Ion channels in the regulation of platelet migration

Platelets have been shown to migrate and thus to invade the vascular wall. Platelet migration is stimulated by SDF-1. In other cell types, migration is dependent on Ca2+ entry via Ca2+ channels. Ca2+ influx is sensitive to cell membrane potential which is maintained by K+ channel activity and/or Cl− channel activity. The present study explored the role of ion channels in the regulation of SDF-1 induced migration. Platelets were isolated from human volunteers as well as from gene targeted mice lacking the Ca2+ activated K+ channel SK4 (sk4−/−) and their wild type littermates (sk4+/+). According to confocal microscopy human platelets expressed the Ca2+ channel Orai1 and the Ca2+-activated K+ channel KCa3.1 (SK4). SDF-1 (100 ng/ml) stimulated migration in human platelets, an effect blunted by Orai1 inhibitors 2-aminoethoxydiphenyl borate 2-APB (10 μM) and SKF-96365 (10 μM), by unspecific K+ channel inhibitor TEA (30 mM), by SK4 specific K+ channel blocker clotrimazole (10 μM), but not by Cl− channel inhibitor 5-nitro-2-(3-phenylpropylamino) benzoic acid NPPB (100 μM). Significant stimulation of migration by SDF-1 was further observed in sk4+/+ platelets but was virtually absent in sk4−/− platelets. In conclusion, platelet migration requires activity of the Ca2+ channel Orai1 and of the Ca2+ activated K+ channel SK4, but not of NPPB-sensitive Cl− channels.

► Blood platelets express the Ca2+ channel Orai1 and the Ca2+ sensitive K+ channel SK4.
► Orai1 blockers 2-APB and SKF-96365 abrogate platelet migration.
► Migration is inhibited by K+ channel blockers TEA and clotrimazole and by genetic SK4 knockout.
► Platelet migration does not require NPPB sensitive Cl− channels.
► Inhibition of platelet migration by channel blockers may counteract vascular inflammation.