alpha(2A)-Adrenergic receptor-mediated Ca2+ signaling and integrin alpha(IIb)beta(3) exposure were investigated in human platelets under conditions where 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 through 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)-adrenergic stimulation resulted in a 20% lowering in the cytosolic cAMP level. In platelets treated with G(s alpha)-stimulating prostaglandin E-1, 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 alpha(IIb)beta(3) 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 InsP(3)-induced, CICR-mediated mobilization of Ca2+ from internal stores in a similar way as did inhibition of cAMP-dependent protein kinase, In summary, a G(i alpha)-mediated decrease in cAMP level appears to play a major role in the platelet-activating effects of alpha(2A)-adrenergic receptor stimulation. Thus, in platelets, unlike other cell types, occupation of the G(i alpha)-coupled alpha(2A)-adrenergic receptors does not result in phospholipase C activation but rather in modulation of the Ca2+ response by relieving cAMP-mediated suppression of InsP(3)-dependent CICR.
Keularts, I. M. L. W., van Gorp Beisser, R. M. A., Feijge, M. A. H., Vuist, M. W. J., & Heemskerk, J. W. M. (2000). alpha2A-Adrenergic receptor stimulation potentiates calcium release in platelets by modulating cAMP levels. Journal of Biological Chemistry, 275(3), 1763-1772. https://doi.org/10.1074/jbc.275.3.1763