K(+)-site-directed pyridine derivative, AU-1421, activates hydrolysis of the K(+)-sensitive phosphoenzyme of sarcoplasmic reticulum Ca(2+)-ATPase and inactivates that of K(+)-transporting ATPases.
(Z)-5-Methyl-2-[2-(1-naphthyl)ethenyl]-4-piperidinopyridine, AU-1421, interacted at 0 degree C with the K(+)-sensitive phosphoenzymes of three transport ATPases, Ca(2+)-, H+/K(+)- and Na+/K(+)-ATPase. In the case of Ca(2+)-ATPase, AU-1421 at about 80 microM stimulated 6-fold the rate of splitting of the phosphoenzyme, on which K+ simply functions as an accelerator from one side of the membrane. Probably AU-1421 also simply interacts with the K(+)-binding site of the phosphoenzyme that is easily accessible from the aqueous phase. In the cases of H(+)/K(+)- and Na(+)/K(+)-ATPases, AU-1421 stabilized the phosphoenzymes which accept K+ as the translocating ion. The rate constants of dephosphorylation for H(+)/K(+)-ATPase and Na(+)/K(+)-ATPase were decreased to half by AU-1421 at about 5 and 10 microM, respectively. Presumably after binding of AU-1421 to a K(+)-recognition site of the phosphoenzyme, local motion of the peptide region near the binding site that serves to move the bound ion into the ion-transport pathway (occlusion center) might be inhibited. Thus AU-1421 may be able to distinguish two modes of K+ action on the K(+)-sensitive phosphoenzymes.
Fukushima
Y
Y
Faculty of Pharmaceutical Sciences, University of Tokushima, Japan.
Asano
S
S
Takada
J
J
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D027682:Cation Transport Proteins; D002412:Cations; D004591:Electrophoresis, Polyacrylamide Gel; D017506:H(+)-K(+)-Exchanging ATPase; D006868:Hydrolysis; D009281:Naphthalenes / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011188:Potassium / Q000378:metabolism*; D006180:Proton-Translocating ATPases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology*; D000254:Sodium-Potassium-Exchanging ATPase
D027682:Cation Transport Proteins; D002412:Cations; D009281:Naphthalenes; D010750:Phosphoproteins; D011725:Pyridines; C063370:AU 1421; D000251:Adenosine Triphosphatases; C022761:potassium transporting ATPase; D017506:H(+)-K(+)-Exchanging ATPase; D006180:Proton-Translocating ATPases; D000252:Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium