Phosphatidylinositol modulates the response of calmodulin-dependent phosphatase to calmodulin.
Phosphatidylinositol (PtdIns) and many other phospholipids activated calmodulin (CaM)-dependent phosphatase in the presence or absence of Ca2+, and the stimulation was more pronounced in the presence of Ca2+. In addition, PtdIns modulated the response of phosphatase to CaM: at low and nonstimulatory concentrations (less than 70 microM), PtdIns augmented the activity of phosphatase by a submaximum concentration of CaM, giving a synergistic effect; and at high concentrations (greater than 100 microM), PtdIns suppressed the synergistic effect. Kinetic experiments indicated that PtdIns (both nonstimulatory and stimulatory concentrations) increased the affinity of phosphatase for CaM. In addition to the CaM regulatory site, phosphatase appears to have two PtdIns regulatory sites: a high-affinity site the occupation of which does not stimulate enzyme activity, and a low-affinity site the occupation of which stimulates enzyme activity in the absence of CaM and inhibits it in the presence of CaM. Modulating the response of phosphatase to CaM is not unique to PtdIns, and was observed with other phospholipids, including some that did not stimulate the enzyme. This raises the possibility that certain phospholipids may regulate phosphatase in two ways: (i) direct activation of the enzyme and (ii) modulation of its response to CaM.
Huang
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SL
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38101.
Merat
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Cheung
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D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000201:enzymology*; D019703:Calcineurin; D002118:Calcium / Q000494:pharmacology; D002147:Calmodulin / Q000378:metabolism / Q000494:pharmacology*; D002148:Calmodulin-Binding Proteins / Q000378:metabolism*; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D007700:Kinetics; D010716:Phosphatidylinositols / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*
D002147:Calmodulin; D002148:Calmodulin-Binding Proteins; D010716:Phosphatidylinositols; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D002118:Calcium