Members of the Department of Pharmacology investigate signalling mechanisms that communicate the extracellular environment to the cell, and these are subsequently integrated into functional ‘decisions’. Earlier ground breaking studies from Pharmacology group leaders and colleagues established Ca2+ signalling as essential for cell function; this research focus has informed much of current investigation. An overall aim of research in Pharmacology is to identify potential drug targets, which can subsequently be employed to develop strategic therapeutic targets.
Ca2+ is utilised by many different receptors to control diverse cellular activities, in particular via phosphatidylinositide signals and its regulated release from intracellular stores. This highlights the importance of spatial organization: a Ca2+ signal in one part of a cell can evoke a very different response to a Ca2+ signal than in another part of the same cell. Additionally, the reliability of Ca2+ signals, which involves small numbers of proteins, is poorly understood. To tackle these issues, inositol trisphosphate-evoked Ca2+ signalling is being addressed at levels ranging from atomic structures, through single-molecule functional analyses and organelle dynamics to cellular behaviours (Taylor). Together with Mike Berridge, members of Pharmacology (Irvine) helped to establish inositol 1,4,5-trisphosphate as a second messenger regulating calcium mobilisation. Current focus is on the small family of phosphatidylinositol 5-phosphate 4-kinases, introducing genomic tagging as a technique to give new insights into their cellular targeting and functions.
Many pathways interact with Ca2+ flux to integrate signalling. Amongst these organisation of adenylyl cyclases in cells and their role as signalling scaffolds is important. Targeted sensors for both cyclic AMP and Ca2+ are employed to study the dynamics and influences upon these messengers (Cooper). Consequences of aberrant adenyl cyclase signalling are investigated in disease states. For example, the in vivo activation of the cystic fibrosis transmembrane conductance regulator is believed to be primarily through stimulation of surface receptors that couple to adenylate cyclase and raise cellular cAMP levels. Drugs proposed to activate phosphodiesterases (PDEs) thus restricting cAMP levels are being investigated (MacVinish).
Murrell-Lagnado is interested in the structure, function and cell biology of the P2X family of membrane receptors. P2X receptors are cation channels that open on binding extracellular ATP and are widely distributed throughout all major systems in the body, playing a key role in afferent signalling, in the regulation of blood flow and the generation of inflammatory responses. Extracellular ATP signals tissue injury, sites of inflammation and cancers. P2X receptors are therefore involved in many diseases and are important targets for the development of new drug therapies.
Signalling pathways (including Ca2+ fluxes) are integrated at the epigenetic level to regulate chromatin structure and gene expression. Changes in the extracellular environment mediated by signalling pathways (e.g. p38 MAPK), which regulate histone posttranslational modifications (and hence chromatin condensation) are being investigated in the context of adult stem cell fate.