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

Recent publications listed in research@st-andrews
Jovanovic, A, Obradovic, M, Sudar-Milovanovic, E, Stewart, AJ, Pitt, SJ, Alvantic, D, Aleksic, E & Isenovic, ER 2017, 'Changes in cardiac Na+/K+-ATPase expression and activity in female rats fed a high fat diet' Molecular and Cellular Biochemistry, vol 436, no. 1-2, pp. 49-58. DOI: 10.1007/s11010-017-3077-y
Jovanovic, A, Sudar-Milovanovic, E, Obradovic, M, Pitt, SJ, Stewart, AJ, Zafirovic, S, Stanimirovic, J, Radak, D & Isenovic, ER 2017, 'Influence of a high-fat diet on cardiac iNOS in female rats' Current Vascular Pharmacology, vol 15, no. 5, pp. 491-500. DOI: 10.2174/1570161114666161025101303
Stanimirovic, J, Obradovic, M, Jovanovic, A, Sudar-Milovanovic, E, Zafirovic, S, Pitt, SJ, Stewart, AJ & Isenovic, ER 2016, 'A high fat diet induces sex-specific differences in hepatic lipid metabolism and nitrite/nitrate in rats' Nitric Oxide, vol 54, pp. 51-59. DOI: 10.1016/j.niox.2016.02.007
Robertson, G, Reilly O'Donnell, B & Pitt, SJ 2015, 'Exploring a novel role for zinc in modulation of sarcoplasmic reticulum calcium release in skeletal muscle' Physiology 2015, Cardiff, United Kingdom, 6/07/15 - 8/07/15, .
Obradovic, M, Stewart, AJ, Pitt, SJ, Labudovic-Borovic, M, Sudar, E, Petrovic, V, Zafirovic, S, Maravic-Stojkovic, V, Vasic, V & Isenovic, ER 2014, 'In vivo effects of 17β-estradiol on cardiac Na+/K+-ATPase expression and activity in rat heart' Molecular and Cellular Endocrinology, vol 388, no. 1-2, pp. 58-68. DOI: 10.1016/j.mce.2014.03.005
Venturi, E, Galfre, E, O'Brien, F, Pitt, SJ, Bellamy, S, Sessions, RB & Sitsapesan, R 2014, 'FKBP12.6 activates RyR1: investigating the amino acid residues critical for channel modulation' Biophysical Journal, vol 106, no. 4, pp. 824-833. DOI: 10.1016/j.bpj.2013.12.041
Venturi, E, Matyjaszkiewicz, A, Pitt, SJ, Tsaneva-Atanasova, K, Nishi, M, Yamazaki, D, Takeshima, H & Sitsapesan, R 2013, 'TRIC-B channels display labile gating: evidence from the TRIC-A knockout mouse model' Pflügers Archiv: European Journal of Physiology, vol 465, no. 8, pp. 1135-1148. DOI: 10.1007/s00424-013-1251-y
Galfre, E, Pitt, SJ, Venturi, E, Sitsapesan, M, Zaccai, NR, Tsaneva-Atanasova, K, O'Neill, S & Sitsapesan, R 2012, 'FKBP12 activates the cardiac ryanodine receptor Ca2+-release channel and is antagonised by FKBP12.6' PLoS One, vol 7, no. 2, e31956. DOI: 10.1371/journal.pone.0031956
Venturi, E, Mio, K, Nishi, M, Ogura, T, Moriya, T, Pitt, SJ, Okuda, K, Kakizawa, S, Sitsapesan, R, Sato, C & Takeshima, H 2011, 'Mitsugumin 23 forms a massive bowl-shaped assembly and cation-conducting channel.' Biochemistry, vol 50, no. 13, pp. 2623-32. DOI: 10.1021/bi1019447
Pitt, SJ, Funnell, TM, Sitsapesan, M, Venturi, E, Rietdorf, K, Ruas, M, Ganesan, A, Gosain, R, Churchill, GC, Zhu, MX, Parrington, J, Galione, A & Sitsapesan, R 2010, 'TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+' Journal of Biological Chemistry, vol 285, no. 45, pp. 35039-35046. DOI: 10.1074/jbc.M110.156927
Pitt, SJ, Park, K-H, Nishi, M, Urashima, T, Aoki, S, Yamazaki, D, Ma, J, Takeshima, H & Sitsapesan, R 2010, 'Charade of the SR K+-channel: two ion-channels, TRIC-A and TRIC-B, masquerade as a single K+-channel' Biophysical Journal, vol 99, no. 2, pp. 417-426. DOI: 10.1016/j.bpj.2010.04.051