Stringent time-dependent transregulation of calcium calmodulin kinase II (CaMKII) is implicated in anti-apoptotic control.
Induction of apoptosis by the PP1/PP2A inhibitor calyculin A was inhibited if the CaMKII inhibitor KN-93 was added no later than 10 min after addition of calyculin A. The physiological relevance and mechanism of CaMKII during apoptosis, however, remains largely unclear. Here we show in MDCK and gastric parietal cells that normal transregulation of CaMKII terminates the initial burst of autophosphorylation after only 10 min. The kinetics of CaMKII involved transregulation by PP1, PP2A, PP2B and PKCalpha. Transregulation of CaMKII resulted in two kinetic phases for phosphorylation of the autoactivation site at T286/287. During the initial phase, there was a clear peak of phosphorylation that lasted 10 min. This phase was subsequently followed by a half but constant level of T286/287 phosphorylation. Calyculin A perturbed this transregulation, resulting in a hyperphosphorylated CaMKII. This effect of CA on the kinetics of CaMKII was observed in vivo as well as in vitro using isolated tubulovesicles. Calyculin A-induced hyperphosphorylation of CaMKII appears to be at least one mechanism used by cells to trigger apoptosis. Therefore, stringent limitation of CaMKII autophosphorylation at T286/287 by transregulation and prevention of hyperphosphorylation seems to restrict apoptosis.
Fährmann
Michael
M
Medizinische Hochschule Hannover, Institut für Pharmakologie OE 5320, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. faehrmann.michael@mh-hannover.de
Honisch
Sarah
S
Kaufhold
Marc-André
MA
Leitges
Michael
M
Beil
Winfried
W
D000818:Animals; D017209:Apoptosis; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002460:Cell Line; D048430:Cell Shape / Q000187:drug effects; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D008297:Male; D008387:Marine Toxins; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D000096926:Benzenesulfonamides
D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004791:Enzyme Inhibitors; D008387:Marine Toxins; D050505:Mutant Proteins; D010080:Oxazoles; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides; C059041:calyculin A