Layers of organization of cAMP microdomains in a simple cell.
Based on a variety of single-cell measurements, the notion that cAMP microdomains exist in cells is being increasingly embraced. The cellular and molecular underpinnings of this organization are also steadily being revealed. A dependence of Ca(2+)-sensitive ACs (adenylate cyclases) in HEK-293 cells (human embryonic kidney cells) on capacitative Ca(2+) entry is enforced by their presence in lipid rafts and protein-protein interactions. In these cells, many of the participants in the cAMP cascade, including AC, phosphodiesterase 4, cAMP-dependent protein kinase [PKA (protein kinase A)] and protein phosphatase 2A, are now seen to be involved in higher order assemblies. Moreover, the presence of Na(+)/H(+) exchanger 1 in these domains creates a microclimate, protected against global swings in cellular pH. The Ca(2+)-stimulatable AC8, which is targeted to these regions, can sequester calmodulin for its own regulatory purposes. These devices are a sampling of the multiple layers of organization that are in place -- even in a simple cell -- to ensure faithful and economical communication of the cAMP message.
Martin
A C L
AC
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
Cooper
D M F
DM
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D002451:Cell Compartmentation; D000242:Cyclic AMP / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D054648:Protein Phosphatase 2
D048868:Adaptor Proteins, Signal Transducing; D002147:Calmodulin; D000242:Cyclic AMP; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D002118:Calcium