Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. 3',5'-cyclic AMP + H2O = AMP + H(+) Binds 2 divalent metal cations per subunit. Site 1 may preferentially bind zinc ions. Binds 2 divalent metal cations per subunit. Site 2 has a preference for magnesium and/or manganese ions. Inhibited by rolipram. Activated by phosphatidic acid (By similarity). Purine metabolism; 3',5'-cyclic AMP degradation; AMP from 3',5'-cyclic AMP: step 1/1. Homodimer for the long isoforms. Isoforms with truncated N-termini are monomeric. Binds ARRB2. Interacts with PDE4DIP (By similarity). Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1). Interacts (via N-terminal region) with SHANK2 (via proline-rich region); the interaction is increased in a PKA-dependent manner. Colocalized with SHANK2 to the apical membrane of colonic crypt cells (By similarity). Found in the soluble fraction, associated with membranes, and associated with the cytoskeleton and the centrosome. Expressed in brain (at protein level). Isoform 7 is detected in heart, brain, lung, kidney and testis. Up-regulated by cAMP and follicle-stimulating hormone. Sumoylation of long isoforms by PIAS4 augments their activation by PKA phosphorylation and represses their inhibition by ERK phosphorylation. Belongs to the cyclic nucleotide phosphodiesterase family. PDE4 subfamily.