Inhibition of cyclic nucleotide phosphodiesterase and calcineurin by spermine, a calcium-independent calmodulin antagonist.
Spermine binding to calmodulin and its effects on two calmodulin-dependent enzymes were studied. Spermine bound to dansylated calmodulin with an apparent Ki of 0.7 mM, and to native calmodulin with a Kd of 1.1 mM in equilibrium dialysis experiments. Its binding was found to be independent of calcium. Spermine inhibited calmodulin-activated cyclic nucleotide phosphodiesterase noncompetitively with respect to calcium (Ki = 1.1 mM). Calmodulin activation of calcineurin was inhibited at similar concentrations (Ki = 1.2 mM). Spermine had little effect on basal phosphodiesterase activity or nickel-activated calcineurin activity. Inhibition of both enzymes correlated well with spermine binding to dansylcalmodulin. These findings suggest that spermine might modulate calcium-dependent events in the cell by inactivation of calmodulin via a novel calcium-independent mechanism.
Walters
J D
JD
College of Dentistry, Ohio State University Medical Center, Columbus.
Johnson
J D
JD
D000818:Animals; D001921:Brain / Q000201:enzymology; D019703:Calcineurin; D002118:Calcium / Q000502:physiology; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors*; D002417:Cattle; D004789:Enzyme Activation / Q000187:drug effects; D007700:Kinetics; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D013096:Spermine / Q000494:pharmacology*
D002147:Calmodulin; D002148:Calmodulin-Binding Proteins; D013096:Spermine; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D002118:Calcium