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 (PubMed:15260978, PubMed:15576036). Site 2 has a preference for magnesium and/or manganese ions (By similarity). Inhibited by rolipram. Activated by phosphatidic acid. 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. Isoform 3 is part of a ternary complex containing PRKAR2A, PRKAR2B and AKAP9. Interacts with PDE4DIP. Identified in a complex composed of RYR1, PDE4D, PKA, FKBP1A and protein phosphatase 1 (PP1) (By similarity). Isoform 5, isoform N3 and isoform 12 bind RACK1 via their unique N-terminus. Binds ARRB2. Interacts (via N-terminal region) with SHANK2 (via proline-rich region); the interaction is increased in a PKA-dependent manner. Found in the soluble fraction, associated with membranes, and associated with the cytoskeleton and the centrosome (By similarity). Colocalized with SHANK2 to the apical membrane of colonic crypt cells. Expressed in colonic epithelial cells (at protein level). Widespread; most abundant in skeletal muscle. Detected in brain. Detected in brain, placenta, lung and kidney. Detected in heart and skeletal muscle. Long isoforms that share a conserved PKA phosphorylation site in the N-terminus are activated by PKA through phosphorylation (By similarity). Isoform 3 and isoform 7 are activated by phosphorylation (in vitro), but not isoform 6. Isoform N3 and isoform 12 are phosphorylated on Ser-49, Ser-51, Ser-55 and Ser-59. Sumoylation of long isoforms by PIAS4 augments their activation by PKA phosphorylation and represses their inhibition by ERK phosphorylation. Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution. The disease is caused by variants affecting the gene represented in this entry. Activated by phosphorylation at Ser-53. Mutagenesis of Ser-54 abolishes activation. Belongs to the cyclic nucleotide phosphodiesterase family. PDE4 subfamily. Leiden Open Variation Database (LOVD)