ANCHORING OF PROTEIN-KINASE-A IS REQUIRED FOR MODULATION OF AMPA KAINATE RECEPTORS ON HIPPOCAMPAL-NEURONS/

PHOSPHORYLATION of molecules involved in synaptic transmission by mult ifunctional protein kinases modulates both pre- and postsynaptic event s 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 nano molar affinity. Here we show that anchoring of protein kinase A by AKA Ps is required for the modulation of pha-amino-3-hydroxy-5'methyl-4-is oxazole-propionic acid (AMPA)/kainate channels(4,5). Intracellular per fusion 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 excitat ory synaptic currents. This effect could be overcome by adding the pur ifiedcatalytic subunit of protein kinase. A control peptide lacking ki nase-bindingactivity had no effect. To our knowledge, these results pr ovide the first evidence that anchoring of protein kinase A is crucial in the regulation of synaptic function.