Dr Samantha Pitt
Reader 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 live cell imaging and 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.
Our research focuses on the structure and function of ion channels present on intracellular Ca2+ stores. This provides insight into how changes in cellular Ca2+ homeostasis can lead to severe disease such as heart failure and high blood pressure.
Our current work is focused within three main areas as described below:
1. Mechanisms of altered calcium handling in the failing heart
Synchronized Ca2+-release is critical to normal cardiac function. In failing hearts, Ca2+-cycling is profoundly altered leading to leak of Ca2+ from the sarcoplasmic reticulum (SR) resulting in impaired contractility and fatal cardiac arrhythmias. Inhibition of diastolic Ca2+-leakage through SR Ca2+-release channels is an emerging therapeutic target in heart failure. The underlying molecular mechanisms governing this leak are unclear. Our work has identified Mitsugumin 23 (MG23) as a SR and nuclear located ion-channel displaying Ca2+-handling properties. We are currently investing whether Mitsugumin 23 (MG23) plays a key role in leakage of Ca2+ from internal stores leading to cardiac dysfunction and heart failure. this work will advance understanding of cardiac intracellular Ca2+-dynamics and highlight MG23 as a new therapeutic target in treatment of the failing heart.
2. The role of zinc in shaping cellular calcium dynamics in the heart
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.
3. 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 new family 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.
Lab Members
External Collaborations
- 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
Recent Grants
- Our research is funded by the British Heart Foundation, BBSRC, Tenovus Scotland
Recent Publications
6 Does mitsugumin 23 play a role in doxorubicin-induced cardiotoxicity?
Abraham, K., Dorward, A. M., Hurst, Q. & Pitt, S. J., 1 Apr 2023, In: Heart. 109, Suppl 2, p. A2-A2 1 p.
Research output: Contribution to journal › Abstract › peer-review
Editorial: Insulin resistance and cardiovascular disease
Stewart, A. J., Tuncay, E., Pitt, S. J. & Rainbow, R. D., 4 Aug 2023, In: Frontiers in Endocrinology. 14, 3 p., 1266173.
Research output: Contribution to journal › Editorial › peer-review
Magnesium deficiency and cardiometabolic disease
Fritzen, R., Davies, A., Veenhuizen, M., Campbell, M., Pitt, S. J., Ajjan, R. A. & Stewart, A. J., 17 May 2023, In: Nutrients. 15, 10, 19 p., 2355.
Research output: Contribution to journal › Article › peer-review
The role of Zn2+ in shaping intracellular Ca2+ dynamics in the heart
Dorward, A. M., Stewart, A. J. & Pitt, S. J., 16 Jun 2023, In: Journal of General Physiology. 155, 7, 18 p., e202213206.
Research output: Contribution to journal › Article › peer-review
A rare missense variant in the ATP2C2 gene is associated with language impairment and related measures
Martinelli, A., Rice, M., Talcott, J. B., Diaz, R., Smith, S., Hashim Raza, M., Snowling, M. J., Hulme, C., Stein, J., Hayiou-Thomas, M. E., Hawi, Z., Kent, L., Pitt, S. J., Newbury, D. F. & Paracchini, S., 15 Jun 2021, In: Human Molecular Genetics. 30, 12, p. 1160–1171 12 p., ddab111.
Research output: Contribution to journal › Article › peer-review
Albumin-mediated alteration of plasma zinc speciation by fatty acids modulates blood clotting in type-2 diabetes
Sobczak, A. I. S., Katundu, K. G. H., Phoenix, F. A., Khazaipoul, S., Yu, R., Lampiao, F., Stefanowicz, F., Blindauer, C. A., Pitt, S. J., Smith, T. K., Ajjan, R. A. & Stewart, A. J., 21 Mar 2021, In: Chemical Science. 12, 11, p. 4079-4093 15 p.
Research output: Contribution to journal › Article › peer-review
Deep tissue contractility sensing with biointegrated microlasers
Schubert, M., Woolfson, L., Barnard, I. R. M., Dorward, A. M., Casement, B., Caixeiro, S., Morton, A., Robertson, G. B., Appleton, P. L., Miles, G. B., Tucker, C. S., Pitt, S. J. & Gather, M. C., 2021, Novel Techniques in Microscopy, NTM 2021. The Optical Society, NW3C.2. (Optics InfoBase Conference Papers).
Research output: Chapter in Book/Report/Conference proceeding › Conference contribution
Levothyroxine treatment and the risk of cardiac arrhythmias – focus on the patient submitted to thyroid surgery
Gluvic, Z., Obradovic, M., Stewart, A. J., Essack, M., Pitt, S. J., Samardzic, V., Soskic, S., Gojobori, T. & Isenovic, E. R., 4 Nov 2021, In: Frontiers in Endocrinology. 12, 12 p., 758043.
Research output: Contribution to journal › Review article › peer-review
Lipidomic profiling of plasma free fatty acids in type-1 diabetes highlights specific changes in lipid metabolism
Sobczak, A. I. S., Pitt, S. J., Smith, T. K., Ajjan, R. A. & Stewart, A. J., Jan 2021, In: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids. 1866, 1, 9 p., 158823.
Research output: Contribution to journal › Article › peer-review
A rare missense variant in the ATP2C2 gene is associated with developmental language disorder (DLD)
Martinelli, A., Rice, M., Smith, S., Talcott, J., Stein, J., Kent, L., Hayiou-Thomas, M., Newbury, D., Hulme, C., Pitt, S. & Paracchini, S., 1 Dec 2020, p. 396-397. 2 p.
Research output: Contribution to conference › Poster › peer-review
Monitoring contractility in cardiac tissue with cellular resolution using biointegrated microlasers
Schubert, M., Woolfson, L., Barnard, I. R. M., Dorward, A., Casement, B., Morton, A., Robertson, G. B., Appleton, P. L., Miles, G. B., Tucker, C. S., Pitt, S. J. & Gather, M. C., Jul 2020, In: Nature Photonics. 14, 7, p. 452–458 12 p.
Research output: Contribution to journal › Article › peer-review
Plasma non-esterified fatty acids contribute to increased coagulability in type-2 diabetes through altered plasma zinc speciation
Sobczak, A. I. S., Katundu, K. G. H., Phoenix, F. A., Khazaipoul, S., Yu, R., Lampiao, F., Stefanowicz, F., Blindauer, C. A., Pitt, S. J., Smith, T. K., Ajjan, R. A. & Stewart, A. J., 27 Jul 2020, In: biorxiv. 2019, 38 p.
Research output: Contribution to journal › Article
Reduced plasma magnesium levels in type-1 diabetes associate with prothrombotic changes in fibrin clotting and fibrinolysis
Sobczak, A. I. S., Phoenix, F. A., Pitt, S. J., Ajjan, R. A. & Stewart, A. J., Feb 2020, In: Thrombosis and Haemostasis. 120, 2, p. 243-252 10 p.
Research output: Contribution to journal › Article › peer-review
A family of Type VI secretion system effector proteins that form ion-selective pores
Mariano, G., Trunk, K., Williams, D. J., Monlezun, L., Strah, H., Pitt, S. J. & Coulthurst, S. J., 2 Dec 2019, In: Nature Communications. 10, 15 p., 5484.
Research output: Contribution to journal › Article › peer-review
Allosteric activation of an ion channel triggered by modification of mechanosensitive nano-pockets
Kapsalis, C., Wang, B., El Mkami, H., Pitt, S. J., Schnell, J., Smith, T. K., Lippiat, J., Bode, B. E. & Pliotas, C., 10 Oct 2019, In: Nature Communications. 10, 14 p., 4619.
Research output: Contribution to journal › Article › peer-review
Functional characterization of ATP2C2, a risk factor for language disorders
Martinelli, A., Diaz, R., Feliciotti, I., Pitt, S. & Paracchini, S., 2019, In: European Neuropsychopharmacology. 29, p. 1194-1195 2 p.
Research output: Contribution to journal › Abstract › peer-review
Microlaser-based contractility sensing in single cardiomyocytes and whole hearts
Schubert, M., Woolfson, L., Barnard, I. R. M., Morton, A., Casement, B., Robertson, G. B., Miles, G. B., Pitt, S. J., Tucker, C. S. & Gather, M. C., 22 Jul 2019, Novel biophotonics techniques and applications V. Amelink, A. & Nadkarni, S. K. (eds.). SPIE, 3 p. 110750C. (Progress in Biomedical Optics and Imaging - Proceedings of SPIE; vol. 11075).
Research output: Chapter in Book/Report/Conference proceeding › Conference contribution
Microlaser-based contractility sensing in single cardiomyocytes and whole hearts
Schubert, M., Woolfson, L., Barnard, I. R. M., Morton, A., Casement, B., Robertson, G. B., Miles, G. B., Pitt, S. J., Tucker, C. S. & Gather, M. C., 8 Apr 2019, Novel Techniques in Microscopy - Proceedings Biophotonics Congress: Optics in the Life Sciences Congress 2019 (BODA, BRAIN, NTM, OMA, OMP). Optical Society of American (OSA), NM4C.2. (Novel Techniques in Microscopy - Proceedings Biophotonics Congress: Optics in the Life Sciences Congress 2019 (BODA, BRAIN, NTM, OMA, OMP)).
Research output: Chapter in Book/Report/Conference proceeding › Conference contribution
Total plasma magnesium, zinc, copper and selenium concentrations in type-I and type-II diabetes
Sobczak, A. I. S., Stefanowicz, F., Pitt, S. J., Ajjan, R. A. & Stewart, A. J., Feb 2019, In: BioMetals. 32, 1, p. 123-138 16 p.
Research output: Contribution to journal › Article › peer-review
Glycosaminoglycan neutralization in coagulation control
Sobczak, A. I. S., Pitt, S. J. & Stewart, A. J., Jun 2018, In: Arteriosclerosis, Thrombosis, and Vascular Biology. 38, 6, p. 1258-1270 14 p.
Research output: Contribution to journal › Review article › peer-review
Influence of zinc on glycosaminoglycan neutralisation during coagulation
Sobczak, A. I. S., Pitt, S. J. & Stewart, A. J., Sept 2018, In: Metallomics. 10, 9, p. 1180-1190 11 p.
Research output: Contribution to journal › Review article › peer-review
17ß-Estradiol protects against the effects of a high fat diet on cardiac glucose, lipid and nitric oxide metabolism in rats
Zafirovic, S., Obradovic, M., Sudar-Milovanovic, E., Jovanovic, A., Stanimirovic, J., Stewart, A. J., Pitt, S. J. & Isenovic, E. R., 5 May 2017, In: Molecular and Cellular Endocrinology. 446, p. 12-20 9 p.
Research output: Contribution to journal › Article › peer-review
Changes in cardiac Na+/K+-ATPase expression and activity in female rats fed a high fat diet
Jovanovic, A., Obradovic, M., Sudar-Milovanovic, E., Stewart, A. J., Pitt, S. J., Alvantic, D., Aleksic, E. & Isenovic, E. R., Dec 2017, In: Molecular and Cellular Biochemistry. 436, 1-2, p. 49-58 10 p.
Research output: Contribution to journal › Article › peer-review
Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage
Reilly-O'Donnell, B., Robertson, G. B., Karumbi, A., McIntyre, C., Bal, W., Nishi, M., Takeshima, H., Stewart, A. J. & Pitt, S. J., 11 Aug 2017, In: Journal of Biological Chemistry. 292, 32, p. 13361-13373 13 p.
Research output: Contribution to journal › Article › peer-review
Influence of a high-fat diet on cardiac iNOS in female rats
Jovanovic, A., Sudar-Milovanovic, E., Obradovic, M., Pitt, S. J., Stewart, A. J., Zafirovic, S., Stanimirovic, J., Radak, D. & Isenovic, E. R., 2017, In: Current Vascular Pharmacology. 15, 5, p. 491-500 10 p.
Research output: Contribution to journal › Article › peer-review
Modulation of the Neisseria gonorrhoeae drug efflux conduit MtrE
Tamburrino, G., Llabrés, S., Vickery, O., Pitt, S. J. & Zachariae, U., 6 Dec 2017, In: Scientific Reports. 7, 10 p., 17091.
Research output: Contribution to journal › Article › peer-review
A high fat diet induces sex-specific differences in hepatic lipid metabolism and nitrite/nitrate in rats
Stanimirovic, J., Obradovic, M., Jovanovic, A., Sudar-Milovanovic, E., Zafirovic, S., Pitt, S. J., Stewart, A. J. & Isenovic, E. R., 1 Apr 2016, In: Nitric Oxide. 54, p. 51-59 9 p.
Research output: Contribution to journal › Article › peer-review
Exploring the biophysical evidence that mammalian two pore channels are NAADP-activated calcium-permeable channels
Pitt, S. J., Reilly O'Donnell, B. & Sitsapesan, R., 1 Aug 2016, In: The Journal of Physiology. 594, 15, p. 4171-4179 9 p.
Research output: Contribution to journal › Review article › peer-review
Response to Qian and Colvin: zinc-mediated regulation of the cardiac ryanodine receptor occurs via multiple binding sites
Woodier, J., Rainbow, R. D., Stewart, A. J. & Pitt, S. J., 19 Feb 2016, In: Journal of Biological Chemistry. 291, 8, p. 4267
Research output: Contribution to journal › Letter › peer-review
Examining a new role for zinc in regulating calcium release in cardiac muscle
Pitt, S. J. & Stewart, A. J., 1 Jun 2015, In: Biochemical Society Transactions. 43, 3, p. 359-363
Research output: Contribution to journal › Article › peer-review
Exploring a novel role for zinc in modulation of sarcoplasmic reticulum calcium release in skeletal muscle
Robertson, G., Reilly O'Donnell, B. & Pitt, S. J., 2015.
Research output: Contribution to conference › Abstract › peer-review
Intracellular zinc modulates cardiac ryanodine receptor-mediated calcium release
Woodier, J., Rainbow, R. D., Stewart, A. J. & Pitt, S. J., 10 Jul 2015, In: Journal of Biological Chemistry. 290, 28, p. 17599-17610 12 p.
Research output: Contribution to journal › Article › peer-review
Zinc controls RyR2 activity during excitation-contraction coupling
Stewart, A. J. & Pitt, S. J., Sept 2015, In: Channels. 9, 5, p. 223-225
Research output: Contribution to journal › Article › peer-review
In vivo effects of 17β-estradiol on cardiac Na+/K+-ATPase expression and activity in rat heart
Obradovic, M., Stewart, A. J., Pitt, S. J., Labudovic-Borovic, M., Sudar, E., Petrovic, V., Zafirovic, S., Maravic-Stojkovic, V., Vasic, V. & Isenovic, E. R., 5 May 2014, In: Molecular and Cellular Endocrinology. 388, 1-2, p. 58-68
Research output: Contribution to journal › Article › peer-review
FKBP12.6 activates RyR1: investigating the amino acid residues critical for channel modulation
Venturi, E., Galfre, E., O'Brien, F., Pitt, S. J., Bellamy, S., Sessions, R. B. & Sitsapesan, R., 18 Feb 2014, In: Biophysical Journal. 106, 4, p. 824-833 10 p.
Research output: Contribution to journal › Article › peer-review