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Ragged spiking of free calcium in ADP-stimulated human platelets: regulation of puff-like calcium signals in vitro and ex vivo

Johan W. M. Heemskerk *†, George M. Willems †, Martin B. Rook ‡ and Stewart O. Sage §

1. Human platelets respond to agonists of G protein (G_q)-coupled receptors by generating an irregular pattern of spiking changes in cytosolic Ca²⁺ ([Ca²⁺]_i). We have investigated the ADP-induced Ca²⁺ responses of single, Fluo-3-loaded platelets in the presence or absence of autologous plasma or whole blood under flow conditions.
2. In plasma-free platelets, incubated in buffer medium, baseline separated [Ca²⁺]_i peaks always consisted of a rapid rising phase (median time 0.8 s) which was abruptly followed by a slower, mono-exponential decay phase. The decay constant differed from platelet to platelet, ranging from 0.23 ± 0.02 to 0.63 ± 0.03 s^-1 (mean ± S.E.M., n = 3-5), and was used to identify individual Ca²⁺ release events and to determine the Ca²⁺ fluxes of the events.
3. Confocal, high-frequency measurements of adherent, spread platelets (diameter 3-5 µm) indicated that different optical regions had simultaneous patterns of both low- and high-amplitude Ca²⁺ release events.
4. With or without plasma or flowing blood, the ADP-induced Ca²⁺ signals in platelets had the characteristics of irregular Ca²⁺ puffs as well as more regular Ca²⁺ oscillations. Individual [Ca²⁺]_i peaks varied in amplitude and peak-to-peak interval, as observed for separated Ca²⁺ puffs within larger cells. On the other hand, the peaks appeared to group into periods of ragged, shorter-interval Ca²⁺ release events with little integration, which were alternated with longer-interval events.
5. We conclude that the spiking Ca²⁺ signal generated in these small cells has the characteristics of a 'poor' oscillator with an irregular frequency being reactivated from period to period. This platelet signal appears to be similar in an environment of non-physiological buffer medium and in flowing, whole blood.

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