Cardiac Calcium Regulation and Nanosignalling Group
Our laboratory investigates the physiology of local calcium signalling in cardiac muscle. Calcium signalling is vital for cardiac muscle contraction and many cardiac diseases are associated with detrimental changes in calcium signalling. The term "local" signalling refers to the fact that critical signalling distances are typically in the 10-50 nm range. Such local interactions are of particular relevance for understanding the functional behaviour of cardiac ryanodine receptors (RyRs) which form tightly packed clusters within specialised membrane structures in ventricular myocytes. These narrow membrane spaces are referred to as dyadic junctions where SR and sarcolemmal membranes form a gap of only ~15 nm. Within these dyadic junctions we find the RyR which is a truly gigantic protein: it is a homo-tetramer of a 500 kD subunit and approximately 30 nm in size. A lot of our recent work has concentrated on how to observe the nanoscale arrangement of RyRs and associated proteins in cardiac myocytes.
We are working on correlating the nanoscale arrangement of RyRs (and related calcium handling proteins) with the functional calcium signals that we observe in myocytes using fluorescent indicators to gain a better understanding of the functional determinants of calcium release. Experimentally, we use advanced fluorescence imaging approaches to investigate cardiac nanoscale physiology. Imaging in general, and fluorescence imaging in particular, is playing an increasingly important role in Physiology (and Biology/Medicine in general). Our ability to arrive at mechanistic understanding of physiological processes depends to a large extent on our ability to see the components of a cell, an organism, etc. Our laboratory therefore applies and develops state-of-the-art microscopy methods to help improve understanding of physiology.
A specific methodological focus in our group is the application and development of super-resolution imaging modalities. Physiological insight often critically depends on quantitative knowledge of protein numbers. Molecular scale fluorescence imaging now provides a number of ways in which quantitative imaging can be achieved and we have been pushing the technology to enable this routinely, using localisation microscopy, often using a modality called DNA-PAINT.
Further details about our research, methodology and current openings you find in our laboratory web pages .