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. 2022 Nov;20(11):2587-2600.
doi: 10.1111/jth.15827. Epub 2022 Aug 7.

Inhibition of platelet aggregation by activation of platelet intermediate conductance Ca2+ -activated potassium channels

Valentina Back  1 , Amir Asgari  1 , Aleksandra Franczak  2 , Max Saito  1 , Diego Castaneda Zaragoza  2 , Shaun L Sandow  3   4 , Frances Plane  2   5 , Paul Jurasz  1   2   5   6
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Free article

Inhibition of platelet aggregation by activation of platelet intermediate conductance Ca2+ -activated potassium channels

Valentina Back et al. J Thromb Haemost. 2022 Nov.
Free article

Abstract

Background: Within the vasculature platelets and endothelial cells play crucial roles in hemostasis and thrombosis. Platelets, like endothelial cells, possess intermediate conductance Ca2+ -activated K+ (IKCa ) channels and generate nitric oxide (NO). Although NO limits platelet aggregation, the role of IKCa channels in platelet function and NO generation has not yet been explored.

Objectives: We investigated whether IKCa channel activation inhibits platelet aggregation, and per endothelial cells, enhances platelet NO production.

Methods: Platelets were isolated from human volunteers. Aggregometry, confocal microscopy, and a novel flow chamber model, the Quartz Crystal Microbalance (QCM) were used to assess platelet function. Flow cytometry was used to measure platelet NO production, calcium signaling, membrane potential, integrin αIIb /β3 activation, granule release, and procoagulant platelet formation.

Results: Platelet IKCa channel activation with SKA-31 inhibited aggregation in a concentration-dependent manner, an effect reversed by the selective IKCa channel blocker TRAM-34. The QCM model along with confocal microscopy demonstrated that SKA-31 inhibited platelet aggregation under flow conditions. Surprisingly, IKCa activation by SKA-31 inhibited platelet NO generation, but this could be explained by a concomitant reduction in platelet calcium signaling. IKCa activation by SKA-31 also inhibited dense and alpha-granule secretion and integrin αIIb /β3 activation, but maintained platelet phosphatidylserine surface exposure as a measure of procoagulant response.

Conclusions: Platelet IKCa channel activation inhibits aggregation by reducing calcium-signaling and granule secretion, but not by enhancing platelet NO generation. IKCa channels may be novel targets for the development of antiplatelet drugs that limit atherothrombosis, but not coagulation.

Keywords: intermediate conductance Ca2+-activated K+ channels; nitric oxide; platelet aggregation; platelets; thrombosis.

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