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Newly synthesized cAMP is integrated at a membrane protein complex signalosome to ensure receptor response specificity
Author(s) -
Guinzberg Raquel,
DíazCruz Antonio,
AcostaTrujillo Carlos,
VilchisLanderos María Magdalena,
VázquezMeza Héctor,
LozanoFlores Carlos,
ChiqueteFelix Natalia,
VarelaEchavarría Alfredo,
UribeCarvajal Salvador,
RiverosRosas Héctor,
Piña Enrique
Publication year - 2017
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13969
Subject(s) - adenylyl cyclase , microbiology and biotechnology , protein kinase a , pde10a , guanine nucleotide exchange factor , g protein coupled receptor , creb1 , phosphodiesterase 3 , phosphodiesterase , receptor , biology , signal transduction , biochemistry , chemistry , kinase , enzyme , transcription factor , creb , gene
Spatiotemporal regulation of c AMP within the cell is required to achieve receptor‐specific responses. The mechanism through which the cell selects a specific response to newly synthesized c AMP is not fully understood. In hepatocyte plasma membranes, we identified two functional and independent c AMP ‐responsive signaling protein macrocomplexes that produce, use, degrade, and regulate their own nondiffusible (sequestered) c AMP pool to achieve their specific responses. Each complex responds to the stimulation of an adenosine G protein‐coupled receptor (Ado‐ GPCR ), bound to either A 2A or A 2B , but not simultaneously to both. Each isoprotein involved in each signaling cascade was identified by measuring changes in c AMP levels after receptor activation, and its participation was confirmed by antibody‐mediated inactivation. A 2A ‐Ado‐ GPCR selective stimulation activates adenylyl cyclase 6 ( AC 6), which is bound to AKAP 79/150, to synthesize c AMP which is used by two other AKAP 79/150‐tethered proteins: protein kinase A ( PKA ) and phosphodiesterase 3A ( PDE 3A). In contrast, A 2B ‐Ado‐ GPCR stimulation activates D‐ AKAP 2‐attached AC 5 to generate c AMP , which is channeled to two other D‐ AKAP 2‐tethered proteins: guanine‐nucleotide exchange factor 2 (Epac2) and PDE 3B. In both cases, prior activation of PKA or Epac2 with selective c AMP analogs prevents de novo c AMP synthesis. In addition, we show that c AMP does not diffuse between these protein macrocomplexes or ‘signalosomes’. Evidence of coimmunoprecipitation and colocalization of some proteins belonging to each signalosome is presented. Each signalosome constitutes a minimal functional signaling unit with its own machinery to synthesize and regulate a sequestered c AMP pool. Thus, each signalosome is devoted to ensure the transmission of a unique and unequivocal message through the cell.