Dr Samantha Pitt
Senior Lecturer in Molecular Medicine
Tel: 01334 463156
Research Summary
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. Understanding new mechanisms of cardiac ryanodine receptor regulation by zinc
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 the cardiac ryanodine receptor Ca2+-release channel (RyR2) and that this change in channel gating may be a major contributor to the generation of cardiac arrhythmias. We are currently investigating at the single-channel level the mechanisms of how Zn2+ regulates RyR function.
Lab Members
External Collaborations
- Professor Antony Galione – Department of Pharmacology, University of Oxford
- Dr Richard Rainbow – Department of Cardiovascular Sciences, University of Leicester
- Professor Rebecca Sitsapesan – Department of Pharmacology, University of Oxford
Recent Grants
- SJP is supported by a Royal Society of Edinburgh Biomedical Personal Fellowship
- Our research is funded by Tenovus Scotland and the British Heart Foundation
Recent Publications
37 (of 37 /dk/atira/pure/researchoutput/status/published available) for sjp24. (source: University of St Andrews PURE)Please click title of any item for full details
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids 2021 vol. 1866
Nature Photonics 2020 vol. 14 pp. 452–458
Thrombosis and Haemostasis 2020 vol. 120 pp. 243-252
Nature Communications 2019 vol. 10
Nature Communications 2019 vol. 10
European Neuropsychopharmacology 2019 vol. 29 pp. 1194-1195
2019
2019
BioMetals 2019 vol. 32 pp. 123-138
Arteriosclerosis, Thrombosis, and Vascular Biology 2018 vol. 38 pp. 1258-1270
Metallomics 2018 vol. 10 pp. 1180-1190
Molecular and Cellular Endocrinology 2017 vol. 446 pp. 12-20
Molecular and Cellular Biochemistry 2017 vol. 436 pp. 49-58
Journal of Biological Chemistry 2017 vol. 292 pp. 13361-13373
Current Vascular Pharmacology 2017 vol. 15 pp. 491-500
Scientific Reports 2017 vol. 7
Nitric Oxide 2016 vol. 54 pp. 51-59
The Journal of Physiology 2016 vol. 594 pp. 4171-4179
Journal of Biological Chemistry 2016 vol. 291 pp. 4267
Biochemical Society Transactions 2015 vol. 43 pp. 359-363
2015
Journal of Biological Chemistry 2015 vol. 290 pp. 17599-17610
Channels 2015 vol. 9 pp. 223-225
Molecular and Cellular Endocrinology 2014 vol. 388 pp. 58-68
Biophysical Journal 2014 vol. 106 pp. 824-833
Science Signaling 2014 vol. 7
Biophysical Journal 2014 vol. 106 pp. 642A-642A
Pflügers Archiv: European Journal of Physiology 2013 vol. 465 pp. 1135-1148
PLoS ONE 2012 vol. 7
Cardiovascular Therapeutics 2012 vol. 30 pp. 109-16
Journal of Membrane Biology 2011 vol. 240 pp. 21-33
Biochemistry 2011 vol. 50 pp. 2623-32
Biophysical Journal 2010 vol. 99 pp. 417-426
Journal of Biological Chemistry 2010 vol. 285 pp. 35039-35046
The Journal of Neuroscience 2008 vol. 28 pp. 11454-11467
Molecular Pharmacology 2005 vol. 67 pp. 1705-13
Blood 2003 vol. 102 pp. 3646-51