Protein kinase-dependent effects of okadaic acid on hepatocytic autophagy and cytoskeletal integrity.
The protein phosphatase inhibitor okadaic acid suppressed autophagy completely in isolated rat hepatocytes, as measured by the sequestration of electroinjected [3H]raffinose into sedimentable autophagic vacuoles. Okadaic acid was effectively antagonized by the general protein kinase inhibitors K-252a and KT-5926, the calmodulin antagonist W-7, and by KN-62, a specific inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMK-II). These inhibitors also antagonized a cytoskeleton-disruptive effect of okadaic acid, manifested as the disintegration of cell corpses after breakage of the plasma membrane. CaMK-II, or a closely related enzyme, would thus seem to play a role in the control of autophagy as well as in the control of cytoskeletal organization.
Holen
I
I
Department of Tissue Culture, Norwegian Radium Hospital, Oslo.
Gordon
P B
PB
Seglen
P O
PO
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives*; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure*; D004988:Ethers, Cyclic / Q000494:pharmacology*; D026121:Indole Alkaloids; D007211:Indoles; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D008297:Male; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D011887:Raffinose / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013449:Sulfonamides / Q000494:pharmacology; D014316:Tritium
D000470:Alkaloids; D002147:Calmodulin; D002227:Carbazoles; D004988:Ethers, Cyclic; D026121:Indole Alkaloids; D007211:Indoles; D007546:Isoquinolines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D014316:Tritium; C063769:KT 5926; D019319:Okadaic Acid; C063302:KN 62; C017967:W 7; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C049985:staurosporine aglycone; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D011887:Raffinose