alpha(2A)-adrenergic receptor stimulation potentiates calcium release in platelets by modulating cAMP levels

alpha(2A)-Adrenergic receptor-mediated Ca2+ signaling and integrin alpha(II b)beta(3) exposure were investigated in human platelets under conditions wh ere indirect, thromboxane- or ADP-mediated effects were absent. The alpha(2 )-adrenergic receptor agonists, UK14304 and epinephrine (EPI), were unable to raise cytosolic levels of inositol 1,4,5-trisphosphate (InsP(3)) or Ca2 but potentiated the [Ca2+](i) rises evoked by other agonists that act thro ugh stimulation of phospholipase C (thrombin or platelet-activating factor) or stimulation of Ca2+-induced Ca2+ release (CICR) in the absence of InsP( 3) generation (thimerosal or thapsigargin), In addition, alpha(2)-adrenergi c stimulation resulted in a 20% lowering in the cytosolic cAMP level. In pl atelets treated with G(s alpha)-stimulating prostaglandin E-1, EPI increase d the Ca2+ signal evoked by either phospholipase C- or CICR-stimulating ago nists mainly through modulation of the cAMP level. The stimulating effects of UK14304 and EPI on platelet Ca2+ responses, and also on integrin alpha(I Ib)beta(3) exposure and platelet aggregation, were abolished by pharmacolog ical stimulation of cAMP-dependent protein kinase, and these effects were m imicked by inhibition of this activity. In permeabilized platelets, UK14304 and EPI potentiated InsP(3)-induced, CICR-mediated mobilization of Ca2+ fr om internal stores in a similar way as did inhibition of cAMP-dependent pro tein kinase, In summary, a G(i alpha)-mediated decrease in cAMP level appea rs to play a major role in the platelet-activating effects of alpha(2A)-adr energic receptor stimulation. Thus, in platelets, unlike other cell types, occupation of the G(i alpha)-coupled alpha(2A)-adrenergic receptors does no t result in phospholipase C activation but rather in modulation of the Ca2 response by relieving cAMP-mediated suppression of InsP(3)-dependent CICR.