Professor Michael Shattock BSc PhD FESC
Professor of Cellular Cardiology
The Rayne Institute
4th Floor, Lambeth Wing
St Thomas' Hospital
Lambeth Palace Rd
London SE1 7EH
Michael Shattock graduated from the University of London (Queen Mary College) in 1979 with a degree in Comparative Physiology. He then completed a PhD under the guidance of Professors David Hearse and Christopher Fry at St Thomas’ Hospital focussing on the effects of moderate hypothermia on cellular Ca handling. On completion of his PhD in 1984 he moved to the University of California where he spent 4 years studying cardiac excitation-contraction coupling in the laboratory of Dr Donald Bers. During this time, one series of studies explained the cellular basis of the well-known, but previously mysterious, negative force-frequency response seen in rat myocardium. For this work he was awarded the Young Investigator Award at the 1989 World Congress of the International Society for Heart Research.
In 1988 he returned to St Thomas’ and in 1990, was awarded a 10-year Basic Science Lectureship/Senior Lectureship. He has held various academic positions within both United Medical & Dental School and King’s College London and was made Professor of Cellular Cardiology in 2003.
Michael Shattock is an elected Fellow of the European Society of Cardiology (FESC) and of the American Heart Association (FAHA). He is currently a Nucleus Member of the European Society of Cardiology’s newly formed Council for Basic Cardiovascular Science and has previously served as Chairman of the ESC’s Working Group on Cellular Biology (2002-2004). He is a Consulting Editor for Cardiovascular Research and Basic Research in Cardiology, and serves on the Editorial Boards of Journal of Molecular and Cellular Cardiology, Journal of Cardiovascular Pharmacology and Current Cardiology Reviews.
The Cardiac Physiology Research Group is a medium-sized multi-disciplinary team of 10 researchers including physiologists, cell biologists, protein biochemists, cardiologists and cardiac surgeons.
The groups research interests involve the application of fundamental physiological and molecular techniques to investigate the response of the myocardium to the stresses of ischaemia, reperfusion and hypertrophy. Their research programme focuses on how the expression, structure, activity, and location of key ion translocating proteins in subcellular as well as sarcolemmal membranes may influence the outcome of these stresses. Current research projects include:
(a) Free radicals, oxidant stress and ion translocators: (P Eaton and J Brennan: (Cardiology))
In the 1980’s, the St Thomas’ group was instrumental in raising awareness of the role of free radicals in myocardial ischemia/reperfusion injury. In this context, the Cardiac Physiology Research Group showed, using a variety of electrophysiological techniques, that ion translocating proteins can be both positively and negatively regulated by thiol oxidation. Specifically, the Na/K ATPase was shown to be exquisitely regulated by changes in cellular redox state. Recently, we have shown for the first time that such protein oxidative modifications actually occur in cardiac ischaemia and reperfusion and have developed novel methods to detect, purify and identify such thiol-modified proteins.
Tissue sections showing heart cells that have been modified as a result of free radical production during ischaemia and reperfusion. Thiol modified proteins are shown in green.
(b) Regulation of the Na/K pump by phospholemman: (W Fuller, J Bell and R Berry)
Our work on the effects of free radicals on the Na/K ATPase led us to a particularly exciting discovery. In the heart, regulation of the Na/K pump by direct phosphorylation is controversial. We have recently shown, however, that the α 1 isoform can be stimulated by PKA while the α 2 cannot. This stimulation involves the indirect phosphorylation of a previously unidentified accessory protein. We have identified this accessory protein as phospholemman (PLM). We propose that PLM regulates Na/K ATPase in a way analogous to the regulation of SERCA by phospholamban (a protein unrelated to PLM apart from in name, and co-incidentally, function) and a significant proportion of our research effort is now devoted to this exciting project.
Three-dimensional structure of the Na/K ATPase alpha subunit (from Sweadner and Feschenko 2001). Details of this structure reveal that the PKA phosphorylation site is inaccessible to this kinase – this, and other observations, triggered the search for a phosphorylatable accessory protein.
(c) Ischaemic Preconditioning: (R Bell, M Baghai, M Mukaida)
We, and others, have become increasingly aware that the cardioprotective effect of ischaemic preconditioning involves free radicals acting as signalling, rather than damaging, entities. In addition, it has been recognised that mitochondrial K channels may play a role in this protection. With our interest and expertise in ion regulation, free radicals and cardioprotection, we continue to focus some of our efforts in this area. We have shown that: partial mitochondrial uncoupling with low-dose protonophores (ie FCCP) can trigger free radical release and cardioprotection, (ii) free radicals released by preconditioning (triggered by agonists or ischaemia) can oxidatively modify key protein thiols including those on PKC, (iii) a key source of these signalling free radicals is the NADPH oxidase. This latter observation has involved a fruitful and continuing collaboration between our Group and that of Professor Shah. For this work, Dr Robert Bell of the Cardiac Physiology Research Group was awarded the prestigious Richard Bing Young Investigator Award at the recent World Congress of the International Society for Heart Research (Brisbane 2004).
Cardiac ventricular myocyte loaded with TMRM showing mitochondrial polarisation. Using this, and other techniques, we have shown that cardioprotection by FCCP requires mitochondrial oxidation without mitochondrial depolarisation.
(d) Myocardial protection and preconditioning in the human neonatal heart: (M Bagaha, M Mukaida)
Babies hearts are not simply small versions of adult hearts! We have shown that preconditioning (which can powerfully protect the adult heart against ischaemic injury) is absent in the neonatal heart. The ability to precondition the human heart develops over the first few months of life. Our aim is to find out what is missing or immature in the neonatal heart that prevents this mechanism being activated. These studies may provide both insights into the essential elements of the preconditioning signalling pathway in the adult heart and, if the “missing link” can be bypassed, improved therapeutic options for limiting ischaemic injury during neonatal cardiac surgery.
(e) T-type Ca channels and cell growth and proliferation: (L McLatchie)
In excitable, and some non-excitable, cells, there is a correlation between cell growth/proliferation and the expression of T-type Ca channels. Since we know Ca is an essential ‘growth factor’, over the last 5 years we have examined whether T-type channels play a causal role in triggering cell growth – i.e. is the T-type Ca channel causal or consequential in cell growth? Despite amassing a huge amount of data, we still do not know the answer.The Cardiac Physiology Research Group’s interests centre on the role of T-type Ca channels in the aberrant proliferation of vascular smooth muscle cells and in hypertrophic growth of cardiac muscle. This project capitalises on the electrophysiological, molecular and cellular biological expertise of the group to probe the control of the cell cycle in a range of cell types.
Dr A Boguslavskyi
Dr D Pavlovic
Tulloch LB, Howie J, Wypijewski KJ, Wilson CR, Bernard WG, Shattock MJ, Fuller W. The inhibitory effect of phospholemman on the sodium pump requires its palmitoylation. J Biol Chem. 2011; 286(41):36020-31.
El-Armouche A, Wittköpper K, Fuller W, Howie J, Shattock MJ, Pavlovic D. Phospholemman-dependent regulation of the cardiac Na/K-ATPase activity is modulated by inhibitor-1 sensitive type-1 phosphatase. FASEB J. 2011; 25(12):4467-75.
Pavlović D, McLatchie LM, Shattock MJ. The rate of loss of T-tubules in cultured adult ventricular myocytes is species dependent. Exp Physiol. 2010; 95(4):518-27.
Bell JR, Lloyd D, Curl CL, Delbridge LM, Shattock MJ. Cell volume control in phospholemman (PLM) knockout mice: do cardiac myocytes demonstrate a regulatory volume decrease and is this influenced by deletion of PLM? Exp Physiol. 2009; 94(3):330-43.
Fuller W, Howie J, McLatchie LM, Weber RJ, Hastie CJ, Burness K, Pavlovic D, Shattock MJ. FXYD1 phosphorylation in vitro and in adult rat cardiac myocytes: threonine 69 is a novel substrate for protein kinase C. Am J Physiol Cell Physiol. 2009; 296(6):C1346-55
Bell JR, Kennington E, Fuller W, Dighe K, Donoghue P, Clark JE, Jia LG, Tucker AL, Moorman JR, Marber MS, Eaton P, Dunn MJ, Shattock MJ. Characterization of the phospholemman knockout mouse heart: depressed left ventricular function with increased Na-K-ATPase activity. Am J Physiol Heart Circ Physiol. 2008; 294(2):H613-21.
Silverman BdZ, Fuller W, Eaton P, Deng J, Moorman JR, Cheung JY, James AF, Shattock MJ. Serine 68 phosphorylation of phospholemman: acute isoform-specific activation of cardiac Na/K ATPase. Cardiovasc Res. 2005;65:93-103.
Gray LS, Perez-Reyes E, Gamorra JC, Haverstick DM, Shattock MJ, McLatchie LM, Harper JV, Brooks G, Heady T, Macdonald TL. The role of voltage gated T type Ca2+ channel isoforms in mediating 'capacitative' Ca2+ entry in cancer cells. Cell Calcium. 2004;36:489-497.
Fuller W, Eaton P, Bell JR, Shattock MJ. Ischemia-induced phosphorylation of phospholemman directly activates rat cardiac Na/K ATPase. FASEB J. 2004;18:197-199.
Fuller W, Parmar V, Eaton P, Bell JR, Shattock MJ. Cardiac ischemia causes inhibition of the Na/K ATPase by a labile cytosolic compound whose production is linked to oxidant stress. Cardiovasc Res. 2003;57:1044-1051.
Fuller W, Eaton P, Bell JR, Shattock MJ. Ischemia-induced phosphorylation of phospholemman directly activates rat cardiac Na/K ATPase. FASEB J. 2003;10:fj.03-0213fje.
Silverman BZ, Warley A, Miller JI, James AF, Shattock MJ. Is there a transient rise in sub-sarcolemmal Na and activation of Na/K pump current following activation of I(Na) in ventricular myocardium. Cardiovasc Res. 2003;57:1025-1034.
Eaton P, Byers HL, Leeds N, Ward MA, Shattock MJ. Detection, purification and identification of cardiac proteins S-thiolated during ischemia and reperfusion. J Biol Chem. 2002;277:9806-9811.
Eaton P, Fuller M, Shattock MJ. S-thiolation of HSP-27 regulates its multimeric size independently of phosphorylation: studies in rat heart during oxidative stress. J Biol Chem. 2002;277:21189-21196.
Eaton P, Fuller W, Bell JR, Shattock MJ. AlphaB crystallin translocation and phosphorylation: signal transduction pathways and preconditioning in the isolated rat heart. J Mol Cell Cardiol. 2001;33:1659-1671.
Eaton P, Hearse DJ, Shattock MJ. Lipid hydroperoxide-induced modification of cardiac proteins during ischemia and reperfusion. Cardiovasc Res. 2001;51:294-303.
Eaton P, Awad W, Miller JIA, Hearse DJ, Shattock MJ. Ischemic preconditioning: a potential role for constitutive low molecular weight stress protein translocation and phosphorylation. J Mol Cell Cardiol. 2000;32:961-971.