Project Details
Projekt
The role of platelet Mg2+ channels in thrombosis and haemostasis
Applicant
Attila Laszlo Braun, Ph.D.
Subject Area
Hematology, Oncology
Term
from 2013 to 2016
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 234386647
Agonist-induced elevation of intracellular Ca2+ concentration ([Ca2+]i) is a central event during platelet activation and aggregation and occurs through Ca2+ release from the intracellular stores and/or Ca2+ influx through the plasma membrane channels, most notably receptor operated Ca2+ channels (ROC) and store operated Ca2+ channels (SOC). Recently, we identified the Ca2+ sensor stromal interaction molecule 1 (STIM1) and the four transmembrane domain protein Orai1 as the principal mediators of store-operated calcium entry (SOCE) in platelets thus establishing this mechanism as a potential target for antithrombotic therapy. We also identified TRPC6 as the major and only DAG mediated ROC channel in platelets. The pathophysiological imbalance in Ca2+ homeostasis is usually associated with the abnormal function of Ca2+ channels, Ca2+ pumps or the Na+/Ca2+ exchanger. Although it has been known for more than 50 years that Mg2+ is a natural antagonist of Ca2+, hence hypomagnesaemia is related to elevated [Ca2+]i in mammalian cells, the molecular mechanisms underlying these observations are still not clear. We speculate that abnormal function of Mg2+ channels may contribute to the development of a Ca2+-overload phenotype in platelets thereby inducing abnormal platelet activation and a pro-thrombotic phenotype in vivo. Although Mg2+ entry has been described in megakaryocytes and platelets, the molecular composites of Mg2+ channels and their signalling function have not been identified. In the current project, we want to use MagT1, Trpm7 and Tusc3 Mg2+ channel knockout and knockin mouse models to identify the major Mg2+ channels in murine megakaryocytes and platelets and study their signalling functions under normal and patho-physiological conditions. Altered Mg2+ homeostasis is described in many cardiovascular diseases, especially in patients with coronary heart disease, arrhythmias, acute myocardial infarction, hypertension and stroke. Under specific clinical conditions, Mg2+ therapy is essential upon intensive care to prevent thrombosis, myocardial infarction or stroke. Therefore, we plan to analyse the physiological consequence of the abolished function of Mg2+ channels in models of cardiovascular diseases including thrombosis and ischemic stroke. The comprehensive analysis of the major Mg2+ channels may lead to a better understanding of the regulatory role of Mg2+ influx in megakaryocytes and platelets. The identification of Mg2+ channel mediated signalling pathways in platelet function may serve as basis for the development of novel antithrombotic agents.
DFG Programme
Research Grants
