Study of calcium transport processes in blood platelets using knock out mouse models. Regulation and role of “store-operated calcium entry” (SOCE)

Platelet activation and aggregation are essential to limit posttraumatic blood loss at sites of vascular injury but also contributes to arterial thrombosis, leading to myocardial infarction and stroke. Agonist-induced elevation of [Ca²⁺]_i is a central step in platelet activation, but the underlying mechanisms are not fully understood. A major pathway for Ca²⁺-entry in non-excitable cells, such as platelets, involves receptor-mediated release of intracellular Ca²⁺ stores, followed by activation of store-operated calcium (SOC) channels in the plasma membrane.

In my PhD work I investigated the molecular background and the physiological relevance of store-operated calcium entry (SOCE) in platelets. I have identified stromal interaction molecule 1 (STIM1) and Orai1 to be the key components of SOCE in these cells, where STIM1 is the calcium sensor in the endoplasmic reticulum – the major calcium store – that upon store release signals to Orai1 – the major SOC channel in platelets – and open it to allow Ca²⁺-entry (Fig.34). Furthermore, I could exclude canonical transient receptor potential channel 1 (TRPC1) to have a major impact on this process. Using in vivo thrombosis models I could show that SOCE is of huge importance for stable thrombus formation under high shear flow conditions, such as found in diseased vessels, but lack of the process does not significantly increase bleeding risk. These latter findings establish platelet SOCE and the proteins involved in it as promising targets in the prevention and treatment of ischemic cardio- and cerebrovascular events.