title: alpha(2A)-adrenergic receptor stimulation potentiates calcium release in platelets by modulating cAMP levels.
abstract: alpha(2A)-Adrenergic receptor-mediated Ca(2+) 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 Ca(2+) but potentiated the [Ca(2+)](i) rises evoked by other agonists that act through stimulation of phospholipase C (thrombin or platelet-activating factor) or stimulation of Ca(2+)-induced Ca(2+) 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(salpha)-stimulating prostaglandin E(1), EPI increased the Ca(2+) 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 Ca(2+) 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 Ca(2+) from internal stores in a similar way as did inhibition of cAMP-dependent protein kinase. In summary, a G(ialpha)-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(ialpha)-coupled alpha(2A)-adrenergic receptors does not result in phospholipase C activation but rather in modulation of the Ca(2+) response by relieving cAMP-mediated suppression of InsP(3)-dependent CICR.
authors.affiliation: Departments of Biochemistry and Human Biology, University of Maastricht, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
authors.forename: I M
authors.initials: IM
authors.lastname: Keularts
authors.forename: R M
authors.initials: RM
authors.lastname: van Gorp
authors.forename: M A
authors.initials: MA
authors.lastname: Feijge
authors.forename: W M
authors.initials: WM
authors.lastname: Vuist
authors.forename: J W
authors.initials: JW
authors.lastname: Heemskerk
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism*; D000068438:Brimonidine Tartrate; D002118:Calcium / Q000378:metabolism*; D002122:Calcium Chloride / Q000494:pharmacology; D002227:Carbazoles; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D010972:Platelet Activating Factor / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000494:pharmacology; D011458:Prostaglandins E / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D013268:Stimulation, Chemical; D019284:Thapsigargin / Q000494:pharmacology; D013849:Thimerosal / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D013997:Time Factors
chemical_list: C547768:ADRA2A protein, human; D000316:Adrenergic alpha-Agonists; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D010972:Platelet Activating Factor; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011458:Prostaglandins E; D011758:Pyrroles; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D013849:Thimerosal; D000068438:Brimonidine Tartrate; D004533:Egtazic Acid; C057416:KT 5720; D019284:Thapsigargin; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D013917:Thrombin; D002122:Calcium Chloride; D001241:Aspirin; D002118:Calcium; D004837:Epinephrine