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Formation of multiple-protein macromolecular complexes at specialized subcellular microdomains increases the specificity and efficiency of signaling in cells. In this study, we demonstrated that phosphodiesterase type 3A (PDE3A) is physically and functionally coupled to cystic fibrosis transmembrane conductance regulator (CFTR). PDE3A inhibition increases cyclic adenosine 3′, 5′-monophosphate (cAMP) levels in a compartmentalized manner at the plasma membrane, which potentiates CFTR channel function and further clusters PDE3A and CFTR into microdomains. Actin skeleton disruption reduces PDE3A-CFTR interaction; segregates PDE3A from its interacting partners thus compromise the integrity of the macromolecular complex. Consequently, PDE3A inhibition no longer activates CFTR channel function in a compartmentalized manner. Physiologically, formation of the CFTR-PDE3A-containing macromolecular complexes was investigated using pig trachea submucosal gland secretion model. PDE3A inhibition augments CFTR-dependent submucosal gland secretion and actin skeleton disruption decreases secretion. These findings are important in understanding the regulation of CFTR function by phosphodiesterases.