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Human platelet signaling defect characterized by impaired production of
inositol-1,4,5-triphosphate and phosphatidic acid and diminished Pleckstrin
phosphorylation: evidence for defective phospholipase C activation
X Yang, L Sun, S Ghosh and AK Rao
Sol Sherry Thrombosis Research Center, Temple University School of
Medicine, Philadelphia, PA 19140, USA.
Signal transduction on platelet activation involves phosphoinositide-
specific phospholipase C (PLC)-mediated hydrolysis of
phosphatidylinositides and formation of inositol-1,4,5-triphosphate
[I(1,4,5)P3], which mediates Ca2+ mobilization, and diacylglycerol (DG),
which activates protein kinase C (PKC) to phosphorylate a 47-kD protein
(Pleckstrin). We studied these events in two related patients previously
reported (Blood 74:664, 1989) to have abnormal aggregation and
14C-serotonin secretion, and impaired intracellular Ca2+ mobilization in
response to several agonists. Thrombin-induced I(1,4,5)P3 and phosphatidic
acid formation were diminished. Pleckstrin phosphorylation was impaired on
activation with thrombin, platelet- activating factor, and ionophore
A23187, but was normal with PKC activator 1,2-dioctonyl-sn-glycerol (DiC8).
Ca2+ mobilization induced by guanosine triphosphate (GTP) analog guanosine
5'-0-(3 thiotriphosphate) (GTP gamma S) was diminished. Pretreatment with
either A23187 or DiC8 did not correct the impaired adenine diphosphate-
induced secretion; however, upon stimulation with A23187 plus DiC8,
pleckstrin phosphorylation and secretion were normal, indicating that both
PKC activation and Ca2+ mobilization are essential for normal secretion. We
conclude that these patients have a unique inherited platelet defect in
formation of two key intracellular mediators [I(1,4,5)P3 and DG] and in the
responses mediated by them due to a defect in postreceptor mechanisms of
PLC activation.
Volume 88,
Issue 5,
pp. 1676-1683,
09/01/1996
Copyright © 1996 by The American Society of Hematology
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