Faculty of Biological Sciences

Dr Sarah Calaghan

BSc, PhD 1991, Leeds.
Associate Professor in Cardiac Physiology
School of Biomedical Sciences

Background: BSc, PhD (Leeds). Postdoctoral Research, Dept of Biochemistry & Molecular Biology, Dept of Physiology, University of Leeds. British Heart Foundation Research Fellow (2000-2003), School of Biomedical Sciences University Research Fellow (2006-), Institute of Membrane and Systems Biology

Contact:  Garstang 7.52d, +44(0) 113 34 34309, email address for  

Research Interests

Control of signalling in the cardiac cell

The heart pumps blood around the body, delivering nutrients to and removing waste products from every organ. Its function is finely tuned to respond to the demands of the body. My research focuses on the mechanisms which control the behaviour of individual cardiac muscle cells in the heart in response to a variety of stimuli. This information can be used to understand the function of the heart in both health and disease.


Caveolae and G-protein coupled receptor signalling

The way that the heart functions in a healthy individual is a result of a balance between the stimulatory sympathetic nervous system and the inhibitory parasympathetic system. These 2 systems work through different receptors (β-adrenoceptors and muscarinic receptors), but many of the components of the downstream signalling pathways are the same. I am interested in how cellular signalling is controlled to allow these receptors to produce such diverse functional responses. One structure that contributes to this is the caveola, which is a small flask shaped pocket in the cell membrane enriched in cholesterol and lined with the protein caveolin (see Figure). Caveolae can concentrate or exclude components of signalling pathways so as to modulate both the efficiency and fidelity of signal transduction. Our recent work shows the first direct evidence for compartmentalisation of β-receptor signalling by caveolae in the adult cardiac myocyte.



 

Caveolae: organising membrane invaginations
Caveolae are specialised lipid rafts enriched in cholesterol and sphingolipids, characterised by the presence of caveolin and cavin proteins. On the left is an electron micrograph of caveolae in the surface membrane of a cardiac muscle cell. On the right, a cartoon of a caveolae depicting the organisation of caveolin (red) and cavin (green) proteins. Cartoon courtesy of Tim Lee (Faculty of Biological Sciences).


Caveolae and disease

Understanding the remodelling of the failing heart with a view to reversing this is a major goal in heart failure treatment. Our on-going work is exploring how changes in caveolae may contribute to remodelling in both right and left ventricular models of heart failure.

Caveolae and statins

Statins, prescribed to over 6 million people in the UK each year, inhibit the production of mevalonate, a precursor of cholesterol, and substantially reduce cardiovascular morbidity and mortality. Initially these effects were ascribed entirely to a reduction in atherosclerosis, however a body of evidence is accumulating that statins have other beneficial (so-called ‘pleiotropic’ effects). Because caveolae require cholesterol to exist, we predict that statins will have an impact on caveolae. We are currently investigating the impact of statins on caveolae and caveolae-regulated function in the cardiac cell with the aim of providing essential insight into the direct cardiac effects of these agents.

One of the main side-effects of statin treatment is skeletal muscle pain and weakness, which is usually exacerbated by exercise. This is a major reason for stopping statin therapy and so impacts on cardiovascular health. Surprisingly, despite decades of research, the mechanism for myopathy – and why this selectively affects skeletal (not cardiac) muscle - is not known. This is a focus of current work in the laboratory.

Mechanotransduction
The heart possesses a unique intrinsic ability to regulate its force of contraction in response to circulatory demand. For example, during exercise, the amount of blood returning to the heart increases and stretches the cardiac muscle. This acts as a stimulus for increased contraction, allowing the chambers of the heart to expel this greater volume of blood. Some of the processes which link stretch to increased contraction are not understood. I have identified a number of elements (stretch-activated channels, the NaH exchanger) which contribute to the slow phase of force increase following stretch both in single cardiac myocytes (see Video) and cardiac muscle. Recent work has explored the role that caveolae, which could act as reservoirs of extra membrane recruited upon stretch, play in the mechanotransductive response of the heart.

 

Current Projects

Determination of the mechanism for statin-induced myopathy: The cause and consequences of increased sarcoplasmic reticulum calcium leak’. BHF project grant. Calaghan, Steele, Hopkins. 2013-2016

Establishment of a model of left ventricular hypertrophy and failure. Biomedical Health Research Centre. Calaghan, Deuchars, Steele, Peers. 2012-2013

Characterisation of dynamic changes in caveolar resident proteins during adrenergic signalling using quantitative proteomics. BHF Project grant. Fuller (Dundee), Calaghan 2011-2013

Statins directly affect cardiac myocyte function through cholesterol-dependent and independent mechanisms. British Heart Foundation. Calaghan, Porter.  2009-2013

Recent Projects

The role of caveolae in generating receptor-specific cyclic AMP signals in the adult cardiac myocyte. Medical Research CouncilCalaghan, Harvey (US), Colyer. 2009-2011

Pleiotropic effects of statins on caveolae of the cardiac myocyte. Heart Research UK. Calaghan, Porter 2008-2009

The role of caveolae in mechanotransduction in the adult heart: Location, translocation, interaction and functional significance of stretch-activated signalling components. British Heart Foundation .  Calaghan, White, Porter. 2006-2009

 

Faculty Research and Innovation



Studentship information

Postgraduate studentship areas:

  • Mechanisms of statin-induced myopathy (cardiac and skeletal muscle)
  • Caveolar remodelling in heart failure

See also:

Modules managed

BMSC3138 - Cellular Cardiology

Modules taught

BMSC1103 - Basic Laboratory and Scientific Skills
BMSC1212 - Introduction to Pharmacology
BMSC1213 - Basic Laboratory and Scientific Skills 2
BMSC2117/3302 - Cardio-respiratory Phys & Med Phar
BMSC2233 - Topics in Medical Sciences
BMSC3138 - Cellular Cardiology
BMSC3140 - Advanced Scientific Skills
BMSC3233/35/36 - Advanced Topics II
BMSC3301 - Research Project in Biomedical Sciences

Centre membership: The Multidisciplinary Cardiovascular Research Centre (MCRC)

Group Leader Dr Sarah Calaghan  (Associate Professor in Cardiac Physiology)

Control of signalling in the cardiac cell 

Miss Sabine Lotteau  (Visiting 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 


Postgraduates

Elizabeth Evans (Co-supervisor) 40% FTE

Rode B, Shi J, Endesh N, Drinkhill MJ, Webster PJ, Lotteau SJ, Bailey MA, Yuldasheva NY, Ludlow MJ, Cubbon RM, Li J, Futers TS, Morley L, Gaunt HJ, Marszalek K, Viswambharan H, Cuthbertson K, Baxter PD, Foster R, Sukumar P, Weightman A, Calaghan SC, Wheatcroft SB, Kearney MT, Beech DJ Piezo1 channels sense whole body physical activity to reset cardiovascular homeostasis and enhance performance Nature Communications 8 -, 2017
DOI:10.1038/s41467-017-00429-3
View abstract

Burton RAB, Rog-Zielinska EA, Corbett AD, Peyronnet R, Bodi I, Fink M, Sheldon J, Hoenger A, Calaghan SC, Bub G, Kohl P Caveolae in Rabbit Ventricular Myocytes: Distribution and Dynamic Diminution after Cell Isolation. Biophys J 113 1047-1059, 2017
DOI:10.1016/j.bpj.2017.07.026
View abstract

MacDougall DA, Pugh SD, Bassi HS, Lotteau S, Porter KE, Calaghan S Simvastatin promotes cardiac myocyte relaxation in association with phosphorylation of troponin I Frontiers in Pharmacology 8 -, 2017
DOI:10.3389/fphar.2017.00203
View abstract

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

Norman R, Fowler E, White E, Calaghan S Metoprolol Reverses beta-Adrenergic Remodeling in the Failing Right Ventricle of Pulmonary Artery Hypertensive (PAH) Rats, 2016

Lotteau S, Yang Z, Venturi E, Steer E, Witschas K, Sitsapesan R, Steele D, Calaghan S Simvastatin has Profound Effects on Sarcoplasmic Reticulum Ca2+ Leak in Skeletal but not Cardiac Muscle: A Mechanism for Myopathy, 2016

Zhang H, Cannell MB, Kim SJ, Watson JJ, Norman R, Calaghan SC, Orchard CH, James AF Cellular hypertrophy and increased susceptibility to spontaneous calcium- release of rat left atrial myocytes due to elevated afterload PLoS ONE 10 -, 2015
DOI:10.1371/journal.pone.0144309
View abstract

Wypijewski KJ, Tinti M, Chen W, Lamont D, Ashford MLJ, Calaghan SC, Fuller W Identification of caveolar resident proteins in ventricular myocytes using a quantitative proteomic approach: Dynamic changes in caveolar composition following adrenoceptor activation Molecular and Cellular Proteomics 14 596-608, 2015
DOI:10.1074/mcp.M114.038570
View abstract

Natali AJ, Fowler ED, Calaghan SC, White E Voluntary exercise delays heart failure onset in rats with pulmonary artery hypertension American Journal of Physiology - Heart and Circulatory Physiology 309 H421-H424, 2015
DOI:10.1152/ajpheart.00262.2015
View abstract

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 Ca<sup>2+</sup>store regulated by the PKA and Epac branches of the b1-adrenergic signaling pathway Science Signaling 8 -, 2015
DOI:10.1126/scisignal.aaa7677
View abstract

Howie J, Reilly L, Fraser NJ, Walker JMV, Wypijewski KJ, Ashford MLJ, Calaghan SC, McClafferty H, Tian L, Shipston MJ, Boguslavskyi A, Shattock MJ, Fuller W Substrate recognition by the cell surface palmitoyl transferase DHHC5 Proceedings of the National Academy of Sciences of the United States of America 111 17534-17539, 2014
DOI:10.1073/pnas.1413627111
View abstract

Pugh SD, MacDougall DA, Agarwal SR, Harvey RD, Porter KE, Calaghan S Caveolin contributes to the modulation of basal andβ-adrenoceptor stimulated function of the adult rat ventricular myocyte by simvastatin: A novel pleiotropic effect PLoS ONE 9 -, 2014
DOI:10.1371/journal.pone.0106905
View abstract

MacDougall DA, Calaghan S A novel approach to the Langendorff technique: preparation of isolated cardiomyocytes and myocardial samples from the same rat heart Experimental Physiology 98 1295-1300, 2013
DOI:10.1113/expphysiol.2013.072827
View abstract

Wypijewski KJ, Howie J, Reilly L, Tulloch LB, Aughton KL, McLatchie LM, Shattock MJ, Calaghan SC, Fuller W A separate pool of cardiac phospholemman that does not regulate or associate with the sodium pump: Multimers of phospholemman in ventricular muscle Journal of Biological Chemistry 288 13808-13820, 2013
DOI:10.1074/jbc.M113.460956
View abstract

MacDougall DA, Agarwal SR, Stopford EA, Chu H, Collins JA, Longster AL, Colyer J, Harvey RD, Calaghan S Caveolae compartmentalise beta 2-adrenoceptor signals by curtailing cAMP production and maintaining phosphatase activity in the sarcoplasmic reticulum of the adult ventricular myocyte JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 52 388-400, 2012
DOI:10.1016/j.yjmcc.2011.06.014

Calaghan S, Steele D, Weiss JN Local signalling in myocytes. J Mol Cell Cardiol 52 295-297, 2012
DOI:10.1016/j.yjmcc.2011.10.019

Harvey RD, Calaghan SC Caveolae create local signalling domains through their distinct protein content, lipid profile and morphology JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 52 366-375, 2012
DOI:10.1016/j.yjmcc.2011.07.007

Fuller W, Tulloch LB, Howie J, Wypijewski KJ, Shattock MJ, Calaghan SC Regulation of the cardiac sodium pump Cellular and Molecular Life Sciences 1-24, 2012
DOI:10.1007/s00018-012-1134-y
View abstract

MacDougall DA, Stopford EA, Calaghan SC Caveolar compartmentation of beta2-adrenoceptor cAMP signalling in the adult cardiac myocyte depends on protein phosphatases, but not phosphodiesterases or phosphoinositide-3-kinase, 2011

Brisson L, Gillet L, Calaghan S, Besson P, Le Guennec JY, Roger S, Gore J Na(V)1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H+ efflux in caveolae ONCOGENE 30 2070-2076, 2011
DOI:10.1038/onc.2010.574

Agarwal SR, MacDougall DA, Tyser R, Pugh SD, Calaghan SC, Harvey RD Effects of cholesterol depletion on compartmentalized cAMP responses in adult cardiac myocytes J MOL CELL CARDIOL 50 500-509, 2011
DOI:10.1016/j.yjmcc.2010.11.015

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
DOI:10.1074/jbc.M110.104976

Pugh SD, Porter KE, Calaghan S A Novel Pleiotropic Effect of Statins: Enhanced Cardiomyocyte beta 2-Adrenoceptor Responsiveness BIOPHYSICAL JOURNAL 98 721A-721A, 2010

Kozera L, White E, Calaghan S Caveolae Act as Membrane Reserves Which Limit Mechanosensitive I-Cl,I-swell Channel Activation during Swelling in the Rat Ventricular Myocyte PLOS ONE 4 -, 2009
DOI:10.1371/journal.pone.0008312

Gillet L, Roger S, Besson P, Bougnoux P, Calaghan S, Le Guennec J-Y Docosahexaenoic acid prevents breast cancer cells invasiveness by regulating voltage-gated sodium channels activity CANCER RESEARCH 69 -, 2009

Calaghan SC, Porter KE, Pugh SD SIMVASTATIN HAS DIRECT EFFECTS ON CARDIAC MYOCYTE CAVEOLAE VIA DEPLETION OF MEMBRANE CHOLESTEROL J PHYSIOL SCI 59 360-360, 2009

Calaghan S, Kozera L, White E Compartmentalisation of cAMP-dependent signalling by caveolae in the adult cardiac myocyte J MOL CELL CARDIOL 45 88-92, 2008
DOI:10.1016/j.yjmcc.2008.04.004

Stones R, Calaghan SC, Billeter R, Harrison SM, White E Transmural variations in gene expression of stretch-modulated proteins in the rat left ventricle PFLUG ARCH EUR J PHY 454 545-549, 2007
DOI:10.1007/s00424-007-0237-z

Shiels H, O'Connell A, Qureshi MA, Howarth FC, White E, Calaghan S Stable microtubules contribute to cardiac dysfunction in the streptozotocin-induced model of type 1 diabetes in the rat MOL CELL BIOCHEM 294 173-180, 2007
DOI:10.1007/s11010-006-9257-9

Shiels HA, Calaghan SC, White E The cellular basis for enhanced volume-modulated cardiac output in fish hearts J GEN PHYSIOL 128 37-44, 2006
DOI:10.1085/jgp.200609543

Calaghan SC, Taggart MJ Compartmentalized signaling in cardiomyocyte lipid domains - Do structure and function match up? J MOL CELL CARDIOL 41 1-3, 2006
DOI:10.1016/j.yjmcc.2006.04.017

Calaghan S, White E Caveolae modulate excitation-contraction coupling and beta(2)-adrenergic signalling in adult rat ventricular myocytes CARDIOVASC RES 69 816-824, 2006
DOI:10.1016/j.cardiores.2005.10.006

Calaghan SC, White E Mechanical modulation of intracellular ion concentrations: Mechanisms and electrical consequences In Mechanosensitivity in Cells and Tissues , 2005

Calaghan S, White E Activation of Na+-H+ exchange and stretch-activated channels underlies the slow inotropic response to stretch in myocytes and muscle from the rat heart J PHYSIOL-LONDON 559 205-214, 2004

Calaghan SC, Le Guennec JY, White E Cytoskeletal modulation of electrical and mechanical activity in cardiac myocytes PROG BIOPHYS MOL BIO 84 29-59, 2004
DOI:10.1016/S0073-6107(03)00057-9

Calaghan SC, Belus A, White E Do stretch-induced changes in intracellular calcium modify the electrical activity of cardiac muscle? PROG BIOPHYS MOL BIO 82 81-95, 2003
DOI:10.1016/S0079-6107(03)00007-5

Miller G, Maycock J, White E, Peckham M, Calaghan S Heterologous expression of wild-type and mutant beta-cardiac myosin changes the contractile kinetics of cultured mouse myotubes J PHYSIOL-LONDON 548 167-174, 2003
DOI:10.1113/jphysiol.2002.031922

Howarth FC, Qureshi MA, White E, Calaghan SC Cardiac microtubules are more resistant to chemical depolymerisation in streptozotocin-induced diabetes in the rat PFLUG ARCH EUR J PHY 444 432-437, 2002
DOI:10.1007/s00424-002-0824-y

Calaghan SC, Le Guennec JY, White E Modulation of Ca(2+) signaling by microtubule disruption in rat ventricular myocytes and its dependence on the ruptured patch-clamp configuration. Circ Res 88 E32-E37, 2001
View abstract

Calaghan SC, White E Contribution of angiotensin II, endothelin 1 and the endothelium to the slow inotropic response to stretch in ferret papillary muscle. Pflugers Arch 441 514-520, 2001
View abstract

Calaghan SC, White E, Le Guennec JY A unifying mechanism for the role of microtubules in the regulation of [Ca2+]i and contraction in cardiac myocytes Circulation Research 89 e31-, 2001

Calaghan SC, White E, Bedut S, Le Guennec JY Cytochalasin D reduces Ca2+ sensitivity and maximum tension via interactions with myofilaments in skinned rat cardiac myocytes J PHYSIOL-LONDON 529 405-411, 2000

Calaghan SC, White E, Bedut S, Le Guennec JY Cytochalasin D reduces Ca<sup>2+</sup>sensitivity and maximum tension via interactions with myofilaments in skinned rat cardiac myocytes Journal of Physiology 529 405-411, 2000
DOI:10.1111/j.1469-7793.2000.00405.x
View abstract

Calaghan SC, Trinick J, Knight PJ, White E A role for C-protein in the regulation of contraction and intracellular Ca2+ in intact rat ventricular myocytes. J Physiol 528 Pt 1 151-156, 2000
View abstract

Brette F, Calaghan SC, Lappin S, White E, Colyer J, Le Guennec JY Biphasic effects of hyposmotic challenge on excitation-contraction coupling in rat ventricular myocytes. Am J Physiol Heart Circ Physiol 279 H1963-H1971, 2000
View abstract

Howarth FC, Calaghan SC, Boyett MR, White E Effect of the microtubule polymerizing agent taxol on contraction, Ca2+ transient and L-type Ca2+ current in rat ventricular myocytes J PHYSIOL-LONDON 516 409-419, 1999

Calaghan SC, Colyer J, White E Cyclic AMP but not phosphorylation of phospholamban contributes to the slow inotropic response to stretch in ferret papillary muscle. Pflugers Arch 437 780-782, 1999
DOI:10.1007/s004240050846
View abstract

Calaghan SC, White E The role of calcium in the response of cardiac muscle to stretch PROG BIOPHYS MOL BIO 71 59-90, 1999

Calaghan SC, White E, Colyer J Co-ordinated changes in cAMP, phosphorylated phospholamban, Ca2+ and contraction following beta-adrenergic stimulation of rat heart. Pflugers Arch 436 948-956, 1998
View abstract

Calaghan S, White E, Colyer J Preservation of the in vivo phosphorylation status of phospholamban in the heart: evidence for a site-specific difference in the dephosphorylation of phospholamban. Biochem Biophys Res Commun 248 701-705, 1998
DOI:10.1006/bbrc.1998.9036
View abstract

Calaghan S Caveolae: Co-ordinating centres for mechanotransduction in the heart In Mechanosensitive ion channels ,