Regulation of cAMP concentration by calmodulin-dependent cyclic nucleotide phosphodiesterase

Bovine brain contains two major calmodulin (CaM) dependent phosphodiesterase isozymes which are homodimeric proteins with subunit molecular masses of 60 and 63 kilodaltons (kDa), respectively. The 60-kDa subunit isozyme can be phosphorylated by cAMP-dependent protein kinase, resulting in a decrease in enzyme affinity towards CaM. The phosphorylation is blocked by Ca²⁺ and CaM and reversed by the CaM-stimulated phosphatase (calcineurin). The 63-kDa subunit isozymes can also be phosphorylated, but in this case by (a) CaM-dependent protein kinase(s). This phosphorylation is also accompanied by a decrease in the isozyme affinity towards CaM and can be reversed by the CaM-dependent phosphatase. Analysis of the complex regulatory properties of the phosphodiesterase isozymes has led to the suggestion that fluxes of cAMP and Ca²⁺ during cell activations are closely coupled and that the CaM-dependent phosphodiesterase isozymes play key roles in this signal coupling phenomenon.