G protein-coupled receptors (GPCRs), one of the largest protein families in the human genome, are the most tractable set of therapeutic targets for novel drug design. GPCRs are regulated in a dynamic and complex manner, and are not static entities inserted into the plasma membrane of cells. My research examines the regulatory mechanisms controlling GPCR traffic whilst assessing the impact of such mechanisms on signalling pathways that initiate important physiological responses. In order to examine these questions we use both biochemical and imaging techniques to study receptor movement and function.
Presently we are examining the regulation of P2Y1 and P2Y12 purinergic receptors in human platelets. Platelets are an essential element in the pathophysiology of heart disease. Adenosine diphosphate (ADP), which influences platelet adhesiveness and induces platelet aggregation, is recognised as one of the most important mediators of haemostasis and thrombosis. ADP activates two G protein-coupled ADP receptors, P2Y1 and P2Y12, to promote platelet aggregation. Indeed these receptors are pharmacological targets for antithrombotic drugs. Alterations in the responsiveness of ADP receptors are likely to have important consequences on platelet function and indeed evidence suggests that such mechanisms, including desensitization, internalization and subsequent endocytic sorting regulate their function. However little work has been performed to determine the underlying details of these mechanisms. Studies examining the molecular mechanisms underlying the control and traffic of these receptors whilst determining the consequences of such mechanisms on receptor function are ongoing. A number of different techniques are employed to answer these questions ranging from measurement of cellular signalling pathways through to immunofluorescent imaging of single cells.
This body of work will provide fundamental new insights into the molecular mechanisms regulating P2Y1 and P2Y12 receptor function and may lead to the discovery of new molecular targets for antithrombotic therapy in heart disease.
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