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J Biol Chem, Vol. 275, Issue 3, 1763-1772, January 21, 2000
2A-Adrenergic Receptor Stimulation Potentiates
Calcium Release in Platelets by Modulating cAMP Levels*
From the Departments of Biochemistry and Human Biology, University
of Maastricht, P.O. Box 616, 6200 MD Maastricht, The Netherlands
2A-Adrenergic
receptor-mediated Ca2+ signaling and integrin
IIb
3 exposure were investigated in human
platelets under conditions where indirect, thromboxane- or ADP-mediated
effects were absent. The 2-adrenergic receptor agonists,
UK14304 and epinephrine (EPI), were unable to raise cytosolic levels of
inositol 1,4,5-trisphosphate (InsP3) or Ca2+
but potentiated the [Ca2+]i rises evoked by other
agonists that act through stimulation of phospholipase C (thrombin or
platelet-activating factor) or stimulation of Ca2+-induced
Ca2+ release (CICR) in the absence of InsP3
generation (thimerosal or thapsigargin). In addition,
2-adrenergic stimulation resulted in a 20% lowering in
the cytosolic cAMP level. In platelets treated with
Gs
-stimulating prostaglandin E1, EPI
increased the Ca2+ signal evoked by either phospholipase C-
or CICR-stimulating agonists mainly through modulation of the cAMP
level. The stimulating effects of UK14304 and EPI on platelet
Ca2+ responses, and also on integrin
IIb3 exposure and platelet aggregation,
were abolished by pharmacological stimulation of cAMP-dependent protein kinase, and these effects were
mimicked by inhibition of this activity. In permeabilized platelets,
UK14304 and EPI potentiated InsP3-induced, CICR-mediated
mobilization of Ca2+ from internal stores in a similar way
as did inhibition of cAMP-dependent protein kinase. In
summary, a Gi-mediated decrease in cAMP level appears to
play a major role in the platelet-activating effects of
2A-adrenergic receptor stimulation. Thus, in platelets, unlike other cell types, occupation of the Gi-coupled
2A-adrenergic receptors does not result in phospholipase
C activation but rather in modulation of the Ca2+ response
by relieving cAMP-mediated suppression of
InsP3-dependent CICR.
To whom correspondence should be addressed: Depts. of Human
Biology/Biochemistry, University of Maastricht, P.O. Box 616, 6200 MD
Maastricht, The Netherlands. Tel.: 31-43-3881684; Fax: 31-43-3884160;
E-mail: JWM.Heemskerk@Bioch.Unimaas.nl.
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