Professor Clive H Orchard

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 Ca ²⁺ 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.