Background: BSc (Glasgow), PhD (Glasgow), Postdoctoral research at Glasgow. Lecturer (1996-2000); Senior Lecturer (2000-2006); Reader in Cellular Physiology (2006-2011); Cardiovascular Group Leader, Institute of Membrane & Systems Biology (2005-2011); Research Director, School of Biomedical Sciences (2011-2014); Professor of Cell Physiology (2011-present)
Contact: Garstang 7.53c, +44(0) 113 34 32912,
Calcium dysregulation in skeletal and cardiac muscle diseases
My research addresses the molecular and cellular events that underlie excitation-contraction coupling in both cardiac and skeletal muscle and how these processes are modified by physiological adaptations or disease. My doctoral and early post-doctoral work was carried out at the University of Glasgow. This involved the characterisation of novel Ca-sensitising drugs, which act directly on the myofilaments to increase force production. A key finding from this early work was that the endogenous amino acid taurine modulates both sarcoplasmic reticulum function and myofilament Ca sensitivity. In 1996 I moved to the University of Leeds where I continued to work on the myocardium, but also developed new research themes addressing skeletal muscle fatigue and malignant hyperthermia. With funding from the Wellcome Trust, the British Heart Foundation and the Medical Research Council I established a bio-imaging facility (2 spectrophometer based systems and 3 confocal microscopes and an Ionscope ion conductance microscope) and live cell imaging now underpins much of my work. Current projects in the cardiac field include studies that address remodelling of local Ca signalling in heart failure, the role of the Golgi apparatus as a Ca signalling organelle and novel mechanisms underlying arrhythmias.
Roles: I am currently Professor of Cellular Physiology within the School of Biomedical Sciences, Faculty of Biological Sciences.
Selected research highlights:
2001- First demonstration that ATP depletion inhibits SR Ca sparks in cardiac cells and that re-introduction causes a synchronised burst of Ca release, which can act as a pro-arrhythmic substrate (1).
2002- First demonstration that the Na/Ca exchanger is localised in the t-tubules in cardiac cells, with consequent effects on cell function (2).
2005- First description of prolonged Ca release events originating at the nuclear poles in adult cardiac myocytes. Highlighted on front cover of Circulation Research (3)
2006- Demonstration that the RyR2 peptide DPc10 can mimic the disease phenotype associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) by disrupting interaction of specific RyR2 channel domains (4)
2010- First evidence that store-operated Ca entry contributes to malignant hyperthermia in humans (5). This work was the outcome of a 4 year collaborative study with clinicians based at the national screening centre for malignant hyperthermia, St James’s University Hospital, Leeds.
2010- First description of a novel mechanism by which the drug flecainide prevents CPVT arrhythmias by acting directly on the cardiac ryanodine receptor to alter Ca spark mass (6).
2012-First demonstration that sub-lethal concentrations of carbon monoxide cause cardiac arrhythmias by activating the late sodium current, secondary to nitrosylation of Nav1.5 (7). It addition, it was shown that the drug ranolazine, a selective inhibitor of the late sodium current, blocks the pro-arrhythmic effects of CO in both cells and animals.
2014- Release of xySpark, an image analysis program written in Java and distributed as a plugin for ImageJ, which allows automatic analysis of Ca sparks in 2D image stacks. (8)
2015- First evidence that the Golgi apparatus operates as a Ca signaling organelle that is functionally distinct from the SR in adult cardiac myocytes (9)
1. Yang Z and Steele DS Effects of cytosolic ATP on Ca sparks and SR Ca content in permeabilized cardiac myocytes. Circ.Res. 89:526-533, 2001.
2. Yang Z et al Na/Ca exchange activity is localized in the T-tubules of rat ventricular myocytes. Circ.Res. 91:315-322, 2002.
3. Yang Z and Steele DS. Characteristics of prolonged Ca release events associated with the nuclei in adult cardiac myocytes. Circ.Res. 96:82-90, 2005.
4. Yang Z et al. The RyR2 central domain peptide DPc10 lowers the threshold for spontaneous Ca release in permeabilized cardiomyocytes. Cardiovasc.Res. 70:475-485, 2006.
5. Duke AM et al. Store operated Ca entry in malignant hyperthermia-susceptible human skeletal muscle. J.Biol.Chem., 285:25645-53, 2010
6. Hilliard FA et al. Flecainide inhibits arrhythmogenic Ca waves by open state block of ryanodine receptor Ca release channels and reduction of Ca spark mass. J.Mol.Cell Cardiol. 48:293-301, 2010.
7. Dallas,M.L et al., Carbon monoxide induces cardiac arrhythmia via induction of the late Na+ Current. Am J Respir Crit Care Med 186:7 648-656, 2012.
8. Steele, E.M. & Steele D.S. Automated detection and analysis of Ca sparks in x-y image stacks using a thresholding algorithm implemented within the open-source image analysis platform, ImageJ Biophysical Journal, 106: 556-576, 2014 See web page for program download: www.fbs.leeds.ac.uk/staff/steele/xySpark/
9. Yang, Z. et al., The Golgi apparatus is a functionally distinct Ca store regulated by the PKA and Epac branches of the β1-adrenergic signaling pathway Science Signaling 8: 1-11, 2015.
BIOL5112M/5312M - Bioimaging
BMSC1103 - Basic Laboratory and Scientific Skills
BMSC1213 - Basic Laboratory and Scientific Skills 2
BMSC2117/3302 - Cardio-respiratory Phys & Med Phar
BMSC2119 - Experimental Skills
BMSC2229 - Experimental Skills in Medical Sciences
BMSC2232 - Topics in Physiology
BMSC3138 - Cellular Cardiology
BMSC3233/35/36 - Advanced Topics II
BMSC3301 - Research Project in Biomedical Sciences
SPSC1221 - Cardio-respiratory Physiology and Exercise
Centre membership: The Multidisciplinary Cardiovascular Research Centre (MCRC)
Dr Hannah Marie Kirton (Research Fellow)
Dr Kathleen Wright (Senior Scientific Officer in Cardiovascular Science)
Providing laboratory research support for multiple PIs, training new staff and laboratory/office management
Dr Zhaokang Yang (Research Fellow)
Al-Owais MM, Hettiarachchi NT, Kirton HM, Hardy ME, Boyle JP, Scragg JL, Steele DS, Peers C A key role for peroxynitrite-mediated inhibition of cardiac ERG (Kv11.1) K(+) channels in carbon monoxide-induced proarrhythmic early afterdepolarizations. FASEB J -, 2017
Yang Z, Kirton HM, Al-Owais M, Thireau J, Richard S, Peers C, Steele DS Epac2-Rap1 Signaling Regulates Reactive Oxygen Species Production and Susceptibility to Cardiac Arrhythmias. Antioxid Redox Signal 27 117-132, 2017
Merritt A, Booms P, Shaw MA, Miller DM, Daly C, Bilmen JG, Stowell KM, Allen PD, Steele DS, Hopkins PM Assessing the pathogenicity of RYR1 variants in malignant hyperthermia British Journal of Anaesthesia 118 533-543, 2017
Yang Z, Kirton HM, Al-Owais M, Peers C, Steele DS Epac2-Rap1 Signaling Influences Reactive Oxygen Species Production and Susceptibility to Cardiac Arrhythmias, 2017
Venturi E, Witschas K, Lotteau SJ, Steer E, Steele DS, Calaghan SC, Sitsapesan R Simvastatin Activates Single Skeletal RyR1 Channels but Exerts More Complex Regulation of the Cardiac Isoform, RyR2, 2016
Kirton HM, Yang Z, Steele DS Conditions that Promote Golgi Ca2+ Release Facilitate Trafficking of VEGFR-1 to the Surface Membrane in Rat Ventricular Myocytes, 2016
Miller L, Steele DS, Greensmith DJ, Hart G, Dobrzynski H, Boyett MR STIMULATION OF CALCIUM SPARKS IN BOTH SINO - ATRIAL NODE AND VENTRICULAR MYOCYTES, 2015
Yang Z, Kirton HM, MacDougall DA, Boyle JP, Deuchars J, Frater B, Ponnambalam S, Hardy ME, White E, Calaghan SC, Peers C, Steele DS The Golgi apparatus is a functionally distinct Ca2+ store regulated by the PKA and Epac branches of theβ1-adrenergic signaling pathway. Sci Signal 8 ra101-, 2015
Fowler ED, Benoist D, Drinkhill MJ, Stones R, Helmes M, Wüst RCI, Stienen GJM, Steele DS, White E Decreased creatine kinase is linked to diastolic dysfunction in rats with right heart failure induced by pulmonary artery hypertension. J Mol Cell Cardiol 86 1-8, 2015
Peers C, Boyle JP, Scragg JL, Dallas ML, Al-Owais MM, Hettiarachichi NT, Elies J, Johnson E, Gamper N, Steele DS Diverse mechanisms underlying the regulation of ion channels by carbon monoxide. Br J Pharmacol 172 1546-1556, 2015
Elies J, Dallas M, Boyle JP, Scragg JL, Duke A, Steele DS, Peers C Inhibition of the cardiac Na⁺ channel Nav1.5 by carbon monoxide. Journal of Biological Chemistry 289 16421-16429, 2014
Steele E, Steele DS Automated detection and analysis of Ca(2+) sparks in x-y image stacks using a thresholding algorithm implemented within the open-source image analysis platform ImageJ. Biophysical Journal 106 566-576, 2014
Steele DS, Hwang H-S, Knollmann BC Triple mode of action of flecainide in catecholaminergic polymorphic ventricular tachycardia. Cardiovasc Res 98 326-327, 2013
Dallas ML, Yang Z, Boyle JP, Boycott HE, Scragg JL, Milligan CJ, Elies J, Duke A, Thireau J, Reboul C, Richard S, Bernus O, Steele DS, Peers C Carbon Monoxide Induces Cardiac Arrhythmia via Induction of the Late Na+ Current. Am J Respir Crit Care Med 186 648-656, 2012
Benoist D, Stones R, Drinkhill MJ, Benson AP, Yang Z, Cassan C, Gilbert SH, Saint DA, Cazorla O, Steele DS, Bernus O, White E Cardiac arrhythmia mechanisms in rats with heart failure induced by pulmonary hypertension. Am J Physiol Heart Circ Physiol 302 H2381-H2395, 2012
Calaghan S, Steele D, Weiss JN Local signalling in myocytes Journal of Molecular and Cellular Cardiology 52 295-297, 2012
Watanabe H, Steele DS, Knollmann BC Mechanism of Antiarrhythmic Effects of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia CIRC RES 109 712-713, 2011
Duke AM, Hopkins PM, Calaghan SC, Halsall JP, Steele DS Store-operated Ca2+ Entry in Malignant Hyperthermia-susceptible Human Skeletal Muscle J BIOL CHEM 285 25645-25653, 2010
Duncan DJ, Yang ZK, Hopkins PM, Steele DS, Harrison SM TNF-alpha and IL-1 beta increase Ca2+ leak from the sarcoplasmic reticulum and susceptibility to arrhythmia in rat ventricular myocytes CELL CALCIUM 47 378-386, 2010
Hilliard FA, Steele DS, Laver D, Yang ZK, Le Marchand SJ, Chopra N, Piston DW, Huke S, Knollmann BC Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass J MOL CELL CARDIOL 48 293-301, 2010
Duncan DJ, Yang Z, Hopkins PM, Steele DS, Harrison SM TNF-α and IL-1β increase Ca<sup>2+</sup>leak from the sarcoplasmic reticulum and susceptibility to arrhythmia in rat ventricular myocytes Cell Calcium 47 378-386, 2010
Duke AM, Hopkins PM, Halsal JP, Steele DS Properties of Store Operated Ca2+ Entry in Malignant Hyperthermia Susceptible Human Skeletal Muscle Fibres BIOPHYSICAL JOURNAL 98 711A-712A, 2010
Carpenter D, Ismail A, Robinson RL, Ringrose C, Booms P, Iles DE, Halsall PJ, Steele D, Shaw MA, Hopkins PM A RYR1 MUTATION ASSOCIATED WITH RECESSIVE CONGENITAL MYOPATHY AND DOMINANT MALIGNANT HYPERTHERMIA IN ASIAN FAMILIES MUSCLE NERVE 40 633-639, 2009
Carpenter D, Robinson RL, Quinnell RJ, Ringrose C, Hogg M, Casson F, Booms P, Iles DE, Halsall PJ, Steele DS, Shaw MA, Hopkins PM Genetic variation in RYR1 and malignant hyperthermia phenotypes BRIT J ANAESTH 103 538-548, 2009
Robinson RL, Carpenter D, Halsall PJ, Iles DE, Booms P, Steele D, Hopkins PM, Shaw MA Epigenetic allele silencing and variable penetrance of malignant hyperthermia susceptibility BRIT J ANAESTH 103 220-225, 2009
Pickering JD, White E, Duke AM, Steele DS DHPR activation underlies SR Ca2+ release induced by osmotic stress in isolated rat skeletal muscle fibers J GEN PHYSIOL 133 511-524, 2009
Amer MS, Li J, O'Regan DJ, Steele DS, Porter KE, Sivaprasadarao A, Beech DJ Translocon closure to Ca2+ leak in proliferating vascular smooth muscle cells AM J PHYSIOL-HEART C 296 H910-H916, 2009
Carpenter D, Morris A, Robinson RL, Booms P, Iles D, Halsall PJ, Steele D, Hopkins PM, Shaw MA Analysis of RYR1 Haplotype Profile in Patients with Malignant Hyperthermia ANN HUM GENET 73 10-18, 2009
Duke AM, Steele DS The presence of a functional t-tubule network increases the sensitivity of RyR1 to agonists in skinned rat skeletal muscle fibres CELL CALCIUM 44 411-421, 2008
Duke AM, Steele DS The presence of a functional t-tubule network increases the sensitivity of RyR1 to agonists in skinned rat skeletal muscle fibres. Cell Calcium 44 411-421, 2008
George CH, Rogers SA, Bertrand BMA, Tunwell REA, Thomas NL, Steele DS, Cox EV, Pepper C, Hazeel CJ, Claycomb WC, Lai FA Alternative splicing of ryanodine receptors modulates cardiomyocyte Ca2+ signaling and susceptibility to apoptosis CIRC RES 100 874-883, 2007
Steele DS, Duke AM Defective Mg2+ regulation of RyR1 as a causal factor in malignant hyperthermia ARCH BIOCHEM BIOPHYS 458 57-64, 2007
Duke AM, Hopkins PM, Halsall PJ, Steele DS Mg2+ dependence of Ca2+ release from the sarcoplasmic reticulum induced by sevoflurane or halothane in skeletal muscle from humans susceptible to malignant hyperthermia BRIT J ANAESTH 97 320-328, 2006
Yang ZK, Ikemoto N, Lamb GD, Steele DS The RyR2 central domain peptide DPc10 lowers the threshold for spontaneous Ca2+ release in permeabilized cardiomyocytes CARDIOVASC RES 70 475-485, 2006
Yang ZK, Steele DS Characteristics of prolonged Ca2+ release events associated with the nuclei in adult cardiac myocytes CIRC RES 96 82-90, 2005
Yang Z, Harrison SM, Steele DS ATP-dependent effects of halothane on SR Ca2+ regulation in permeabilized atrial myocytes. Cardiovasc Res 65 167-176, 2005
Duke AM, Hopkins PM, Halsal JP, Steele DS Mg2+ dependence of halothane-induced Ca2+ release from the sarcoplasmic reticulum in skeletal muscle from humans susceptible to malignant hyperthermia. Anesthesiology 101 1339-1346, 2004
Duke AM, Hopkins PM, Steele DS Mg2+ dependence of halothane-induced Ca2+ release from the sarcoplasmic reticulum in rat skeletal muscle. J Physiol 551 447-454, 2003
Duke AM, Hopkins PM, Steele DS Effects of Mg2+ and SR luminal Ca2+ on caffeine-induced Ca2+ release in skeletal muscle from humans susceptible to malignant hyperthermia J PHYSIOL-LONDON 544 85-95, 2002
Yang Z, Pascarel C, Steele DS, Kornukai K, Brette F, Orchard CH Na+-Ca2+ exchange activity is localized in the T-tubules of rat ventricular myocytes CIRC RES 91 315-322, 2002
Yang Z, Pascarel C, Steele DS, Komukai K, Brette FP, Orchard CH Na<sup>+</sup>-Ca<sup>2+</sup>Exchange Activity Is Localized in the T-Tubules of Rat Ventricular Myocytes Circulation Research 91 315-322, 2002
Yang ZK, Steele DS Effects of phosphocreatine on SR Ca2+ regulation in isolated saponin-permeabilized rat cardiac myocytes J PHYSIOL-LONDON 539 767-777, 2002
Yang Z, Steele DS Effects of phosphocreatine on SR Ca2+ regulation in isolated saponin-permeabilized rat cardiac myocytes. Journal of Physiology 539 767-778, 2002
Yang ZK, Steele DS Effects of cytosolic ATP on Ca2+ sparks and SR Ca2+ content in permeabilized cardiac myocytes CIRC RES 89 526-533, 2001
Yang Z, Steele DS Effects of Cytosolic ATP on Ca<sup>2+</sup>Sparks and SR Ca<sup>2+</sup>Content in Permeabilized Cardiac Myocytes Circulation Research 89 526-533, 2001
Duke AM, Steele DS Interdependent effects of inorganic phosphate and creatine phosphate on sarcoplasmic reticulum Ca2+ regulation in mechanically skinned rat skeletal muscle J PHYSIOL-LONDON 531 729-742, 2001
Darnley GM, Duke AM, Steele DS, MacFarlane NG Effects of reactive oxygen species on aspects of excitation-contraction coupling in chemically skinned rabbit diaphragm muscle fibres EXP PHYSIOL 86 161-168, 2001
Duke AM, Steele DS Mechanisms of reduced SR Ca2+ release induced by inorganic phosphate in rat skeletal muscle fibers American Journal of Physiology: Cell Physiology 281 C418-C429, 2001
Yang ZK, Steele DS Effects of cytosolic ATP on spontaneous and triggered Ca2+-induced Ca2+ release in permeabilised rat ventricular myocytes J PHYSIOL-LONDON 523 29-44, 2000
Duke AM, Steele DS Characteristics of phosphate-induced Ca2+ efflux from the SR in mechanically skinned rat skeletal muscle fibers American Journal of Physiology: Cell Physiology 278 C126-C135, 2000
Duke AM, Steele DS Mechanisms of Ca2+ release induced by inorganic phosphate in mechanically skinned rat skeletal muscle fibres American Journal of Physiology 278 1444-1153, 2000
Steele DS Effects of creatine phosphate on Ca2+ regulation by the sarcoplasmic reticulum in mechanically skinned rat skeletal muscle fibres Journal of Physiology 517.2 447-458, 1999
Duke AM, Steele DS Effects of caffeine and adenine nucleotides on Ca2+ release by the sarcoplasmic reticulum in saponin-permeabilized frog skeletal muscle fibres J PHYSIOL-LONDON 513 43-53, 1998
Duke AM, Steele DS Effects of phosphocreatine on Ca2+ regulation by the sarcoplasmic reticulum in isolated mechanically skinned rat skeletal muscle fibres J PHYSIOL-LONDON 509P 45P-45P, 1998
Duke AM, Steele DS Effects of cyclopiazonic acid on Ca2+ regulation by the sarcoplasmic reticulum in saponin-permeabilized skeletal muscle fibres PFLUG ARCH EUR J PHY 436 104-111, 1998
Orchard CH, Smith GL, Steele DS Effects of cytosolic Ca2+ on the Ca2+ content of the sarcoplasmic reticulum in saponin-permeabilized rat ventricular trabeculae PFLUG ARCH EUR J PHY 435 555-563, 1998
Orchard CH, Smith GL, Steele DS Effects of cytosolic [Ca2+] on the Ca2+ content of the sarcoplasmic reticulum in saponin permeabilized rat ventricular trabeculae Pflugers Archiv: European Journal of Physiology 435 555-563, 1998
Steele DS Measurement of SR Ca2+ content of in the presence of caffeine in permeabilized rat cardiac trabeculae Unknown Journal - Requested journal to be added to ULPD 437 139-148, 1998
Steele DS Effects of cyclopiazonic acid on Ca2+ regulation by the sarcoplasmic reticulum in saponin permeabilized skeletal muscle fibres Unknown Journal - Requested journal to be added to ULPD 436 112-116, 1998
Steele DS, Duke AM Effects of cyclopiazonic acid on caffeine-induced Ca2+ release in isolated saponin skinned frog skeletal muscle fibres J PHYSIOL-LONDON 501P P144-P144, 1997
Neary P, Steele DS, Orchard CH, Smith GL Measurement of Ca2+ release from saponin-permeabilized single cardiac myocytes J PHYSIOL-LONDON 497P P7-P7, 1996
Steele DS, McAinsh AM, Smith GL Comparative effects of inorganic phosphate and oxalate on the uptake and release of Ca2+ by the sarcoplasmic reticulum in saponin skinned rat cardiac muscle Journal of Physiology 490.3 565-576, 1996
Steele DS Effects of creatine phosphate and inorganic phosphate on the sarcoplasmic reticulum of saponin-treated rat heart Journal of Physiology 483.1 155-166, 1995
MACFARLANE NG, MILLER DJ, SMITH GL, STEELE DS EFFECTS OF OXIDANTS ON THE SARCOPLASMIC-RETICULUM OF SAPONIN-TREATED RAT VENTRICULAR TRABECULAE CARDIOVASC RES 28 1647-1652, 1994
SMITH GL, STEELE DS EFFECTS OF PH AND INORGANIC-PHOSPHATE ON RIGOR TENSION IN CHEMICALLY SKINNED RAT VENTRICULAR TRABECULAE J PHYSIOL-LONDON 478 505-512, 1994
STEELE DS, SMITH GL EFFECTS OF 2,3-BUTANEDIONE MONOXIME ON SARCOPLASMIC-RETICULUM OF SAPONIN-TREATED RAT CARDIAC-MUSCLE AM J PHYSIOL 265 H1493-H1500, 1993
Steele DS 2,3-butanedione methoxime induces Ca2+-release from the sarcoplasmic reticulum in saponin-treated rat ventricular trabeculae Am. J. Physiol 265 H1493-H1500, 1993
SMITH GL, STEELE DS INORGANIC-PHOSPHATE DECREASES THE CA2+ CONTENT OF THE SARCOPLASMIC-RETICULUM IN SAPONIN-TREATED RAT CARDIAC TRABECULAE J PHYSIOL-LONDON 458 457-473, 1992
STEELE DS, MILLER DJ EFFECTS OF CAMP AND FORSKOLIN ON CAFFEINE-INDUCED CONTRACTURES AND MYOFILAMENT CA-SENSITIVITY IN SAPONIN-TREATED RAT VENTRICULAR TRABECULAE J MUSCLE RES CELL M 13 146-152, 1992
Steele DS, Smith GL Intracellular effects of taurine: studies on skinned cardiac preparations. Adv Exp Med Biol 315 163-172, 1992
Steele DS The effects of caffeine and Ca2+ on rigor force in Triton-treated rat ventricular trabeculae. Pflugers Arch 412 343-349, 1992
Smith GL, Steele DS, Crichton CA Effects of inorganic phosphate on calcium and tension oscillations in saponin-treated rat cardiac muscle. Adv Exp Med Biol 311 387-388, 1992
MILLER DJ, STEELE DS THE CALCIUM SENSITIZING EFFECTS OF ORG30029 IN SAPONIN-SKINNED OR TRITON-SKINNED RAT CARDIAC-MUSCLE BRIT J PHARMACOL 100 843-849, 1990
STEELE DS, SMITH GL, MILLER DJ THE EFFECTS OF TAURINE ON CA-2+ UPTAKE BY THE SARCOPLASMIC-RETICULUM AND CA-2+ SENSITIVITY OF CHEMICALLY SKINNED RAT-HEART J PHYSIOL-LONDON 422 499-511, 1990