Channels Receptors and Signalling

Receptors, ion channels and transporters play central roles in signalling between cells. The common interest of our grouping is in understanding the physiology, pharmacology and molecular basis of these processes. These families of membrane proteins are important therapeutic targets for treating a wide range of human disease. There is a focus on the cardiovascular system with groups working on regulation of arterial tone (Davies, Storey, Willets), cardiac muscle (Mitcheson), endothelial cell proliferation (Brindle), and blood clotting (Mahaut-Smith). Additional model systems include the respiratory airways (Vial), neuronal/glial interactions (Challiss) as well as recombinant expression of receptors important in diabetes and obesity (Willars). As well as an interest in the consequences for cellular signalling there is also a focus to understand the molecular and structural basis of channel/receptor/transporter properties for example in terms of mapping the binding sites of physiological ligands and drugs  (Brindle, Evans, Mitcheson, Vuister). 

Research Groups

There are eleven groups working in the area of receptors, channels, transporters and signalling. Our work is underpinned by considerable overlap in technical approaches including electrophysiological recordings of ion channel activity, imaging based approaches to investigate G-protein coupled receptor signalling, and protein biochemistry, protein engineering and NMR. Our research is funded by a number of research councils and charities including the BBSRC, MRC, EPSRC and British Heart Foundation. There are opportunities for PhD study on many aspects of ion channel and receptor physiology and pharmacology (see available projects on areas of focus below).

Areas of focus

• Nick Brindle - Signalling and structure of Tie family receptor tyrosine kinases
• John Challiss - Molecular pharmacology of G protein-coupled receptors
• Martyn Mahaut-Smith - Ion channels and calcium-dependent proteins in platelet function
• Nina Storey – Cardiac ion channel modulation by intracellular signalling pathways
• Catherine Vial – The roles of purinergic receptors in respiratory and cardiovascular physiology
• Geerten Vuister - Structural biology of calcium-transport regulation complexes
• Gary Willars – GLP-1 and NmU receptor signalling and regulation
• Jon Willets - G protein-coupled receptor kinase function in smooth muscle

These projects address fundamental mechanisms underlying physiological signalling processes in health and disease at a molecular, cellular and whole organ level. We also have collaborations with clinical colleagues in Departments such as Cardiovascular Sciences, Infection, Immunity and Inflammation and Respiratory Science and contribute to the development of novel therapeutics for patients. We also have close ties with the Leicester Institute of Structural and Chemical Biology and Institute for Precision Health.

Achievement Highlights

• A heme-binding domain controls regulation of ATP-dependent potassium channels. PNAS April 5, 2016. 113 (14) 3785-3790. doi.org/10.1073/pnas.1600211113
• A mechanism for CO regulation of ion channels. Nature Communications. 2018 Mar 2;9(1):907. doi: 10.1038/s41467-018-03291-z
• Unique residues in the ATP gated human P2X7 receptor define a novel allosteric pocket for the selective antagonist AZ10606120.  Scientific Reports. 2017 7:725. doi: 10.1038/s41598-017-00732-5
• Regulation of Angiopoietin Signalling by Soluble Tie2 Ectodomain and Engineered Ligand Trap. Science Reports 7(1): 3658.  doi: 10.1038/s41598-017-03981-6