Dr Samantha Pitt
Senior Lecturer in Molecular Medicine
Tel: 01334 463156
In healthy individuals, the controlled release of calcium causes the heart to beat strongly. In heart failure and fatal arrhythmias the release of calcium becomes erratic leading to weakened contraction of heart muscle and cell death. Using a combination of low noise electrophysiological recordings in combination with molecular and biochemical methods, my group investigates intracellular calcium dynamics and the molecular function of ion channels that are involved in the control and regulation of calcium-release from intracellular stores. The aim of our research is to try to understand what happens to channel function under pathophysiological conditions.
We currently have two main areas of research:
1. Elucidating the molecular mechanisms of NAADP-regulated signalling via Two Pore Channels
Recent research has discovered that a biological agent called “nicotinic acid dinucleotide phosphate” (NAADP) causes the release of calcium by opening a newfamily of pore forming proteins called two pore channels (TPCs) located on acidic intracellular calcium stores. The mechanism of NAADP-regulated signalling via TPCs is not well understood. In humans there are two isoforms of TPC (TPC1 and TPC2) and we are currently investigating the single-channel behaviour of these putative Ca2+-release channels. Owing to their Ca2+-handling properties aberrant TPC function may impact on diseases where disruption of Ca2+-signals are central, including cytotoxicity and cell death, heart failure, and neurodegenerative processes. Furthermore, genetic studies have linked the gene coding TPC2 to hearing defects and cancer. Understanding the role of TPCs in regulating calcium-release will enable the design of drugs that can manipulate the release of calcium via these channels and help combat diseases associated with abnormal calcium-movements.
2. Zinc is at the heart of cellular calcium dynamics
We are also interested in how Zn2+ modulates Ca2+-signalling in the heart. Aberrant Zn2+-homeostasis is a hallmark of certain cardiomyopathies associated with altered contractile force and is likely a consequence of altered excitation-contraction coupling. How Zn2+ impacts upon the contractile force and the release of Ca2+ from intracellular stores in cardiac muscle is unknown. Our latest findings suggest that physiological concentrations of Zn2+ modify the function of both the cardiac ryanodine receptor (RyR2) and Mitsugumin 23 (MG23). We hypothesise that this change in channel gating may lead to unregulated Ca2+ leakage from the sarcoplasmic reticulum and that this is a major contributor to the generation of cardiac arrhythmias. Using a combination of electrophysiological techniques, molecular biology and cardiac live cell/slice imaging we are currently investigating how Zn2+ shapes cellular Ca2+ dynamics in the heart.
- Professor Hiroshi Takeshima – Graduate School of Pharmaceutical Science, Kyoto University, Japan
- Dr Richard Rainbow – Department of Cardiovascular Sciences, University of Leicester
- Dr Colin Murdoch – School of Medicine, University of Dundee
- Professor Antony Galione – Department of Pharmacology, University of Oxford
- Our research is funded by the British Heart Foundation, BBSRC
Recent PublicationsData could not be retrieved from PURE at this time. (research-outputs/persons)