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)
Supporting laboratory research development, training and management in the department of Cardiovascular Sciences
Dr Zhaokang Yang (Research Fellow)