Lithium modulation of second messenger signal amplification in man: inhibition of phosphatidylinositol-specific phospholipase C and adenylate cyclase activity.
The activity of phosphatidylinositol-specific phospholipase C was significantly reduced in platelets obtained from 20 euthymic manic-depressive patients on therapeutic lithium doses (mean blood level 0.85 mEq/l) compared to an age- and sex-matched group of 36 control subjects. The activities of prostaglandin E1-, aluminum/NaF-, and forskolin-stimulated platelet adenylate cyclase activity were also measured in a similar group of 16 lithium-treated and 22 control subjects. A marked reduction in both postreceptor (aluminum/NaF and forskolin) and receptor-stimulated (prostaglandin E1) platelet adenylate cyclase activity was observed in the lithium-treated group (mean blood level 0.81 mEq/l). These findings support the hypothesis that lithium's therapeutic mode of action in manic-depressive psychosis is mediated by the combined down-regulation of both principal second messenger systems, inositol phosphates and cyclic adenosine monophosphate, by reducing the activity of phosphatidylinositol-specific phospholipase C and adenylate cyclase.
Ebstein
R P
RP
Department of Research, Nashim Hospital, Jerusalem, Israel.
Lerer
B
B
Bennett
E R
ER
Shapira
B
B
Kindler
S
S
Shemesh
Z
Z
Gerstenhaber
N
N
D000067956:Adenylyl Cyclase Inhibitors; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000201:enzymology; D001792:Blood Platelets / Q000187:drug effects; D005260:Female; D006801:Humans; D008094:Lithium / Q000627:therapeutic use*; D016651:Lithium Carbonate; D008297:Male; D008875:Middle Aged; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D010726:Phosphodiesterase Inhibitors; D054801:Phosphoinositide Phospholipase C; D010727:Phosphoric Diester Hydrolases
D000067956:Adenylyl Cyclase Inhibitors; D010726:Phosphodiesterase Inhibitors; D016651:Lithium Carbonate; D008094:Lithium; D010727:Phosphoric Diester Hydrolases; D054801:Phosphoinositide Phospholipase C; D043265:Phosphatidylinositol Diacylglycerol-Lyase