons with peptides derived from the conserved kinase binding region of AKAPs prevented the protein kinase A-mediated regulation of AMPA/kainate currents as well as fast excitatory synaptic currents. This effect could be overcome by adding the purified catalytic subunit of protein kinase. A control peptide lacking kinase-binding activity had no effect. To our knowledge, these results provide the first evidence that anchoring of protein kinase A is crucial in the regulation of synaptic function.
Rosenmund
C
C
Vollum Institute, Oregon Health Sciences University, Portland 97201.
Carr
D W
DW
Bergeson
S E
SE
Nilaver
G
G
Scott
J D
JD
Westbrook
G L
GL
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000378:metabolism*; D013569:Synapses / Q000502:physiology
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D005576:Colforsin; D017868:Cyclic AMP-Dependent Protein Kinases; D010446:Peptide Fragments; D011506:Proteins; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; C487775:AKAP5 protein, human; C415703:Akap5 protein, rat