Samantha Pitt

Samantha-Pitt_photo

Dr. Samantha Pitt

Dr Samantha Pitt

Royal Society of Edinburgh Biomedical Fellow

Principal Investigator

sjp24@st-andrews.ac.uk

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

29 (of 29 published available) for sjp24. (source: University of St Andrews PURE)
Please click title of any item for full details

Total plasma magnesium, zinc, copper and selenium concentrations in type-I and type-II diabetes Fiona Stefanowicz, Samantha J. Pitt, Ramzi A. Ajjan, Alan J. Stewart
BioMetals 2019 vol.32 pp.123-138
Glycosaminoglycan neutralization in coagulation control Samantha J. Pitt, Alan J. Stewart
Arteriosclerosis, Thrombosis, and Vascular Biology 2018 vol.38 pp.1258-1270
Influence of zinc on glycosaminoglycan neutralisation during coagulation Samantha J. Pitt, Alan J. Stewart
Metallomics 2018 vol.10 pp.1180-1190
17ß-Estradiol protects against the effects of a high fat diet on cardiac glucose, lipid and nitric oxide metabolism in rats Sonja Zafirovic, Milan Obradovic, Emina Sudar-Milovanovic, Alexsandra Jovanovic, Julijana Stanimirovic, Alan J. Stewart, Samantha J. Pitt, Esma R. Isenovic
Molecular and Cellular Endocrinology 2017 vol.446 pp.12-20
Changes in cardiac Na+/K+-ATPase expression and activity in female rats fed a high fat diet Aleksandra Jovanovic, Milan Obradovic, Emina Sudar-Milovanovic, Alan J. Stewart, Samantha J. Pitt, Dragan Alvantic, Ema Aleksic, Esma R. Isenovic
Molecular and Cellular Biochemistry 2017 vol.436 pp.49-58
Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage Angela Karumbi, Connor McIntyre, Wojciech Bal, Miyuki Nishi, Hiroshi Takeshima, Alan J. Stewart, Samantha J. Pitt
Journal of Biological Chemistry 2017 vol.292 pp.13361-13373
Influence of a high-fat diet on cardiac iNOS in female rats Aleksandra Jovanovic, Emina Sudar-Milovanovic, Milan Obradovic, Samantha J. Pitt, Alan J. Stewart, Sonja Zafirovic, Julijana Stanimirovic, Djordje Radak, Esma R. Isenovic
Current Vascular Pharmacology 2017 vol.15 pp.491-500
Modulation of the Neisseria gonorrhoeae drug efflux conduit MtrE Giulia Tamburrino, Salome Llabres, Owen Vickery, Samantha J. Pitt, Ulrich Zachariae
Scientific Reports 2017 vol.7
A high fat diet induces sex-specific differences in hepatic lipid metabolism and nitrite/nitrate in rats Julijana Stanimirovic, Milan M Obradovic, Aleksandra Jovanovic, Emina Sudar-Milovanovic, Sonja Zafirovic, Samantha J. Pitt, Alan J. Stewart, Esma R Isenovic
Nitric Oxide 2016 vol.54 pp.51-59
Exploring the biophysical evidence that mammalian two pore channels are NAADP-activated calcium-permeable channels Samantha J. Pitt, Rebecca Sitsapesan
The Journal of Physiology 2016 vol.594 pp.4171-4179
Response to Qian and Colvin Jason Woodier, Richard D Rainbow, Alan J. Stewart, Samantha J. Pitt
Journal of Biological Chemistry 2016 vol.291 pp.4267
Examining a new role for zinc in regulating calcium release in cardiac muscle Samantha J. Pitt, Alan J. Stewart
Biochemical Society Transactions 2015 vol.43 pp.359-363
Intracellular zinc modulates cardiac ryanodine receptor-mediated calcium release Jason Woodier, Richard Rainbow, Alan J. Stewart, Samantha J. Pitt
Journal of Biological Chemistry 2015 vol.290 pp.17599-17610
Zinc controls RyR2 activity during excitation-contraction coupling Alan J. Stewart, Samantha J. Pitt
Channels 2015 vol.9 pp.223-225
In vivo effects of 17β-estradiol on cardiac Na+/K+-ATPase expression and activity in rat heart Milan Obradovic, Alan J. Stewart, Samantha J. Pitt, Milica Labudovic-Borovic, Emina Sudar, Voin Petrovic, Sonja Zafirovic, Vera Maravic-Stojkovic, Vesna Vasic, Esma R Isenovic
Molecular and Cellular Endocrinology 2014 vol.388 pp.58-68
FKBP12.6 activates RyR1 Elisa Venturi, Elena Galfre, Fiona O'Brien, Samantha J. Pitt, Stuart Bellamy, Richard B. Sessions, Rebecca Sitsapesan
Biophysical Journal 2014 vol.106 pp.824-833
Reconstituted human TPC1 is a proton-permeable ion channel and is activated by NAADP or Ca2+ Samantha J. Pitt, Andy K M Lam, Katja Rietdorf, Antony Galione, Rebecca Sitsapesan
Science Signaling 2014 vol.7
TPC1 is a proton permeable channel that can be independently activated by cytosolic calcium or NAADP Samantha J. Pitt, Andy Lam, Antony Galione, Rebecca Sitsapesan
Biophysical Journal 2014 vol.106 pp.642A-642A
TRIC-B channels display labile gating Elisa Venturi, Antoni Matyjaszkiewicz, Samantha J. Pitt, Krasimira Tsaneva-Atanasova, Miyuki Nishi, Daiju Yamazaki, Hiroshi Takeshima, Rebecca Sitsapesan
Pflügers Archiv: European Journal of Physiology 2013 vol.465 pp.1135-1148
FKBP12 activates the cardiac ryanodine receptor Ca2+-release channel and is antagonised by FKBP12.6 Elena Galfre, Samantha J. Pitt, Elisa Venturi, Mano Sitsapesan, Nathan R Zaccai, Krasimira Tsaneva-Atanasova, Stephen O'Neill, Rebecca Sitsapesan
PLoS One 2012 vol.7
From eggs to hearts: what is the link between cyclic ADP-ribose and ryanodine receptors? Elisa Venturi, Samantha J. Pitt, Elena Galfre, Rebecca Sitsapesan
Cardiovascular Therapeutics 2012 vol.30 pp.109-16
Ca2+-dependent phosphorylation of RyR2 can uncouple channel gating from direct cytosolic Ca2+ regulation Simon Carter, Samantha J. Pitt, John Colyer, Rebecca Sitsapesan
Journal of Membrane Biology 2011 vol.240 pp.21-33
Mitsugumin 23 forms a massive bowl-shaped assembly and cation-conducting channel. Elisa Venturi, Kazuhiro Mio, Miyuki Nishi, Toshihiko Ogura, Toshio Moriya, Samantha J. Pitt, Kazutaka Okuda, Sho Kakizawa, Rebecca Sitsapesan, Chikara Sato, Hiroshi Takeshima
Biochemistry 2011 vol.50 pp.2623-32
Charade of the SR K+-channel Samantha J. Pitt, Ki-Ho Park, Miyuki Nishi, Toshiki Urashima, Sae Aoki, Daijyu Yamazaki, Jianjie Ma, Hiroshi Takeshima, Rebecca Sitsapesan
Biophysical Journal 2010 vol.99 pp.417-426
TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+ Samantha J. Pitt, Tim M Funnell, Mano Sitsapesan, Elisa Venturi, Katja Rietdorf, Margarida Ruas, A Ganesan, Rajendra Gosain, Grant C Churchill, Michael X Zhu, John Parrington, Antony Galione, Rebecca Sitsapesan
Journal of Biological Chemistry 2010 vol.285 pp.35039-35046
High intracellular chloride slows the decay of glycinergic currents Samantha J. Pitt, Lucia G Sivilotti, Marco B Beato
The Journal of Neuroscience 2008 vol.28 pp.11454-11467
Potentiation of P2Y receptors by physiological elevations of extracellular K+ via a mechanism independent of Ca2+ influx. Samantha J. Pitt, Juan Martinez-Pinna, Eric A Barnard, Martyn P Mahaut-Smith
Molecular Pharmacology 2005 vol.67 pp.1705-13
Lack of evidence for functional ADP-activated human P2X1 receptors supports a role for ATP during hemostasis and thrombosis. Catherine Vial, Samantha J. Pitt, Jon A Roberts, Michael G Rolf, Martyn P Mahaut-Smith, Richard J Evans
Blood 2003 vol.102 pp.3646-51