Dr Sarah Calaghan

BSc, PhD 1991, Leeds.
Lecturer
Institute of Membrane and Systems Biology

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

Office: Garstang 7.52d
Phone: +44(0) 113 34 34309
Email: s.c.calaghan@leeds.ac.uk 

Centre membership: The Multidisciplinary Cardiovascular Research Centre (MCRC)

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 (Fig 1). Caveolae can concentrate or exclude components of signalling pathways so as to modulate both the efficiency and fidelity of signal transduction. Our  work published in Journal of Molecular and Cellular Cardiology (2008) and Cardiovascular Research (2006) shows the first direct evidence for compartmentalisation of β-receptor signalling by caveolae in the adult cardiac myocyte.

Caveolae and statins
Statins, prescribed to over 2 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.

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. My current work explores the role that caveolae, which could act as reservoirs of extra membrane recruited upon stretch, play in the mechanotransductive response of the heart (see Kozera et al. PLoS ONE (2009)).

Diabetes
Cardiac function is adversely affected by many different diseases. For example, cardiovascular complications are a major cause of disability and death in patients with diabetes. We have recently made a novel finding that changes in the microtubules, a network of hollow fibres (Fig. 2), contribute to adverse alterations in cardiac cell function in a model of type 1 diabetes.

Figure 1: A caveola in the cell membrane (courtesy of Tim Lee, Faculty of Biological Sciences)

Figure 2: A cardiac cell from a model of type 1 diabetes stained to show the microtubular cytoskeleton

Recent and Current Projects

Statins directly affect cardiac myocyte function through cholesterol-dependent and independent mechanisms. British Heart Foundation £185,063 (S Calaghan, K Porter; Aug 09-July 12).

The role of caveolae in generating receptor-specific cyclic AMP signals in the adult cardiac myocyte. Medical Research Council £273,000 (S Calaghan, R Harvey (US), J Colyer; Feb 09-Jan 11).

Pleiotropic effects of statins on caveolae of the cardiac myocyte. Heart Research UK £79,322 (S Calaghan, K Porter; Jan 08-July 09).

The role of caveolae in mechanotransduction in the adult heart: Location, translocation, interaction and functional significance of stretch-activated signalling components. British Heart Foundation £192,642 (S Calaghan, E White, K Porter; Oct 06-Sept 09).

Current Projects

Funded by British Heart Foundation, Heart Research UK, Medical Research Council

Studentship information

Postgraduate studentship areas:

• Caveolar control of mechanotransductive signalling in the cardiac muscle cell

See also:

• Faculty Graduate School
• Project details at FindaPhD.com

Publications

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 JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 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

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

Agarwal SR; MacDougall DA; Tyser R; Pugh SD; Calaghan SC; Harvey RD Effects of cholesterol depletion on compartmentalized cAMP responses in adult cardiac myocytes JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 50 500-509, 2011
DOI:10.1016/j.yjmcc.2010.11.015

Brisson L; Gillet L; Calaghan S; Besson P; Le Guennec J; 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

Duke AM; Hopkins PM; Calaghan SC; Halsall JP; Steele DS Store-operated Ca2+ Entry in Malignant Hyperthermia-susceptible Human Skeletal Muscle JOURNAL OF BIOLOGICAL CHEMISTRY 285 25645-25653, 2010
DOI:10.1074/jbc.M110.104976

Calaghan SC; Porter KE; Pugh SD SIMVASTATIN HAS DIRECT EFFECTS ON CARDIAC MYOCYTE CAVEOLAE VIA DEPLETION OF MEMBRANE CHOLESTEROL JOURNAL OF PHYSIOLOGICAL SCIENCES 59 360-360, 2009

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

Calaghan S; Kozera L; White E Compartmentalisation of cAMP-dependent signalling by caveolae in the adult cardiac myocyte JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 45 88-92, 2008
DOI:10.1016/j.yjmcc.2008.04.004

Calaghan S; Kozera L; White E Caveolae promote confinement of beta(2) adrenoceptor signalling to the sarcolemma in the adult cardiac myocyte, 2007

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 MOLECULAR AND CELLULAR BIOCHEMISTRY 294 173-180, 2007
DOI:10.1007/s11010-006-9257-9

Stones R; Calaghan SC; Billeter R; Harrison SM; White E Transmural variations in gene expression of stretch-modulated proteins in the rat left ventricle PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY 454 545-549, 2007
DOI:10.1007/s00424-007-0237-z

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

Calaghan SC; Taggart MJ Compartmentalized signaling in cardiomyocyte lipid domains - Do structure and function match up? JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY 41 1-3, 2006
DOI:10.1016/j.yjmcc.2006.04.017

Shiels HA; Calaghan SC; White E The cellular basis for enhanced volume-modulated cardiac output in fish hearts JOURNAL OF GENERAL PHYSIOLOGY 128 37-44, 2006
DOI:10.1085/jgp.200609543

O'Connell AD; Calaghan SC Action potential configuration following microtubule disruption in rat right ventricular cardiac myocytes, 2005

Calaghan S Integrin signalling through laminin selectively enhances the response to beta(2)-adrenergic stimulation in adult rat ventricular myocytes, 2005

Calaghan S; White E Disruption of caveolae modulates excitation-contraction coupling in the adult cardiac myocyte, 2005

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 JOURNAL OF PHYSIOLOGY-LONDON 559 205-214, 2004
DOI:10.1113/jphysiol.2004.069021

Calaghan SC; Le Guennec JY; White E Cytoskeletal modulation of electrical and mechanical activity in cardiac myocytes PROGRESS IN BIOPHYSICS&MOLECULAR BIOLOGY 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? PROGRESS IN BIOPHYSICS&MOLECULAR BIOLOGY 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 JOURNAL OF PHYSIOLOGY-LONDON 548 167-174, 2003
DOI:10.1113/jphysiol.2002.031922

Bird SD; Calaghan SC; White E Microtubule disruption with colchicine does not modify the cell volume or contractile response to hyposmotic challenge in the adult rat ventricular myocyte, 2002

Howarth FC; Qureshi MA; White E; Calaghan SC Cardiac microtubules are more resistant to chemical depolymerisation in streptozotocin-induced diabetes in the rat PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY 444 432-437, 2002
DOI:10.1007/s00424-002-0824-y

Ansari SS; Shiels HA; Calaghan SC; White E Laminin potentiates the contractile response to beta-adrenergic, but not endothelin-1, stimulation in rat ventricular myocytes, 2002

Calaghan S; White E The slow inotropic response to stretch is independent of endothelin 1 in single rat ventricular myocytes, 2002

Calaghan S; Miller G; White E; Peckham M Effect of familial hypertrophic cardiomyopathy (FHC) mutations in beta-cardiac myosin on the contractile kinetics of cultured myotubes, 2002

Calaghan S; White E Signalling pathways that underlie the slow inotropic response to myocardial stretch, 2002

Calaghan SC; Le Guennec JY; White E Microtubule disruption by colchicine modulates I-Ca,I-L in ruptured but not perforated patch-clamped cardiomyocytes., 2001

Calaghan S; White E; Le Guennec JY A unifying mechanism for the role of microtubules in the regulation of [Ca2+](i) and contraction in the cardiac myocyte CIRCULATION RESEARCH 89 E31-E31, 2001

Calaghan SC; White E; Qureshi MA; Howarth FC Does the microtubular cytoskeleton contribute to cardiac dysfunction in streptozotocin-induced diabetes in the rat?, 2001

Calaghan SC; Le Guennec JY; White E Modulation of Ca2+ signaling by microtubule disruption in rat ventricular myocytes and its dependence on the ruptured patch-clamp configuration CIRCULATION RESEARCH 88 E32-E37, 2001

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 pp.31-, 2001

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 ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY 441 514-520, 2001
DOI:10.1007/s004240000458

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 JOURNAL OF PHYSIOLOGY-LONDON 529 405-411, 2000
DOI:10.1111/j.1469-7793.2000.00405.x

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 AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 279 H1963-H1971, 2000

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 JOURNAL OF PHYSIOLOGY-LONDON 528 151-156, 2000
DOI:10.1111/j.1469-7793.2000.00151.x

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 Journal of Physiology 528 151-156, 2000

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 ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY 437 780-782, 1999
DOI:10.1007/s004240050846

Calaghan SC; White E The role of calcium in the response of cardiac muscle to stretch PROGRESS IN BIOPHYSICS&MOLECULAR BIOLOGY 71 59-90, 1999
DOI:10.1016/S0079-6107(98)00037-6

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 JOURNAL OF PHYSIOLOGY-LONDON 516 409-419, 1999
DOI:10.1111/j.1469-7793.1999.0409v.x

Calaghan SC; White E; Colyer J Co-ordinated changes in cAMP, phosphorylated phospholamban, Ca2+ and contraction following beta-adrenergic stimulation of rat heart PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY 436 948-956, 1998
DOI:10.1007/s004240050728

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 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 248 701-705, 1998
DOI:10.1006/bbrc.1998.9036

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