The type and the localization of cAMP-dependent protein kinase regulate transmission of cAMP signals to the nucleus in cortical and cerebellar granule cells

cAMP signals are received and transmitted by multiple isoforms of cAMP-depe ndent protein kinases, typically determined by their specific regulatory su bunits. In the brain the major regulatory isoform RII beta and the RII-anch or protein, AKAP150 (rat) or 75 (bovine), are differentially expressed. Cor tical neurons express RII beta and AKAP75; conversely, granule cerebellar c ells express predominantly RI alpha and RII alpha Cortical neurons accumula te PKA catalytic subunit and phosphorylated cAMP responsive element binding protein very efficiently into nuclei upon cAMP induction, whereas granule cerebellar cells fail to do so. Down-regulation of RII beta synthesis by an tisense oligonucleotides inhibited cAMP-induced nuclear signaling in cortic al neurons. Expression in cerebellar granule cells of RII beta and ARAP75 g enes by microinjection of specific expression vectors, markedly stimulated cAMP-induced transcription of the lacZ gene driven by a cAMP-responsive ele ment promoter. These data indicate that the composition of PKA in cortical and granule cel ls underlies the differential ability of these cells to transmit cAMP signa ls to the nucleus.