Professor Clive Orchard

Summary

My research is focused on cardiac excitation-contraction coupling and its regulation. Using a variety of techniques (for example voltage clamp, fluorescent ion indicators,whole cell and confocal microscopy, immunohistochemistry, RT-PCR and computer modelling) we are investigating how the rise of intracellular Ca²⁺ that causes contraction is initiated, and how it is regulated by intracellular 2nd messenger pathways. A particular interest is the role of the t-tubules (invaginations of the surface membrane of cardiac ventricular myocytes) in this process. We have recently developed a technique that allows us to physically and functionally uncouple the t-tubules from the surface membrane, enabling us to investigate their function.

Using this technique we have been able to show that the t-tubules form a specialised region of the cell membrane for ion handling: many of the key proteins involved in excitation-contraction coupling are found predominantly at the t-tubules, and the regulation of these proteins appears to be better coupled to second messenger pathways at the t-tubules than at the surface membrane. This work not only helps our understanding of cardiac cell function, but may also be important in understanding heart failure, in which t-tubule density decreases and ion channel expression and regulation are altered. We are also interested in how a variety of physiological and pathophysiological interventions, such as beta adrenergic stimulation and acidosis, alter excitation - contraction coupling and hence cardiac cell function.

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Activities / Findings

• Tonic phosphorylation by PKA- and CamKII-dependent phosphorylation of L-type Ca2+ channels, which are localised at t-tubules, maintains ICa
• Ca2+ efflux from the sarcoplasmic reticulum via the Ca2+ ATPase occurs only at t-tubules  
• Inhibition of either the NCX or SERCA blocked both spontaneous Ca2+ transients and action potentials in the AVN pacemaker 

Skills

• arrhythmia
• hypertension

Methodologies

• Molecular Biology
• PCR
• Ca2+ imaging
• Immunocytochemistry
• Immunohistochemistry
• Electrophysiological recording

Memberships

Organisations

School of Physiology and Pharmacology

Other sites

• Bhi

Research Areas

• Ion channels and cardiac function

Research Themes

• Cardiovascular Research

Selected publications

• Du, C, Harchi, AE, Zhang, Y, Orchard, C & Hancox, J 2011, ‘Pharmacological Inhibition of the hERG Potassium Channel Is Modulated by Extracellular But Not Intracellular Acidosis’. J Cardiovasc Electrophysiol., pp. in press
• Chase, A & Orchard, C 2011, ‘Ca efflux via the sarcolemmal Ca ATPase occurs only in the t-tubules of rat ventricular myocytes’. Journal of Molecular and Cellular Cardiology, vol 50., pp. 187 - 193
• Du, C, Harchi, AE, McPate, M, Orchard, C & Hancox, J 2011, ‘Enhanced inhibitory effect of acidosis on hERG potassium channels that incorporate the hERG1b isoform’. Biochem Biophys Res Comm, vol 405., pp. 222 - 227
• Orchard, C, Brette, F, Chase, A & Fowler, M 2011, ‘Role of the t-tubules in the response of cardiac ventricular myocytes to inotropic interventions’. in: U Ravens, M Sanguinetti, O Tripathi (eds) Heart Rate & Rhythm. Springer

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Recent publications

• Orchard, CH, Bryant, SM & James, AF 2013, ‘Do t-tubules play a role in arrhythmogenesis in cardiac ventricular myocytes?’. The Journal of Physiology.
• Cheng, H, Smith, G, Orchard, CH, Hancox, JC & Burton, F 2012, ‘Inhibition of sarcoplasmic reticulum Ca2+-ATPase decreases atrioventricular node-paced heart rate in rabbits.’. Experimental Physiology, vol 97., pp. 1131-1139
• Pasek, M, Simurda, J & Orchard, CH 2012, ‘Role of t-tubules in the control of trans-sarcolemmal ion flux and intracellular Ca2+ in a model of the rat cardiac ventricular myocyte’. European biophysics journal with biophysics letters, vol 41., pp. 491-503
• Cheng, H, Smith, G, Hancox, J & Orchard, C 2011, ‘Inhibition of spontaneous activity of rabbit atrioventricular node cells by KB-R7943 and inhibitors of sarcoplasmic reticulum Ca2+ ATPase’. Cell Calcium, vol 49., pp. 56 - 65
• Chase, A, Colyer, J & Orchard, C 2010, ‘Localised Ca channel phosphorylation modulates the distribution of L-type Ca current in cardiac myocytes’. Journal of Molecular and Cellular Cardiology, vol 49., pp. 121 - 131
• Du, C, Adeniran, I, Cheng, H, Zhang, Y, Harchi, AE, McPate, M, Zhang, H, Orchard, C & Hancox, J 2010, ‘Acidosis Impairs the Protective Role of hERG K(+) Channels Against Premature Stimulation’. Journal of Cardiovascular Electrophysiology, vol 21., pp. 1160 - 1169

View complete publications list in the University of Bristol publications system

Networks & contacts

• Jules Hancox - Bristol
• Andrew James - Bristol