Hydrolyzes the second messenger 3',5'-cyclic AMP (cAMP), which is a key regulator of many important physiological processes. Efficiently hydrolyzes cAMP. Efficiently hydrolyzes cAMP. Efficiently hydrolyzes cAMP. The phosphodiesterase activity is not affected by calcium, calmodulin or cyclic GMP (cGMP) levels. Does not hydrolyze cGMP. Efficiently hydrolyzes cAMP. Efficiently hydrolyzes cAMP. Efficiently hydrolyzes cAMP. 3',5'-cyclic AMP + H2O = AMP + H(+) 3',5'-cyclic AMP + H2O = AMP + H(+) 3',5'-cyclic AMP + H2O = AMP + H(+) 3',5'-cyclic AMP + H2O = AMP + H(+) 3',5'-cyclic AMP + H2O = AMP + H(+) 3',5'-cyclic AMP + H2O = AMP + H(+) 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:17727341, Ref.20). Site 2 has a preference for magnesium and/or manganese ions (By similarity). Inhibited by rolipram, cilomilast, Ro 20-1724, roflumilast and denbufylline. Inhibited by rolipram, cilomilast, Ro 20-1724, roflumilast and denbufylline. Inhibited by rolipram. Inhibited by rolipram. Inhibited by rolipram, cilomilast, Ro 20-1724, roflumilast and denbufylline. Inhibited by rolipram and cilomilast. Purine metabolism; 3',5'-cyclic AMP degradation; AMP from 3',5'-cyclic AMP: step 1/1. Interacts with LYN (via SH3 domain). Interacts with ARRB2. Interacts with LYN (via SH3 domain). Interacts with ARRB2. Interacts with LYN (via SH3 domain). Interacts with ARRB2. Isoform 4 has propensity for association with membranes. Predominantly cytosolic. Additional isoforms seem to exist. Expressed in lymphoid cell subsets including CD8-positive T cells and T-helper 2 cells. Expressed in dendritic cells. Highly expressed in liver, stomach, testis, thyroid and adrenal glands and at a lower extent in placenta, kidney, pancreas, ovary, uterus and skin. Expressed in myeloid cell subsets including dendritic cells, monocytes, macrophages, eosinophils and mast cells. Expressed in natural killer cells. Expressed in bronchial smooth muscle. Expressed at high levels in the heart and small intestine. It is also found in the brain, kidney, spleen, colon, salivary gland, ovary and peripheral blood lymphocytes. Expressed predominantly in skeletal muscle and brain and at lower levels in the testis. Found in specific neuronal subpopulations including cortical pyramidal neurons, horn neurons in the spinal cord and Purkinje cells in cerebellum (at protein level). Expressed in fetal brain. Proteolytically cleaved by CASP3. Phosphorylated at Ser-119 by PKA. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Probably represents a non-functional splice isoform. Belongs to the cyclic nucleotide phosphodiesterase family. PDE4 subfamily.