cAMP Signaling Compartmentation: Adenylyl Cyclases as Anchors of Dynamic Signaling Complexes
It is widely accepted that cAMP signaling is compartmentalized within cells. However, our knowledge of how receptors, cAMP signaling enzymes, effectors and other key proteins form specific signaling complexes to regulate specific cell responses is limited. The multi-component nature of these systems and the spatiotemporal dynamics involved as proteins interact and move within a cell, make cAMP responses highly complex. Adenylyl cyclases, the enzymatic source of cAMP production, are key starting points for understanding cAMP compartments and defining the functional signaling complexes. Three basic elements are required to form a signaling compartment. First, a localized signal is generated by a G protein-coupled receptor paired to one or more of the nine different transmembrane adenylyl cyclase isoforms that generate the cAMP signal in the cytosol. The diffusion of cAMP is subsequently limited by several factors, including expression of any number of phosphodiesterases (of which there are 24 genes plus spice variants). Lastly, signal response elements are differentially localized in order to respond to cAMP produced within each locale. A kinase anchoring proteins, of which there are 43 different isoforms, facilitate this by targeting protein kinase A to specific substrates. Thousands of potential combinations of these three elements are possible in any given cell type, making the characterization of cAMP signaling compartments daunting. This review will focus on what is known about how cells organize cAMP signaling components as well as identify the unknowns. We make an argument for adenylyl cyclases being central to the formation and maintenance of these signaling complexes.
Johnstone TB, Agarwal SR, Harvey RD, Ostrom RS. cAMP signaling compartmentation: Adenylyl cyclases as anchors of dynamic signaling complexes. Mol Pharmacol. 2017. doi: 10.1124/mol.117.110825
American Society for Pharmacology and Experimental Therapeutics