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. Vmax values for isoforms 2, 3 and 4 relative to isoform 1 are 3.8, 1.6 and 2.1. Purine metabolism; 3',5'-cyclic AMP degradation; AMP from 3',5'-cyclic AMP: step 1/1. Interacts with DISC1. Widely expressed. Expressed in brain, heart, lung and liver. Expressed in liver and brain. In Sertoli cells, induced by FSH. In the pineal gland, exhibits night/day variations with a 7-fold increased expression at night. Up-regulation is due to a large degree to the release of norepinephrine from nerve terminals in the pineal gland and cAMP signaling pathway. Activated by phosphorylation at Ser-56. Mutagenesis of Ser-56 abolishes activation. Belongs to the cyclic nucleotide phosphodiesterase family. PDE4 subfamily.