Gi-Proteins and platelets

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Platelet activation is not only essential for normal haemostasis but also a major pathomechanism underlying acute ischemic disease states such as stroke or myocardial infarction. Hence, platelet function is under tight control by various cell surface receptors including Gi-protein-coupled receptors. For instance Gi-protein-coupled P2Y12-receptors transmit agonist-induced platelet activation leading to platelet aggregation. P2Y12-receptors are therapeutically targeted by antagonists, which harbor an increased risk for bleeding. Of the three known receptor-coupled Galpha-i-isoforms, we confirmed expression of Galpha-i2 and Galpha-i3 in murine platelets. In our previous work, we demonstrated that Galpha-i-isoforms are differentially involved in platelet functions. However, the underlying mechanisms remain to be elucidated. We hypothesize that Galpha-i2 and Galpha-i3 have both overlapping as well as independent functions in platelets and that both isoforms differently regulate haemostasis, thrombus formation and inflammation. In the proposed project, we want to (1) examine which functions are selectively or redundantly regulated by Galpha-i2 and Galpha-i3 in platelets, (2) identify the regulators and effectors involved in Galpha-i-signaling, and (3) decipher the molecular mechanisms underlying Galpha-i-governed haemostasis and inflammatory responses.