A novel mechanism of glucocorticosteroid (GC) action in suppression of phospholipase A2 (PLA2) activity stimulated by Ca2+ ionophore A23187: induction of protein phosphatases.
The present article deals with the stimulation of membrane PLA2 induced by activated protein kinase C (PKC), and the effect of a deficiency in cellular PKC activity in reducing in PLA2 activity. The mode of glucocorticoid (GC) inhibition action in regulation of PLA2 activity, by enhancement of protein dephosphorylation in general, and PLA2 in particular, is hypothesized and discussed. Indirect evidence strongly suggests that activated PKC enzyme is essential for the stimulation of membrane PLA2 activity induced by the Ca2+ ionophore A23187 and other agonists. Our hypothesis suggests that membrane-associated PKC directly phosphorylates PLA2 leading to its activation. Dephosphorylation of activated PLA2, possibly by a serine/threonine protein phosphatase reduces PLA2 activity. GC could induce membrane protein phosphatases which mediate their inhibitory action on PLA2 activity. This mode of action of GC is complementary to their effect in reducting in elevated [Ca2+]i, which is essential for full expression of PLA2 activity. Thus, GC exhibits multiple actions which specifically culminate in suppression of PLA2 and other phospholipases (PI-PLC and PLD) and generally in cellular inactivation (relaxation) and reduction of allergic and inflammatory responses.
Zor
U
U
Dept. of Hormone Research, Weizmann Institute of Science, Rehovot, Israel.
Her
E
E
Braquet
P
P
Ferber
E
E
Reiss
N
N
D000818:Animals; D017302:Annexins; D000001:Calcimycin / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D054801:Phosphoinositide Phospholipase C; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D017302:Annexins; D002135:Calcium-Binding Proteins; D000001:Calcimycin; D003907:Dexamethasone; D010741:Phospholipases A; D054467:Phospholipases A2; D010749:Phosphoprotein Phosphatases; D010727:Phosphoric Diester Hydrolases; D054801:Phosphoinositide Phospholipase C; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D013755:Tetradecanoylphorbol Acetate