Abstract
Thrombo-occlusive diseases such as myocardial infarction, ischemic stroke and deep vein thrombosis with subsequent pulmonary embolism still represent a major health burden worldwide. Besides the cells of the vasculature or other hematopoietic cells, platelets are primarily responsible for the development and progression of an occluding thrombus. The activation and function of platelets crucially depend on free cytosolic calcium (Ca2+) as second messenger, which modulates platelet secretion, aggregation and thrombus formation. Ca2+ is elevated upon platelet activation by release of Ca2+ from intracellular stores thus triggering of the subsequent store-operated Ca2+ entry (SOCE), which is facilitated by Ca2+ release-activated channels (CRACs). In general, CRACs are assembled by the pore-forming unit Orai in the plasma membrane and the Ca2+-sensing stromal interaction molecule (STIM) in the endoplasmic reticulum after the depletion of internal Ca2+ stores. In the last few years, there is a growing body of the literature demonstrating the importance of STIM and Orai-mediated mechanism in thrombo-occlusive disorders. Thus, this review provides an overview of the recent understanding of STIM and Orai signaling in platelet function and its implication in the development and progression of ischemic thrombo-occlusive disorders. Moreover, potential pharmacological implications of STIM and Orai signaling in platelets are anticipated and discussed in the end.
Highlights
Received: 10 January 2022Thrombo-occlusive disorders of the arterial and venous vascular system such as myocardial infarction, ischemic stroke and venous thromboembolism with accompanying complications still represent a major cause of morbidity and mortality in the western civilization [1]
Right panel: Upon receptor-mediated platelet activation by a wide variety of agonists, the IP3R clustering/sensitization is supported by casein kinase 2 (CK2)-dependent processes and the PLC-dependent generation of IP3 causes a depletion of internal Ca2+ stores and the unloading of the EF hand of stromal interaction molecule 1 (STIM1)
Right panel: Upon receptor-mediated platelet activation by a wide variety of agonists, the IP3 receptors (IP3 Rs) clustering/sensitization is supported by casein kinase 2 (CK2)-dependent processes and the PLC-dependent generation of IP3 causes a depletion of internal Ca2+ stores and the unloading of the EF hand of STIM1
Summary
Thrombo-occlusive disorders of the arterial and venous vascular system such as myocardial infarction, ischemic stroke and venous thromboembolism with accompanying complications still represent a major cause of morbidity and mortality in the western civilization [1]. In addition to the binding of IP3 , the intracellular Ca2+ release is highly dependent on the clustering and activation of the IP3 R, a mechanism which requires microtubule-associated linkage of the end binding protein EB3 in endothelial cells [28] In this regard, the ubiquitous serine/threonine-selective protein kinase casein kinase 2 (CK2) was described to regulate tubulin polymerization and EB3 binding in platelets affecting IP3 -induced intracellular Ca2+ release and thrombus formation [29]. Right panel: Upon receptor-mediated platelet activation by a wide variety of agonists, the IP3R clustering/sensitization is supported by casein kinase 2 (CK2)-dependent processes and the PLC-dependent generation of IP3 causes a depletion of internal Ca2+ stores and the unloading of the EF hand of STIM1. The assembly of the CRAC results in the influx of extracellular Ca2+ by means of the SOCE and platelet activation
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