The Differential Response of Protein Kinase A to Cyclic AMP in Discrete Brain Areas Correlates with the Abundance of Regulatory Subunit II |
| |
Authors: | Carmelo Ventra †Antonio Porcellini †Antonio Feliciello †Adriana Gallo Mayra Paolillo ‡Evelina Mele †‡Vittorio Enrico Avvedimento § Gennaro Schettini |
| |
Institution: | Dipartimento di Neuroscienze e della Comunicazione Interumana, Sezione di Farmacologia;; Cattedra di Farmacologia, Dipartimento di Oncologia Clinica e Sperimentale, Facoltàdi Medicina, Universitàdi Genova;; Centro di Biotecnologie Avanzate, Istituto Nazionale per la Ricerca sul Cancro, Genova;; Dipartimento di Biologia e Patologia Molecolare e Cellulare, Centro di Endocrinologia ed Oncologia Sperimentale del CNR, Facoltàdi Medicina e Chirurgia, Universitàdegli Studi di Napoli "Federico II," Napoli;and; Dipartimento di Medicina Sperimentale e Clinica, Facoltàdi Medicina a Catanzaro, Universitàdi Reggio Calabria, Reggio Calabria, Italy |
| |
Abstract: | Abstract: We analyzed the expression and relative distribution of mRNA for the regulatory subunits (RIα, RIIα, and RIIβ) and of 150-kDa RIIβ-anchor proteins for cyclic AMP (cAMP)-dependent protein kinase (PKA) into discrete brain regions. The subcellular distribution of both holoenzyme and free catalytic subunit was evaluated in the same CNS areas. In the neocortex and corpus striatum high levels of RIIβ paralleled the presence of specific RII-anchoring proteins, high levels of membrane-bound PKA holoenzyme, and low levels of cytosolic free catalytic activity (C-PKA). Conversely, in brain areas showing low RIIβ levels (cerebellum, hypothalamus, and brainstem) we found an absence 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, prototypic areas of the two different patterns of PKA distribution. We found that cerebellar holoenzyme PKA was highly sensitive to cAMP-induced dissociation, without, however, a consistent translocation of C-PKA into the nucleus. In contrast, in the neocortex holoenzyme PKA was mainly in the undissociated state and poorly sensitive to cAMP. In nuclei of cortical cells cAMP stimulated the import of C-PKA and phosphorylation of cAMP-responsive element binding protein. Taken together, these data suggest that RIIβ (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 different brain areas, by controlling cAMP-induced holoenzyme PKA dissociation and nuclear accumulation of catalytic subunits. |
| |
Keywords: | Adenylyl cyclase Cyclic AMP-dependent kinase RII-binding protein Rat Gene expression Central nervous system |
|
|