William Fuller

Biography

Dr Fuller gained his BA in Pharmacology from University of Cambridge (Emmanuel College) and remained in the Department of Pharmacology in Cambridge to study for a PhD investigating the misfolding of the F508 mutant of CFTR under the supervision of the then head of department Professor AW Cuthbert. He then moved on to King's College London (St Thomas Hospital campus) where he worked on regulation of the cardiac sodium pump in the laboratory of Professor Michael Shattock. During 8 years in this lab Dr Fuller developed interests in the hormonal regulation of cardiac ion transport - working first on the sodium pump, and later on its cardiac accessory protein phospholemman. He moved to Dundee in 2006 to establish an independent research lab with a specific interest in protein-protein interactions and post-translational modifications in cardiac muscle.

Research Interest

Heart disease is the biggest killer in the western world. The underlying cause of heart disease is varied, but it is often characterised by major changes in ion channel expression and function in cardiac myocytes that compromise contractility and predispose to the development of lethal arrhythmias. Research in my laboratory is split along 3 major themes: 1. Regulation of the cardiac sodium pump The primary active means of ion transport in the cardiomyocyte sarcolemma is the sodium pump (Na/K ATPase). In cardiac muscle, the transarcolemmal sodium (Na) gradient established by Na/K ATPase activity is essential not only for generating the rapid upstroke of the action potential but also for driving a number of ion exchange and transport processes that are crucial for normal cellular function, excitation contraction coupling, ion homeostasis, mitochondrial homeostasis and the control of cell volume. By determining the set point for the sodium-calcium exchanger, the Na/K ATPase controls the predominant mechanism of transmembrane calcium flux, and hence indirectly controls intracellular calcium load and myocardial contractility. Interventions that influence either the activity of the Na/K ATPase, or indirectly the transmembrane sodium gradient, can therefore profoundly affect normal cardiac function. Misregulation of the Na/K ATPase in human heart failure not only leads to abnormalities in the Na gradient, but also knock-on effects on intracellular calcium stores and therefore alterations in cardiac contractility, as well as supply-demand mismatching at the level of mitochondria. Regulation of the catalytic activity of the Na/K ATPase by protein kinases is through phosphorylation of phospholemman by protein kinase A and protein kinase C. Current research is directed towards understanding the relationship between these proteins in health and disease. This will increase our understanding of cardiac Na/K ATPase function and dysfunction in cardiac physiology and heart disease, and has the potential to identify new therapeutic targets in heart failure. 2. Protein Palmitoylation S-palmitoylation is the reversible covalent post-translational attachment of the fatty acid palmitic acid to the thiol group of cysteine, via an acyl-thioester linkage. While the technology to study this post-translational modification has lagged behind commonly studied modifications such as protein phosphorylation, protein S-palmitoylation is now emerging as an important and common post-translational modification in a variety of tissues. Protein S-palmitoylation is catalysed by palmitoyl acyltransferases and reversed by protein thioesterases, and occurs dynamically and reversibly in a manner analogous to protein phosphorylation. Many different classes of protein have been identified as targets for palmitoylation, including G-proteins, ion channels, transporters, receptors and protein kinases. Palmitoylation can alter enzymatic/ion channel activity, stability or subcellular localisation of the target protein, and this is usually achieved by the recruitment of the palmitoylated cysteine to the lipid bilayer. As such, palmitoylation is largely specific for membrane-associated and integral membrane proteins, and has the potential to induce substantial changes in protein secondary structure and therefore function, through the recruitment of intracellular loops to the inner surface of the membrane bilayer. Every single route by which sodium and calcium enters and leaves a cardiac myocyte is subjected to palmitoylation, so dynamic protein palmitoylation has the potential to be as important as protein phosphorylation in the regulation of cardiac function. Indeed, since palmitoylation is restricted to integral membrane and membrane-associated proteins (i.e proteins connected with ion transport at the cell surface), it is likely to play a key role in the regulation of the cardiac output by regulating cardiac ion transporters. Palmitoylation of phospholemman contributes to its regulation of the cardiac sodium pump (see above). 3. Caveolae Caveolae are small flask-like invaginations of the cell membrane around 50-100 nm in diameter, found in almost all cells of the body. They represent a specialised form of lipid raft, an area of the cell membrane enriched in cholesterol and sphingolipids, characterised by the presence of the protein caveolin. The lipid environment, caveolin content and morphology of caveolae are central to their diverse functional roles, which include co-ordination of signal transduction, cholesterol homeostasis, and endocytosis. One of caveolae’s best-characterised roles is as a signalosome, a compartment that brings together components of signal transduction cascades (including receptors, effectors and targets). Caveolae have been assigned a key role in regulation of signalling in the heart. For example, adrenoceptors and their effector molecules and downstream targets such as phospholemman are found in caveolae-containing membrane fractions of the adult heart. The distribution of receptors, effectors and their targets is key to the efficiency and fidelity of their coupling. A considerable number of cardiac ion transporters are resident in cardiac caveolae. Physical co-localisation of ion transporters in the caveolar compartment may functionally link ion flow by providing a restricted diffusional space and facilitates hormonal regulation of these transporters by placing them physically adjacent to signalling molecules. Furthermore, the presence of ion transporters in caveolae is likely to have functional relevance beyond signal transduction since the lipid composition of the bilayer in which an ion transporter resides is likely to influence its activity. We are currently evaluating dynamic changes in the caveolar compartment during adrenergic signalling in cardiac muscle.