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. Activated by phosphatidic acid (By similarity). Inhibited by rolipram. 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. Isoform 33 is part of a ternary complex containing PRKAR2A, PRKAR2B and AKAP9. Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1) (By similarity). Interacts with PDE4DIP. Isoform 5 interacts (via N-terminal region) with SHANK2 (via proline-rich region); the interaction is increased in a PKA-dependent manner. Isoform 33, isoform 4, isoform 7, isoform 8 and isoform 9 but not isoform 32 and isoform 6 interact with SHANK2. Isoform 31 interacts weakly with SHANK2. Found in the soluble fraction, associated with membranes, and associated with the cytoskeleton and the centrosome. Colocalized with SHANK2 to the apical membrane of colonic crypt cells. Expressed in epithelial cells. Isoform 33, isoform 4, isoform 5 and isoform 9 are expressed in brain. Isoform 33, isoform 5, isoform 8 and isoform 9 are expressed in heart (at protein level). Isoform 4 and isoform 6 are strongly expressed in cortex and cerebellum. Isoform 7 is strongly expressed in cortex and testis; weakly expressed in kidney, lung, spleen and cerebellum. Isoform 8 is strongly expressed in lung, heart and liver. Isoform 31, isoform 32, isoform 33, isoform 5 and isoform 9 are widely distributed. Up-regulated by cAMP and follicle-stimulating hormone. Isoform 1 and isoform 9 are rapidly activated by PKA through phosphorylation. Long isoforms that share a conserved PKA phosphorylation site in the N-terminus are also activated. 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.