CRACking the Molecular Regulatory Mechanism of SOCE during Platelet Activation in Thrombo-Occlusive Diseases

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.

Novel regulators identified by quantitative phosphoproteomics analysis during ticagrelor-induced inhibition of platelet

“…neurotransmission [52], and apoptosis [53]. Notably, STIM1 plays a crucial role in SOCE and regulates the release and influx during platelet activation [54]. Missense mutations in STIM1 can lead to impaired platelet activation in mice [55].…”

Reduction in SOCE and Associated Aggregation in Platelets from Mice with Platelet-Specific Deletion of Orai1

“…Many of them can be grouped into G-protein coupled receptors (GPCR) and immunoreceptor tyrosine based activation motif (ITAM)-linked receptors. These groups of receptors, which can be activated by different physiological agonists such as collagen, thromboxane A2 (TxA2), thrombin or ADP, retain clear differences in signalling pathways including signatures of Ca 2+ mobilization from the endoplasmic reticulum [ 9 , 10 ]. Platelets express several receptors for collagen, including the integrin α2β1 having a major role in adhesion and platelet anchoring, and the GPVI, which is found as complex with the homodimeric Fc receptor γ-chain and mediates signalling, platelet activation and thrombi stabilization [ 9 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

“…However, the input of each Orai isoform to endogenous SOCE can variates in primary cells as shown in subtypes of lymphocytes [ 28 ]. The role of Orai1 proteins in murine and human platelets and its contribution for SOCE has been described and reviewed [ 10 , 21 , 29 , 30 , 31 ]. In human platelets, especial attention on the regulation of Orai1 by STIM proteins has been developed, which act as sensors of Ca 2+ levels inside the stores and after Ca 2+ store depletion STIM proteins get in close proximity to the plasma membrane where they trigger activation of Orai1 [ 32 , 33 , 34 , 35 ].…”