Regulation of platelet purinergic receptor function by Sodium-Hydrogen Exchanger Regulatory Factor adaptor proteins

Heart attacks occur when blood flow is blocked, often by a blood clot, while strokes are caused either by blocked or burst blood vessels in the brain. Platelet activation, which helps to stop us bleeding when we cut ourselves plays a major role in causing thrombosis, and so play a significant role in both stroke and heart attacks. One of the main drugs used in the prevention of heart attacks is clopidogrel which inhibits platelet activation by preventing a substance called ADP binding to receptors on the surface of platelets. The function of these ADP receptors is tightly controlled by multiple proteins in platelets. One possible family of proteins that may regulate ADP receptor function are the Sodium-Hydrogen Exchanger Regulatory Factor (NHERF) adaptors. We plan to investigate the functional importance of these NHERF proteins to platelet and specifically ADP receptor function, work that we hope will open a path for the development of novel therapeutic approaches to prevent thrombosis and heart attacks.

Platelet activation is central to the development of the arterial thrombosis, a major cause of morbidity and mortality in heart disease. ADP is an important mediator of haemostasis and thrombosis influencing platelet activation by the coordinated stimulation of P2Y1 and P2Y12 purinergic receptors. The signalling of these pro-thrombotic receptors is regulated in a dynamic and complex manner with mechanisms, including desensitization and internalization regulating their function. If receptor traffic is blocked P2Y receptor resensitization and platelet function is attenuated. Little is known about the mechanisms regulating these processes that are critical for platelet function. Sodium-Hydrogen Exchanger Regulatory Factor (NHERF)1 and 2 are a novel family of proteins, expressed in platelets, which regulate the signalling and subsequent sorting of a variety of surface receptors. In this study we will examine the consequences of knockout of either or both NHERF isoforms upon P2Y receptor function in both cell models and in mouse platelets determining the relevance of these proteins upon whole platelet function.