Impaired signal transduction in neonatal platelets.
Previous in vitro studies of cord blood platelets from full-term and preterm neonates have demonstrated decreased responses to most physiologic agonists. This hyporesponsiveness is, in part, related to both deficient synthesis of, and response to, an important mediator of platelet function, thromboxane A2(TxA2). The poor response of neonatal platelets to TxA2 is not due to differences in TxA2 receptor binding characteristics, when compared with platelets from adult controls. Therefore, the postreceptor signal transduction pathway was investigated. The TxA2 receptor is linked via the trimeric GTP-binding protein, Gq, to phospholipase C-beta (PLC beta), and stimulation of platelets with the stable TxA2 mimetic, U46619, leads to activation of PLC beta and subsequent intracellular signaling events. U46619-induced 32P-phosphatidic acid formation, an index of PLC beta activation, was decreased in platelets of neonates (166 +/- 10%) when compared with adult controls (206 +/- 22%) (p < 0.05). Mobilization of intracellular calcium was impaired in platelets of newborns (175 +/- 49 nM) in comparison to adult controls (506 +/- 130 nM) (p < 0.01), after stimulation with U46619. U46619-stimulated GTPase activity was blunted in platelet membrane fractions from full-term neonates and almost absent in platelet membranes from preterm infants. Immunoblotting studies of the platelet membrane fractions, quantified by densitometric analysis, showed that levels of the G alpha q subunit were not significantly different between adult and neonate, and were not the cause of the marked differences in GTPase activity. These data suggest that signal transduction through the TxA2 receptor is affected by decreased activity of Gq in platelets of neonates, and that this defect in signal transduction through PLC beta contributes to the observed poor response of newborns' platelets to TxA2 and consequently to TxA2-dependent agonists such as collagen.
Israels
S J
SJ
Department of Pediatrics, University of Manitoba, Winnipeg, Canada.
Cheang
T
T
Roberston
C
C
McMillan-Ward
E M
EM
McNicol
A
A
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000328:Adult; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000097:blood; D002462:Cell Membrane / Q000201:enzymology; D003600:Cytosol / Q000378:metabolism; D005312:Fetal Blood; D020558:GTP Phosphohydrolases / Q000097:blood; D019204:GTP-Binding Proteins / Q000097:blood; D006801:Humans; D007231:Infant, Newborn / Q000097:blood*; D007234:Infant, Premature / Q000097:blood*; D010716:Phosphatidylinositols / Q000097:blood; D012016:Reference Values; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology
D010716:Phosphatidylinositols; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013917:Thrombin; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D002118:Calcium