THE DIFFERENTIAL RESPONSE OF PROTEIN-KINASE-A TO CYCLIC-AMP IN DISCRETE BRAIN-AREAS CORRELATES WITH THE ABUNDANCE OF REGULATORY SUBUNIT-II

We analyzed the expression and relative distribution of mRNA for the r egulatory subunits (RI alpha, RII alpha, and RII beta) and of 150-kDa RII beta-anchor proteins for cyclic AMP (cAMP)-dependent protein kinas e (PKA) into discrete brain regions. The subcellular distribution of b oth holoenzyme and free catalytic subunit was evaluated in the same CN S areas. In the neocortex and corpus striatum high levels of RII beta paralleled the presence of specific RII-anchoring proteins, high level s of membrane-bound PKA holoenzyme, and low levels of cytosolic free c atalytic activity (C-PKA). Conversely, in brain areas showing low RII beta levels (cerebellum, hypothalamus, and brainstem) we found an abse nce of RII-anchoring proteins, low levels of membrane-bound holoenzyme PKA, and high levels of cytosolic dissociated C-PKA. Response to cAMP stimuli was specifically evaluated in the neocortex and cerebellum, p rototypic areas of the two different patterns of PKA distribution. We found that cerebellar holoenzyme PKA was highly sensitive to cAMP-indu ced dissociation, without, however, a consistent translocation of C-PK A into the nucleus. In contrast, in the neocortex holoenzyme PKA was m ainly in the undissociated state and poorly sensitive to cAMP, In nucl ei of cortical cells cAMP stimulated the import of C-PKA and phosphory lation of cAMP-responsive element binding protein. Taken together, the se data suggest that RII beta (whose distribution is graded throughout the CNS, reaching maximal expression in the neocortex) may represent the molecular cue of the differential nuclear response to cAMP in diff erent brain areas, by controlling cAMP-induced holoenzyme PKA dissocia tion and nuclear accumulation of catalytic subunits.