Differential Regulation of Calmodulin-Dependent Cyclic Nucleotide Phosphodiesterase Isozymes

Calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) is one of the key enzymes involved in the complex interactions that occur between the cyclic nucleotide and Ca2+ second messenger systems. This enzyme is characterized by a high Km for cAMP and a lower Km for cGMP. CaMPDE exists in different isozymic forms that exhibit distinct molecular and /or catalytic properties. Four CaMPDE isozymes have been purified close to homogeneity from bovine tissue in this laboratory. Immunologic, kinetic, and regulatory characterization have revealed subtle differences among these enzymes. The 63 kD CaMPDE is kinetically distinct from the other three isozymes. This isozyme is also further distinguished from other isozymes by the ginsenoside inhibition study. Ginsenosides are found to be potent inhibitors of brain 60 kD, heart and lung CaMPDE isozymes, but not of the brain 63 kD isozyme. The three other members — brain 60 kD CaMPDE, heart CaMPDE, and lung CaMPDE — show differential activation by calmodulin and Ca2+. These observations are consistent with the notion that differential regulation by calmodulin and Ca2+ kinetics inhibition are important functions of these isozymes that provide fine-tuning mechanisms for calmodulin action.