Regulation of phospholipid biosynthesis by Ca(2+)-calmodulin-dependent protein kinase inhibitors.
Inhibitors of Ca(2+)-calmodulin (CaM)-dependent protein kinases strongly modify phospholipid metabolism. Two compounds, KN62 and KT5926 recognized as blockers of Ca(2+)-CaM-dependent protein kinase II, induced a specific increase in phosphatidylserine (PtdSer) synthesis without noticeable changes in phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn) biosynthesis. The increase of PtdSer synthesis was dependent on the presence of Ca2+ in the incubation medium and was impaired in cells whose Ca2+ stores were depleted by pretreatment with CD3 mAb, thapsigargin or EGTA. The mechanism of the stimulation of PtdSer synthesis by these two compounds seems to involve an accumulation of Ca2+ into the endoplasmic reticulum, possibly due to an increased activity of the endoplasmic reticulum Ca(2+)-ATPase. By contrast, ML-7 and ML-9, two inhibitors of the myosin light chain kinase (MLCK), another Ca(2+)-CaM-dependent kinase, were both capable of increasing PtdSer synthesis and decreasing PtdCho and PtdEtn synthesis, reproducing the effect previously described with CaM-antagonists. The increase of PtdSer caused by ML-7 and ML-9 was Ca(2+)-dependent while the inhibition of PtdCho and PtdEtn synthesis was not. The use of these four protein kinase inhibitors thus suggests the possible existence of two CaM-dependent pathways that differentially regulates phospholipid metabolism in T cells.
Dumaurier
M J
MJ
Interactions Cellulaires et Moleculaires en Immunologie, INSERM U343, Hôpital de l'Archet, Nice, France.
Pelassy
C
C
Marhaba
R
R
Breittmayer
J P
JP
Aussel
C
C
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002227:Carbazoles; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007211:Indoles; D019169:Jurkat Cells; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors; D009281:Naphthalenes / Q000494:pharmacology; D010713:Phosphatidylcholines / Q000096:biosynthesis; D010714:Phosphatidylethanolamines / Q000096:biosynthesis; D010718:Phosphatidylserines / Q000096:biosynthesis; D010743:Phospholipids / Q000096:biosynthesis*
D000470:Alkaloids; D001381:Azepines; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D009281:Naphthalenes; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010718:Phosphatidylserines; D010743:Phospholipids; C056218:ML 9; C070571:ML 7; C063769:KT 5926; D016718:Arachidonic Acid; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D009219:Myosin-Light-Chain Kinase; D002118:Calcium