Regulation of platelet activation by agonist concentration gradient-dependent inhibition

Platelets are central to thrombus formation, which is pivotal in myocardial infarction and stroke. Therefore, inhibition of undue platelet activation is vital for the treatment.

Currently available drugs are effective but have a major drawback, i.e. bleeding, and thus novel approaches are required.

We have discovered a novel regulatory mechanism, agonist concentration gradient dependent inhibition (GDI) of G-protein coupled receptors (GPCRs), that can control platelet activation through GPCRs.

We have strong evidence of involvement of a c-AMP dependent pathway, and cytoskeletal remodeling in GDI platelets, however, the details are not known.

Further, how sex, platelet thrombin receptor PAR4 polymorphisms and platelet secretions affect GDI as well as the role of GDI in thrombus formation and propagation is yet to be established.

Therefore, the purpose of the proposed project is to elucidate the mechanism of GDI with focus on the link between stimulatory GPCRs and c-AMP, role of cytoskeletal rearrangement, finding clinically useful specific markers of GDI, and its pathophysiological relevance.

We will use established methodology, e.g. aggregometry, mass-spectrometry, microscopy, flow cytometry and our in vitro thrombus model.

Our findings may have implications for cardiovascular research as they identify new and potentially thrombo-protective regulatory mechanism. Since GPCRs are common in many tissues and GDI is not limited to platelet GPCRs, it may have wide implications.