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Dr Lowri Thomas
Lecturer
School of Pharmacy and Pharmaceutical Sciences
- Welsh speaking
- Available for postgraduate supervision
Overview
I began working as a lecturer at the School of Pharmacy & Pharmaceutical Sciences in 2018, having spent most of my career as a British Heart Foundation funded researcher. My research focusses on the massive intracellular cardiac ion channel, the ryanodine receptor (RyR2) and its role in health and disease - in particular, the generation of cardiac arrhythmia. I use mutagenesis and expression techniques to make recombinant ion channel proteins and assess their gating behaviour (i.e. the pattern of opening and closing) using single channel recording in artificial planar lipid bilayers. I'm also interested in looking at in how these molecular events translate into calcium release dysfunction at the cellular level using calcium imaging in live cell systems, as well as how differential regulation and drug treatment affect these phenomena. My teaching interests originate from these studies, including cardiac and vascular physiology and pathophysiology, Ca2+ signalling, ion channel biophysics and drug interactions.
Publication
2023
- Thomas, N. L., Dart, C. and Helassa, N. 2023. Editorial: The role of calcium and calcium binding proteins in cell physiology and disease. Frontiers in Physiology 14, article number: 1228885. (10.3389/fphys.2023.1228885)
2022
- Prakash, O. et al. 2022. Calmodulin variant E140G associated with long QT syndrome impairs CaMKIIδ autophosphorylation and L-type calcium channel inactivation. Journal of Biological Chemistry 299(1), article number: 102777. (10.1016/j.jbc.2022.102777)
- Prakash, O. et al. 2022. CPVT-associated calmodulin variants N53I and A102V dysregulate calcium signalling via different mechanisms. Journal of Cell Science 135(2), article number: jcs258796. (10.1242/jcs.258796)
2021
- Seidel, M. et al. 2021. Identification of an amino-terminus determinant critical for ryanodine receptor/Ca2+ release channel function. Cardiovascular Research 117(3), pp. 780-791., article number: cvaa043. (10.1093/cvr/cvaa043)
2020
- Olubando, D. et al. 2020. Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationships. Journal of Human Genetics 65, pp. 531-539. (10.1038/s10038-020-0738-6)
2019
- Williams, A. and Thomas, N. L. 2019. Reconstitution of ion channels from intracellular membranes and bacteria not amenable to conventional electrophysiological techniques. In: Roberts, G. and Watts, A. eds. Encyclopedia of Biophysics. Berlin, Germany: Springer
2016
- Handhle, A., Ormonde, C. E., Thomas, N. L., Bralesford, C., Williams, A. J., Lai, F. A. and Zissimopoulos, S. 2016. Calsequestrin interacts directly with the cardiac ryanodine receptor luminal domain. Journal of Cell Science 129(21), pp. 3983-3988. (10.1242/jcs.191643)
- Bannister, M., Thomas, N. L., Markus, S., Mukherjee, S., Chloe, M., Kenneth, M. and George, C. H. 2016. Questioning flecainide's mechanism of action in the treatment of catecholaminergic polymorphic ventricular tachycardia [Letter]. The Journal of Physiology 594(21), pp. 6431-6432. (10.1113/JP272497)
- Mukherjee, S., Thomas, N. L. and Williams, A. J. 2016. Unambiguous observation of blocked states reveals altered, blocker-induced, cardiac ryanodine receptor gating. Scientific Reports 6, article number: 34452. (10.1038/srep34452)
- Bannister, M. L. et al. 2016. Effect of flecainide derivatives on sarcoplasmic reticulum calcium release suggests a lack of direct action on the cardiac ryanodine receptor. British Journal of Pharmacology 173(15), pp. 2446-2459. (10.1111/bph.13521)
2015
- Bannister, M. L. et al. 2015. The mechanism of flecainide action in CPVT does not involve a direct effect on RyR2. Circulation Research 116(8), pp. 1324-1335. (10.1161/CIRCRESAHA.116.305347)
- Seidel, M., Thomas, N. L., Williams, A. J., Lai, F. A. and Zissimopoulos, S. 2015. Dantrolene rescues aberrant N-terminus intersubunit interactions in mutant pro-arrhythmic cardiac ryanodine receptors. Cardiovascular Research 105(1), pp. 118-128. (10.1093/cvr/cvu240)
2014
- Mukherjee, S., Thomas, N. L. and Williams, A. J. 2014. Insights into the gating mechanism of the ryanodine-modified human cardiac Ca2+- release channel (ryanodine receptor 2). Molecular Pharmacology 86(3), pp. 318-329. (10.1124/mol.114.093757)
2013
- Zissimopoulos, S. et al. 2013. Amino-terminus oligomerization regulates cardiac ryanodine receptor function. Journal of Cell Science n/a (10.1242/jcs.133538)
- Euden, J., Mason, S., Viero, C., Thomas, N. L. and Williams, A. J. 2013. Investigations of the contribution of a putative glycine hinge to ryanodine receptor channel gating. Journal of Biological Chemistry 288(23), pp. 16671-16679. (10.1074/jbc.M113.465310)
- Zissimopoulos, S. et al. 2013. N-terminus oligomerization regulates the function of cardiac ryanodine receptors. Journal of Cell Science 126(21), pp. 5042-5051. (10.1242/jcs.133538)
2012
- Mukherjee, S., Thomas, N. L. and Williams, A. J. 2012. A mechanistic description of gating of the human cardiac ryanodine receptor in a regulated minimal environment. The Journal of General Physiology 140(2), pp. 139-158. (10.1085/jgp.201110706)
- Thomas, N. L. and Williams, A. J. 2012. Pharmacology of ryanodine receptors and Ca2+-induced Ca2+ release. Wiley Interdisciplinary Reviews: Membrane Transport and Signaling 1(4), pp. 383-397. (10.1002/wmts.34)
- Viero, C., Thomas, N. L., Euden, J., Mason, S. A., George, C. H. and Williams, A. J. 2012. Techniques and methodologies to study the ryanodine receptor at the molecular, subcellular and cellular level. In: Calcium Signaling. Advances in Experimental and Medical Biology Dordrecht: Springer, pp. 183-215., (10.1007/978-94-007-2888-2_8)
- Viero, C., Thomas, N. L., Euden, J., Mason, S., George, C. H. and Williams, A. J. 2012. Techniques and methodologies to study the ryanodine receptor at the molecular, subcellular and cellular level. In: Islam, M. S. ed. Calcium Signaling. Advances in Experimental Medicine and Biology Vol. 740. Dordrecht: Springer, pp. 183-215., (10.1007/978-94-007-2888-2_8)
2010
- Thomas, N. L., Maxwell, C., Mukherjee, S. and Williams, A. J. 2010. Ryanodine receptor mutations in arrhythmia: the continuing mystery of channel dysfunction. FEBS Letters 584(10), pp. 2153-2160. (10.1016/j.febslet.2010.01.057)
2009
- Zissimopoulos, S., Thomas, N. L., Jamaluddin, W. W. and Lai, F. A. 2009. FKBP12.6 binding of ryanodine receptors carrying mutations associated with arrhythmogenic cardiac disease. Biochemical Journal 419(2), pp. 273-278. (10.1042/BJ20082324)
2007
- George, C. H. et al. 2007. Alternative splicing of ryanodine receptors modulates cardiomyocyte Ca2+ signalling and susceptibility to apoptosis. Circulation Research 100(6), pp. 874-883. (10.1161/01.RES.0000260804.77807.cf)
- Fry, D., Jundi, H., Thomas, N. L., Lai, F. A. and George, C. H. 2007. Modulating intracellular Ca2+ signaling using recombinant fragments of the human cardiac ryanodine receptor (RyR2). Biophysical Journal, pp. 260A-260A.
- George, C. H., Jundi, H., Thomas, N. L., Fry, D. L. and Lai, F. A. 2007. Ryanodine receptors and ventricular arrhythmias: Emerging trends in mutations, mechanisms and therapies. Journal of Molecular and Cellular Cardiology 42(1), pp. 34-50. (10.1016/j.yjmcc.2006.08.115)
- George, C. H., Thomas, N. L., Williams, A. J. and Lai, F. A. 2007. Ryanodine receptor mutations in arrhythmias: advances in understanding the mechanisms of channel dysfunction. Biochemical Society Transactions 35(5), pp. 946-951. (10.1042/BST0350946)
2006
- George, C. H., Thomas, N. L. and Lai, F. A. 2006. Role of ryanodine receptor mutations in cardiac pathology: more questions than answers?. Biochemical Society Transactions 34(5), pp. 913-918. (10.1042/BST0340913)
2005
- George, C., Jundi, H., Walters, N., Thomas, N. L., West, R. R. and Lai, F. A. 2005. Arrhythmogenic mutation-linked defects in ryanodine receptor autoregulation reveal a novel mechanism of Ca2+ release channel dysfunction. Circulation Research 98(12), pp. 88-97. (10.1161/01.RES.0000199296.70534.7c)
- Thomas, N. L. 2005. Molecular mechanisms underlying cardiac ryanodine receptor dysfunction in sudden cardiac death.. PhD Thesis, Cardiff University.
- George, C. H., Thomas, N. L. and Lai, F. A. 2005. Ryanodine receptor dysfunction in arrhythmia and sudden cardiac death. Future Cardiology 1(4), pp. 531-541. (10.2217/14796678.1.4.531)
- Thomas, N. L., Lai, F. A. and George, C. H. 2005. Differential Ca2+ sensitivity of RyR2 mutations reveals distinct mechanisms of channel dysfunction in sudden cardiac death. Biochemical and Biophysical Research Communications 331(1), pp. 231-238. (10.1016/j.bbrc.2005.02.194)
2004
- Thomas, N. L., George, C. and Lai, F. A. 2004. Functional heterogeneity of ryanodine receptor mutations associated with sudden cardiac death. Cardiovascular Research 64(1), pp. 52-60. (10.1016/j.cardiores.2004.06.009)
- George, C., Jundi, H., Thomas, N. L., Scoote, M., Walters, N., Williams, A. J. and Lai, F. A. 2004. Ryanodine receptor regulation by intramolecular interaction between cytoplasmic and transmembrane domains. Molecular biology of the cell 15(6), pp. 2627-2638. (10.1091/mbc.E03-09-0688)
Articles
- Thomas, N. L., Dart, C. and Helassa, N. 2023. Editorial: The role of calcium and calcium binding proteins in cell physiology and disease. Frontiers in Physiology 14, article number: 1228885. (10.3389/fphys.2023.1228885)
- Prakash, O. et al. 2022. Calmodulin variant E140G associated with long QT syndrome impairs CaMKIIδ autophosphorylation and L-type calcium channel inactivation. Journal of Biological Chemistry 299(1), article number: 102777. (10.1016/j.jbc.2022.102777)
- Prakash, O. et al. 2022. CPVT-associated calmodulin variants N53I and A102V dysregulate calcium signalling via different mechanisms. Journal of Cell Science 135(2), article number: jcs258796. (10.1242/jcs.258796)
- Seidel, M. et al. 2021. Identification of an amino-terminus determinant critical for ryanodine receptor/Ca2+ release channel function. Cardiovascular Research 117(3), pp. 780-791., article number: cvaa043. (10.1093/cvr/cvaa043)
- Olubando, D. et al. 2020. Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationships. Journal of Human Genetics 65, pp. 531-539. (10.1038/s10038-020-0738-6)
- Handhle, A., Ormonde, C. E., Thomas, N. L., Bralesford, C., Williams, A. J., Lai, F. A. and Zissimopoulos, S. 2016. Calsequestrin interacts directly with the cardiac ryanodine receptor luminal domain. Journal of Cell Science 129(21), pp. 3983-3988. (10.1242/jcs.191643)
- Bannister, M., Thomas, N. L., Markus, S., Mukherjee, S., Chloe, M., Kenneth, M. and George, C. H. 2016. Questioning flecainide's mechanism of action in the treatment of catecholaminergic polymorphic ventricular tachycardia [Letter]. The Journal of Physiology 594(21), pp. 6431-6432. (10.1113/JP272497)
- Mukherjee, S., Thomas, N. L. and Williams, A. J. 2016. Unambiguous observation of blocked states reveals altered, blocker-induced, cardiac ryanodine receptor gating. Scientific Reports 6, article number: 34452. (10.1038/srep34452)
- Bannister, M. L. et al. 2016. Effect of flecainide derivatives on sarcoplasmic reticulum calcium release suggests a lack of direct action on the cardiac ryanodine receptor. British Journal of Pharmacology 173(15), pp. 2446-2459. (10.1111/bph.13521)
- Bannister, M. L. et al. 2015. The mechanism of flecainide action in CPVT does not involve a direct effect on RyR2. Circulation Research 116(8), pp. 1324-1335. (10.1161/CIRCRESAHA.116.305347)
- Seidel, M., Thomas, N. L., Williams, A. J., Lai, F. A. and Zissimopoulos, S. 2015. Dantrolene rescues aberrant N-terminus intersubunit interactions in mutant pro-arrhythmic cardiac ryanodine receptors. Cardiovascular Research 105(1), pp. 118-128. (10.1093/cvr/cvu240)
- Mukherjee, S., Thomas, N. L. and Williams, A. J. 2014. Insights into the gating mechanism of the ryanodine-modified human cardiac Ca2+- release channel (ryanodine receptor 2). Molecular Pharmacology 86(3), pp. 318-329. (10.1124/mol.114.093757)
- Zissimopoulos, S. et al. 2013. Amino-terminus oligomerization regulates cardiac ryanodine receptor function. Journal of Cell Science n/a (10.1242/jcs.133538)
- Euden, J., Mason, S., Viero, C., Thomas, N. L. and Williams, A. J. 2013. Investigations of the contribution of a putative glycine hinge to ryanodine receptor channel gating. Journal of Biological Chemistry 288(23), pp. 16671-16679. (10.1074/jbc.M113.465310)
- Zissimopoulos, S. et al. 2013. N-terminus oligomerization regulates the function of cardiac ryanodine receptors. Journal of Cell Science 126(21), pp. 5042-5051. (10.1242/jcs.133538)
- Mukherjee, S., Thomas, N. L. and Williams, A. J. 2012. A mechanistic description of gating of the human cardiac ryanodine receptor in a regulated minimal environment. The Journal of General Physiology 140(2), pp. 139-158. (10.1085/jgp.201110706)
- Thomas, N. L. and Williams, A. J. 2012. Pharmacology of ryanodine receptors and Ca2+-induced Ca2+ release. Wiley Interdisciplinary Reviews: Membrane Transport and Signaling 1(4), pp. 383-397. (10.1002/wmts.34)
- Thomas, N. L., Maxwell, C., Mukherjee, S. and Williams, A. J. 2010. Ryanodine receptor mutations in arrhythmia: the continuing mystery of channel dysfunction. FEBS Letters 584(10), pp. 2153-2160. (10.1016/j.febslet.2010.01.057)
- Zissimopoulos, S., Thomas, N. L., Jamaluddin, W. W. and Lai, F. A. 2009. FKBP12.6 binding of ryanodine receptors carrying mutations associated with arrhythmogenic cardiac disease. Biochemical Journal 419(2), pp. 273-278. (10.1042/BJ20082324)
- George, C. H. et al. 2007. Alternative splicing of ryanodine receptors modulates cardiomyocyte Ca2+ signalling and susceptibility to apoptosis. Circulation Research 100(6), pp. 874-883. (10.1161/01.RES.0000260804.77807.cf)
- Fry, D., Jundi, H., Thomas, N. L., Lai, F. A. and George, C. H. 2007. Modulating intracellular Ca2+ signaling using recombinant fragments of the human cardiac ryanodine receptor (RyR2). Biophysical Journal, pp. 260A-260A.
- George, C. H., Jundi, H., Thomas, N. L., Fry, D. L. and Lai, F. A. 2007. Ryanodine receptors and ventricular arrhythmias: Emerging trends in mutations, mechanisms and therapies. Journal of Molecular and Cellular Cardiology 42(1), pp. 34-50. (10.1016/j.yjmcc.2006.08.115)
- George, C. H., Thomas, N. L., Williams, A. J. and Lai, F. A. 2007. Ryanodine receptor mutations in arrhythmias: advances in understanding the mechanisms of channel dysfunction. Biochemical Society Transactions 35(5), pp. 946-951. (10.1042/BST0350946)
- George, C. H., Thomas, N. L. and Lai, F. A. 2006. Role of ryanodine receptor mutations in cardiac pathology: more questions than answers?. Biochemical Society Transactions 34(5), pp. 913-918. (10.1042/BST0340913)
- George, C., Jundi, H., Walters, N., Thomas, N. L., West, R. R. and Lai, F. A. 2005. Arrhythmogenic mutation-linked defects in ryanodine receptor autoregulation reveal a novel mechanism of Ca2+ release channel dysfunction. Circulation Research 98(12), pp. 88-97. (10.1161/01.RES.0000199296.70534.7c)
- George, C. H., Thomas, N. L. and Lai, F. A. 2005. Ryanodine receptor dysfunction in arrhythmia and sudden cardiac death. Future Cardiology 1(4), pp. 531-541. (10.2217/14796678.1.4.531)
- Thomas, N. L., Lai, F. A. and George, C. H. 2005. Differential Ca2+ sensitivity of RyR2 mutations reveals distinct mechanisms of channel dysfunction in sudden cardiac death. Biochemical and Biophysical Research Communications 331(1), pp. 231-238. (10.1016/j.bbrc.2005.02.194)
- Thomas, N. L., George, C. and Lai, F. A. 2004. Functional heterogeneity of ryanodine receptor mutations associated with sudden cardiac death. Cardiovascular Research 64(1), pp. 52-60. (10.1016/j.cardiores.2004.06.009)
- George, C., Jundi, H., Thomas, N. L., Scoote, M., Walters, N., Williams, A. J. and Lai, F. A. 2004. Ryanodine receptor regulation by intramolecular interaction between cytoplasmic and transmembrane domains. Molecular biology of the cell 15(6), pp. 2627-2638. (10.1091/mbc.E03-09-0688)
Book sections
- Williams, A. and Thomas, N. L. 2019. Reconstitution of ion channels from intracellular membranes and bacteria not amenable to conventional electrophysiological techniques. In: Roberts, G. and Watts, A. eds. Encyclopedia of Biophysics. Berlin, Germany: Springer
- Viero, C., Thomas, N. L., Euden, J., Mason, S. A., George, C. H. and Williams, A. J. 2012. Techniques and methodologies to study the ryanodine receptor at the molecular, subcellular and cellular level. In: Calcium Signaling. Advances in Experimental and Medical Biology Dordrecht: Springer, pp. 183-215., (10.1007/978-94-007-2888-2_8)
- Viero, C., Thomas, N. L., Euden, J., Mason, S., George, C. H. and Williams, A. J. 2012. Techniques and methodologies to study the ryanodine receptor at the molecular, subcellular and cellular level. In: Islam, M. S. ed. Calcium Signaling. Advances in Experimental Medicine and Biology Vol. 740. Dordrecht: Springer, pp. 183-215., (10.1007/978-94-007-2888-2_8)
Thesis
- Thomas, N. L. 2005. Molecular mechanisms underlying cardiac ryanodine receptor dysfunction in sudden cardiac death.. PhD Thesis, Cardiff University.
- Seidel, M. et al. 2021. Identification of an amino-terminus determinant critical for ryanodine receptor/Ca2+ release channel function. Cardiovascular Research 117(3), pp. 780-791., article number: cvaa043. (10.1093/cvr/cvaa043)
Research
The cardiac ryanodine receptor is responsible for the release of stored intracellular Ca2+ in response to activating signals at the cell membrane. This is a pivotal event in cardiac excitation-coupling: the process which transduces electrical activation of the heart to physical contraction during each heartbeat. Genetic mutation or dysregulation of this massive ion channel can result in cardiac arrhythmia, which can often be fatal. My research uses molecular techniques to investigate the mechanisms by which this channel dysfunction occurs. We use mutagenesis and recombinant expression techniques to re-create dysfunctional channel proteins, so that we can monitor any Ca2+ release changes in human cell systems. We can also look in great detail at how channel opening and closing patterns are affects (i.e. gating mechanisms) using single channel recoding in artificial planar lipid bilayers. This kind of unique information about channel function will give insight into mutational heterogeneity of dysfunction, which could affect the efficacy of future therapies. Read more about my British Heart Foundation projects here.
Teaching
MPharm:
- PH1124 Human Body Systems: lecturer and workshop lead for cardiovascular physiology
- PH2113 Diseases and Drugs I: lecturer and workshop lead for cardiovascular pharmacology
- PH4116 Pharmacy Research Project: research project supervisor
- Contribute to OSCE marking for MPharm years 1-4
- Personal tutor
MSc Cancer Biology & Therapeutics:
- PHT801 Cellular & Molecular Biology of Cancer: lecturer for Ca2+ signalling and ion channel involvement in cancer
- I have supervised projects on PHT805 (non-lab research) and contributed to poster marking
Biography
- Lecturer, school of Pharmacy and Pharmaceutical Sciences, 2018 – present
- Research Fellow and co-applicant on BHF Programme grant [Predicting anti-arrhythmic drug efficacy from the divergent molecular basis of RyR2 dysfunction in genetic arrhythmia syndromes (£995,228)], Swansea University Medical School, 2016-2018
- Senior research associate in the group of Prof Alan Williams, Wales Heart Institute, UHW, Cardiff University School of Medicine 2007 -2016.
During this time I was awarded several BHF research grants as principal investigator [Functional assessment of cardiac ryanodine receptor Ca2+ release channel populations: a direct demonstration of coupled gating? (Project grant, 2016-2019, £223,056) and Resolving the contribution of luminal and cytosolic Ca2+ in the dysfunction of sudden cardiac death-linked mutant RyR2 channels (Studentship, 2014- 2017, (£102,393) and co-investigator [Uncovering the mechanisms involved in the block of Ca2+ release from the cardiac sarcoplasmic reticulum by flecainide (Project grant, 2011-2013,£274,862)], supervised 4 PhD students to completion as well as the work of PDRAs.
- Research associate in the group of Prof Tony Lai, Wales Heart Institute, UHW, Cardiff University School of Medicine, 2006-2007
- PhD, Cardiac calcium signalling, Cardiff University, 2005
- BSc (hons) Genetics, Cardiff University, 2001
Engagement
Having been fortunate enough to receive the support of the BHF throughout my career I have been involved in a number of engagement opportunities with fundraisers and members of the general public to raise awareness of the research they fund, including: school visits, presentations at the National Eisteddfod, lab tours, radio and television interviews.
Supervisions
I am an accomplished supervisor of post-graduate students and am interested in all projects relating to the function of ryanodine receptors in any setting.
Current Supervision:
Aisha Gendra (2021-) Title: "Investigation of the effects of variant calmodulin on RyR2 in generating arrhythmogenic Ca2+ release: resolving the contribution of phosphorylation"
Tessa Harris (2021- ) Title: “Investigation of cardiomyopathy linked RyR2 mutation within the clamp region and its effects on channel function and arrangement”
Contact Details
ThomasNL1@cardiff.ac.uk
+44 29208 70636
Redwood Building, Room 1.85, King Edward VII Avenue, Cardiff, CF10 3NB
+44 29208 70636
Redwood Building, Room 1.85, King Edward VII Avenue, Cardiff, CF10 3NB
