Dr Stuart Mundell

Summary

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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Activities / Findings

• Purinergic receptors are regulated by multiple signalling pathways in platelets. Read more >

Keywords

• G-protein coupled receptor
• purinergic
• signalling

Processes and functions

• endocytosis
• exocytosis

Methodologies

• Cell culture
• confocal imaging
• wide field and TIRF microscopy
• molecular biology
• 2nd messenger assays
• radioligand binding

Memberships

Organisations

School of Physiology and Pharmacology

Bristol Heart Institute

Other sites

• Bhi

Research Areas

• Cell signalling
• Platelet function

Research Themes

• Cell Biology

Links

•   Bristol Platelets webpage

Recent publications

• Cunningham, MR, McIntosh, KA, Pediani, JD, Robben, J, Cooke, AE, Nilsson, M, Gould, GW, Mundell, S, Milligan, G & Plevin, R 2012, ‘Novel role for proteinase-activated receptor 2 (PAR2) in membrane trafficking of proteinase-activated receptor 4 (PAR4)’. Journal of Biological Chemistry, vol 287., pp. 16656-69
• Ferreira, F, Foley, M, Cooke, A, Cunningham, M, Smith, G, Woolley, R, Henderson, G, Kelly, E, Mundell, S & Smythe, E 2012, ‘Endocytosis of G protein-coupled receptors is regulated by clathrin light chain phosphorylation’. Current biology : CB, vol 22., pp. 1361-70
• Kanamarlapudi, V, Owens, SE, Saha, K, Pope, RJ & Mundell, SJ 2012, ‘ARF6-Dependent Regulation of P2Y Receptor Traffic and Function in Human Platelets’. PLoS ONE, vol 7., pp. e43532
• Nisar, SP, Cunningham, M, Saxena, K, Pope, RJ, Kelly, E & Mundell, SJ 2012, ‘Arrestin scaffolds NHERF1 to the P2Y12 receptor to regulate receptor internalization’. Journal of Biological Chemistry, vol 287., pp. 24505-15
• Rivero, G, Llorente, J, McPherson, J, Cooke, A, Mundell, S, McArdle, C, Rosethorne, E, Charlton, S, Crasel, C, Bailey, C, Henderson, G & Kelly, E 2012, ‘Endomorphin-2: A Biased Agonist at the μ Opioid Receptor’. Mol Pharmacol, vol 82., pp. 178-188
• Nisar, S, Daly, ME, Federici, AB, Artoni, A, Mumford, AD, Watson, SP & Mundell, SJ 2011, ‘An intact PDZ motif is essential for correct P2Y12 purinoceptor traffic in human platelets’. Blood, vol 118., pp. 5641-51
• Kelly, E & Mundell, S 2011, ‘Adenosine receptor desensitization and trafficking’. Biochim Biophys Acta., pp. 1319 - 1328
• Nisar, S, Daly, M, Federici, A, Artoni, A, Mumford, A, Watson, S & Mundell, S 2011, ‘An intact PDZ-motif is essential for correct P2Y12 purinoceptor traffic in human platelets’. Blood., pp. (in press)
• Nisar, S, Kelly, E, Cullen, P & Mundell, S 2010, ‘Regulation of P2Y₁ receptor traffic by sorting nexin 1 is retromer independent’. Traffic, vol 11 (4)., pp. 508 - 519
• Mundell, S & Kelly, E 2010, ‘Deletion of the distal COOH-terminus of the A(2B) adenosine receptor switches internalization to an arrestin- and clathrin-independent pathway and inhibits recycling’. British Journal of Pharmacology, vol 159., pp. 518 - 533

View complete publications list in the University of Bristol publications system