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 postsynaptic events in the central nervous system(1,2). 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(4,5). 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.