A key role for dense granule secretion in potentiation of the Ca2+ signal arising from store-operated calcium entry in human platelets.

Recent work has demonstrated a role for Na(+)/Ca(2+) exchange in potentiation of the Ca(2+) entry elicited through the human platelet store-operated channel by controlling a Mn(2+)-impermeable Ca(2+) entry pathway. Here we demonstrate that this involves control over the secretion of dense granules by a Na(+)/Ca(2+) exchanger (NCX) and so autocrine signalling between platelets. NCX inhibition reduced dense granule secretion. The reduction in SOCE elicited by NCX inhibition could be reversed by the addition of uninhibited donor cells, their releasate alone, or exogenous ADP and 5-HT. The use of specific receptor antagonists indicated that ATP, ADP and 5-HT all played a role in NCX-dependent autocrine signalling between platelets following thapsigargin stimulation, by activating Mn(2+)-impermeable Ca(2+) entry pathways. These data provide further insight into the mechanisms underlying the known interrelationship between platelet Ca(2+) signalling and dense granule secretion, and suggest an important role for the NCX in potentiation of platelet activation via dense granule secretion and so autocrine signalling. Our results caution the interpretation of platelet Ca(2+) signalling studies involving pharmacological or other manipulations that do not assess possible effects on NCX activity and dense granule secretion.