My group’s research is directed towards understanding how the heart adapts to changing stresses to ensure sufficient cardiac output. Of particular interest are the stresses of exercise, cardiac damage and aging. Failure of the heart to adapt leads to cardiac insufficiency whereas undesirable adaptations cause increased susceptibility to arrhythmias and sudden death. By studying cardiac function at the global, cellular and sub-cellular levels we hope to develop an understanding of how intrinsic cardiac responses are controlled and may be manipulated.
One aspect of our research is directed at the initiation of heart beat. What makes the heart beat spontaneously and how is the beating rate regulated? This is a controversial topic. By measuring cardiac electrical activity in the presence of a variety of pharmacological modulators of intracellular calcium and with accompanying direct measurement of intracellular calcium using fluorescent probes (see Fig. 1) we have discovered that calcium regulation is highly heterogeneous in the dominant cardiac pacemaker, the sinoatrial node. The work gives insight into the actions of catecholamines such as adrenaline and the generation of abnormal pacemaking.
An increasingly important aspect of cardiac physiology is the effect of aging on cardiac muscle performance. The aged heart is more susceptible to arrhythmias, shows reduced capacity for adaptation to common stresses such as exercise, and shows reduced tolerance to damaging insults such as a myocardial infarction. Research performed in conjunction with Dr Sandra Jones has begun to identify factors placing the aging heart at increased risk and limiting its adaptive capability. Identification of changes in ion-channel expression and intracellular signalling has already identified potential mechanisms underlying an increased propensity for atrial arrhythmias in the elderly and we are building on this work.
Funding: Strategic Promotion of Ageing Research Capacity, a BBSRC/EPSRC joint venture
Overseas collaborators: Haruo Honjo (Japan) and Scott Powers (USA)
Hatch F; Lancaster MK; Jones SA Aging is a primary risk factor for cardiac arrhythmias: Disruption of intracellular Ca 2+ regulation as a key suspect Expert Review of Cardiovascular Therapy9 1059-1067, 2011
Dawson A; Lancaster MK; Jones SA AGEING REDUCES CARDIAC PROGENITOR CELL EXPRESSION WHICH EXISTS AS A TRANSMURAL GRADIENT ACROSS THE LEFT VENTRICULAR WALL HEART97 15-15, 2011 DOI:10.1136/heartjnl-2011-300920b.43
Walton RD; Jones SA; Lancaster MK Male-Specific Changes in Myocyte Size and Calcium Channel Expression in Old Age, 2009
Jones SA; Yamamoto M; Tellez JO; Billeter R; Boyett MR; Honjo H; Lancaster MK Distinguishing Properties of Cells From the Myocardial Sleeves of the Pulmonary Veins A Comparison of Normal and Abnormal Pacemakers CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY1 39-48, 2008 DOI:10.1161/CIRCEP.107.748467
Lancaster MK; Walton RD; Jones SA Transmural Gradient of the Task-1 Channel Exists Across the Left Ventricular Wall, 2008
Jones SA; Lancaster MK Calcium-channel blockers and cardiac arrhythmias within the elderly population Future Cardiology4 207-209, 2008
Lancaster MK; Jones SA Increased levels of activated C-jnk N-terminal kinase have been associated with the downregulation of cardiac ion channel expression during in vivo aging, 2007
Boyett MR; Honjo H; Kodama I; Lancaster MK; Lei M; Musa H; Zhang H The sinoatrial node: CEll size does matter CIRCULATION RESEARCH101 E81-E82, 2007 DOI:10.1161/CIRCRESAHA.107.161190
Jones SA; Lancaster MK Age-dependent increased activation of c-Jun N-terminal kinase is associated with decreased connexin43 in vivo, 2006
Morton MJ; Thompson B; Stones R; Lancaster MK; White E; Harrison SM; Hunter M; Jones SA Exercise, and left ventricle transmural gradient of TASK-1 protein expression, 2005
Lancaster MK; Jones SA; Honjo H; Boyett MR Intracellular calcium regulation in cells from the base of the pulmonary veins, causes for sources of ectopic pacemaking, 2005
Dobrzynski H; Li J; Tellez J; Greener ID; Nikolski VP; Wright SE; Parson SH; Jones SA; Lancaster MK; Yamamoto M; Honjo H; Takagishi Y; Kodama I; Efimov IR; Billeter R; Boyett MR Computer three-dimensional reconstruction of the sinoatrial node CIRCULATION111 846-854, 2005 DOI:10.1161/01.CIR.0000152100.04087.DB
Jones SA; Thompson B; Lancaster MK; Hunter M; Harrison SM; Morton MJ Transmural differences of TASK-1 expression across the left ventricular wall, 2005
Lei M; Jones SA; Liu J; Lancaster MK; Fung SSM; Dobrzynski H; Camelliti P; Maier SKG; Noble D; Boyett MR Requirement of neuronal- and cardiac-type sodium channels for murine sinoatrial node pacemaking JOURNAL OF PHYSIOLOGY-LONDON559 835-848, 2004 DOI:10.1113/jphysiol.2004.068643
Jones SA; Lancaster MK; Boyett MR Ageing-related changes of connexins and conduction within the sinoatrial node JOURNAL OF PHYSIOLOGY-LONDON560 429-437, 2004 DOI:10.1113/jphysiol.2004.072108
Lancaster MK; Jones SA; Harrison SM; Boyett MR Intracellular Ca2+ and pacemaking within the rabbit sinoatrial node: heterogeneity of role and control JOURNAL OF PHYSIOLOGY-LONDON556 481-494, 2004 DOI:10.1113/jphysiol.2003.057372
Zhang H; Noble D; Cannell M; Orchard CH; Lancaster M; Jones SA; Boyett MR; Holden AV; Jafri MS; Sobie EA; Lederer WJ; Demir SS; Michailova A; Delprincipe F; Egger M; Niggli E; Smith GL; Loughrey CM; MacQuaide N; Dempster J; Trafford AW Dynamics of cardiac intracellular Ca2+ handling - From experiments to virtual cells INTERNATIONAL JOURNAL OF BIFURCATION AND CHAOS13 3535-3560, 2003 DOI:10.1142/S0218127403008843
Boyett MR; Dobrzynski H; Lancaster MK; Jones SA; Honjo H; Kodama I Sophisticated architecture is required for the sinoatrial node to perform its normal pacemaker function JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY14 104-106, 2003 DOI:10.1046/j.1540-8167.2003.02307.x
Nikolski VP; Jones SA; Lancaster MK; Boyett MR; Efimov IR Cx43 and dual-pathway electrophysiology of the atrioventricular node and atrioventricular nodal reentry CIRCULATION RESEARCH92 469-475, 2003 DOI:10.1161/01.RES.0000059304.97120.2F
Honjo H; Inada S; Lancaster MK; Yamamoto M; Niwa R; Jones SA; Shibata N; Mitsui K; Horiuchi T; Kamiya K; Kodama I; Boyett MR Sarcoplasmic reticulum Ca2+ release is not a dominating factor in sinoatrial node pacemaker activity CIRCULATION RESEARCH92 E41-E44, 2003 DOI:10.1161/01.RES.0000055904.21974.BE
Jones SA; Lancaster MK; Boyett MR Changes associated with ageing in connexin43 protein expression within the sinoatrial node, 2002
Dobrzynski H; Lei M; Jones SA; Lancaster MK; Boyett MR The gradient model of the rabbit sinoatrial node Korean Journal of Physiology and Pharmacology6 173-181, 2002
Boyett MR; Billeter R; Dobrzynski H; Honjo H; Inada S; Jones SA; Kodama I; Lancaster MK; Tellez J Heterogeneity and ageing of the sinoatrial node, 2002
Lancaster MK; Jones SA; Boyett MR Differences in intracellular calcium release and removal within the sinoatrial node, 2002
Musa H; Lei M; Honjo H; Jones SA; Dobrzynski H; Lancaster MK; Takagishi Y; Henderson Z; Kodama I; Boyett MR Heterogeneous expression of Ca2+ handling proteins in rabbit sinoatrial node JOURNAL OF HISTOCHEMISTRY&CYTOCHEMISTRY50 311-324, 2002
Lancaster MK; Jones SA; Boyett MR Differences in intracellular calcium release and removal within the sinoatrial node. Journal of Physiology544 48-49, 2002
Lei M; Lancaster MK; Jones SA; Boyett MR Role of fast sodium current, i(Na), in murine sino-atrial node pacemaking, 2002
Dobrzynski H; Wright SE; Parson SH; Li J; Jones SA; Lancaster MK; Boyett MR Immunocytochemistry supports the gradient rather than the mosaic model of the assembly of single cells to produce the intact SA node, 2002
Dobrzynski H; Wright SE; Parson SH; Li J; Jones SA; Lancaster MK; Boyett MR Immunocytochemistry supports the gradient rather than the mosaic model of the assembly of single cells to produce the intact SA node. Journal of Physiology544 pp.41-, 2002
Boyett MR; Billeter-Clark R; Dobrzynski H; Honjo H; Inada S; Jones SA; Kodama I; Lancaster MK; Tellez J Heterogeneity and ageing of the sinoatrial node. Journal of Physiology544 3-4, 2002 DOI:10.1113/jphysiol.2002.020255
Jones SA; Lancaster MK; Boyett MR Changes associated with ageing in connexin43 protein expression within the sinoatrial node. Journal of Physiology544 50-51, 2002
Lei M; Lancaster MK; Jones SA; Boyett MR Role of fast sodium current iNa, in murine sino-atrial node pacemaking. Journal of Physiology544 pp.39-, 2002 DOI:10.1113/jphysiol.2002.025353
Lancaster MK; Jones SA; Harrison SM; Boyett MR Differences in the intracellular Ca2+ transient within the rabbit sinoatrial node JOURNAL OF PHYSIOLOGY-LONDON533 30P-30P, 2001
Jones SA; Lancaster MK; Boyett MR Age-associated disappearance of connexin43 within the sinoatrial node CIRCULATION104 134-134, 2001
Dibb KM; Leach R; Lancaster MK; Findlay JBC; Boyett MR Cs+ block of the cardiac muscarinic K+ channel, GIRK1/GIRK4, is not dependent on the aspartate residue at position 173 PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY440 740-744, 2000 DOI:10.1007/s004240000344
Lancaster MK; Dibb KM; Quinn CC; Leach R; Lee JK; Findlay JBC; Boyett MR Residues and mechanisms for slow activation and Ba2+ block of the cardiac muscarinic K+ channel, Kir3.1/Kir3.4 JOURNAL OF BIOLOGICAL CHEMISTRY275 35831-35839, 2000 DOI:10.1074/jbc.M006565200
Lancaster MK; Bennett DL; Cook SJ; O'Neill SC Na/K pump a subunit expression in rabbit ventricle and regional variations of intracellular sodium regulation PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY440 735-739, 2000 DOI:10.1007/s004240000328
Lancaster MK; Harrison SM Changes in contraction, cytosolic Ca2+ and pH during metabolic inhibition and upon restoration of mitochondrial respiration in rat ventricular myocytes EXPERIMENTAL PHYSIOLOGY83 349-360, 1998
Lancaster MK; Harrison SM Changes in contraction, cytosolic Ca2+ and pH during metabolic inhibition and upon restoration of mitochondrial respiration in rat ventricular myocytes Experimental Physiology83 349-360, 1998
Lancaster MK; Cook SJ The effects of levosimendan on [Ca2+](i) in guinea-pig isolated ventricular myocytes EUROPEAN JOURNAL OF PHARMACOLOGY339 97-100, 1997 DOI:10.1016/S0014-2999(97)01362-9
Cook SJ; Chamunorwa JP; Lancaster MK; ONeill SC Regional differences in the regulation of intracellular sodium and in action potential configuration in rabbit left ventricle PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY433 515-522, 1997 DOI:10.1007/s004240050307
Diaz ME; Cook SJ; Chamunorwa JP; Trafford AW; Lancaster MK; ONeill SC; Eisner DA Variability of spontaneous Ca2+ release between different rat ventricular myocytes is correlated with Na+-Ca2+ exchange and [Na+](i) CIRCULATION RESEARCH78 857-862, 1996
Zhang H; Noble D; Cannell M; Orchard CH; Lancaster MK; Boyett MR; Holden AV; Saleet Jafri M; Sobie EA; Lederer WJ; Demir SS; Michailova A; DelPrincipe F; Egger M; Niggli E; Smith GL; Loughrey CM; MacQuaide N; Dempster J; Trafford AT Dynamics of cardiac intracellular Ca2+ handling - from experiments to virtual cells International Journal of Bifurcations and Chaos in Applied Sciences and Engineering -,
