Figure 1: Compartmentalized regulation of CFTR function coupled to a cAMP efflux transporter MRP4. Under the apical plasma membrane in the gut epithelia, there exist highly localized compartments that are composed of a series of signaling molecules such as adenosine receptor (A2b); G protein (Gs); AC; PKA and its anchoring protein AKAPs (not shown here); CFTR; cAMP transporter (MRP4); and PDZ scaffolding protein (PDZK1), which physically connects CFTR to MRP4. This multi-protein signaling complex provides an anatomical basis for generating and modulating local cAMP compartments. When an agonist (such as ADO) binds A2b, a series of G-protein-mediated reactions leads to activation of AC present in the apical membrane. Sufficient cAMP is locally generated in a diffusionally restricted apical microdomain (but not in other cellular compartments). cAMP activates PKA, which is anchored also to the apical membrane by AKAP (i.e., ezrin), and phosphorylates CFTR Cl- channel in close vicinity, resulting in an increase of Cl- currents. The CFTR-mediated Cl- currents can be further potentiated through the additional increase of local cAMP resulting from the reduced or blocked efflux via a neighboring apical membrane cAMP transporter (MRP4) in the same subcellular compartment.