Two types of calcium-dependent protein phosphorylations modulated by calmodulin antagonists. Naphthalenesulfonamide derivatives.
Ca2-dependent protein phosphorylations activated by calmodulin or phospholipid were studied using selective inhibitors. Both protein phosphorylations were inhibited by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) and its derivatives. Kinetic analysis indicated that the primary effect of these agents was mediated through a competitive inhibition of enzyme activation by interaction with calmodulin or phospholipid, and Ki values of W-7 for calmodulin-dependent phosphorylation and phospholipid-dependent protein kinase were 12 microM and 110 microM, respectively. The addition of Ca2+ inhibited the binding of [3H]W-7 to phosphatidylserine but not the binding to calmodulin. The potencies of naphthalenesulfonamide derivatives as derivatives as inhibitors of Ca2+, calmodulin-dependent protein kinase were dependent on the length of the alkyl chain (C2-C10) but not on Ca2+-activated, phospholipid-dependent protein kinase. These results suggest that naphthalenesulfonamide derivatives may be more selective inhibitors of Ca2+, calmodulin-dependent protein phosphorylation than is Ca2+-activated, phospholipid-dependent protein kinase and that the mechanism of interaction between W-7 and phosphatidylserine differs from the interaction between W-7 and calmodulin. These agents are useful tools for elucidating the physiological role of Ca2+-dependent protein phosphorylation.
D002118:Calcium / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors*; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009219:Myosin-Light-Chain Kinase; D010718:Phosphatidylserines / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology*
D002135:Calcium-Binding Proteins; D002147:Calmodulin; D010718:Phosphatidylserines; D013449:Sulfonamides; C017967:W 7; D011494:Protein Kinases; D009219:Myosin-Light-Chain Kinase; D002118:Calcium