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.