cAMP renders Ca2+-dependent phosphodiesterase refractory to inhibition by a calmodulin-binding protein (calcineurin).
Calmodulin is a ubiquitous, multifunctional, Ca2+-dependent regulatory protein, controlling a wide variety of Ca2+-mediated reactions. The versatility of calmodulin raises the question of how it exerts specificity at the molecular level. Cyclic nucleotide phosphodiesterase consists of multiple forms, one of which requires calmodulin for full activity. Calcineurin, a calmodulin-binding protein, inhibits the calmodulin-stimulated phosphodiesterase activity by competing with the enzyme for calmodulin. In this report, we present experiments which indicate that, although calcineurin potentially inhibits calmodulin-supported enzyme activity, its effectiveness as an inhibitor depends on the level of cAMP. In the presence of elevated levels of cAMP, the affinity of calmodulin for phosphodiesterase increased markedly, but that for calcineurin was not altered. Thus, the enzyme became relatively refractory to inhibition by calcineurin. This finding suggests that an increase of cellular cAMP could lead to a condition favorable to its own hydrolysis and that this phenomenon might represent an example of molecular specificity in calmodulin-regulated reactions.
D000818:Animals; D001921:Brain / Q000201:enzymology*; D002118:Calcium / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000494:pharmacology*; D002147:Calmodulin / Q000378:metabolism / Q000494:pharmacology*; D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins / Q000494:pharmacology*; D002417:Cattle; D000242:Cyclic AMP / Q000494:pharmacology*; D007700:Kinetics; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011485:Protein Binding
D002135:Calcium-Binding Proteins; D002147:Calmodulin; D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D002118:Calcium