cAMP Signaling Compartmentation: Adenylyl Cyclases as Anchors of Dynamic Signaling Complexes

Abstract

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 multicomponent 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). Finally, signal response elements are differentially localized 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.

Fig. 1.

Schematic diagram of proposed cAMP signaling compartments in HASM cells. Two main cAMP signaling compartments have been defined, one centered around β₂AR-AC6 in lipid raft domains (consisting of sphingolipid, shown in red, and cholesterol) and another around EP_2/4R-AC2 in nonraft domains (consisting of phospholipid, shown in blue). Illustrated are the main AKAP and PDE isoforms known to assemble in these signaling complexes or regulate cAMP emanating from each location. Cytoskeletal elements likely also form barriers to cAMP diffusion. Cell responses that have been linked to specific compartments are listed. A number of AKAP and PDE isoforms are expressed in HASM but the locations of some are unknown, and thus are not shown. These include PDE3, AKAP2, AKAP3, ezrin, and Map2B. It is also unknown if PDE4D splice variants have different localizations. PDE8A is located in lipid rafts where it regulates β₂AR-AC6 signaling, but it is unknown how it is tethered specifically in this location. AKAP12 (gravin), AKAP5 (AKAP79), AKAP9 (yotiao).