Current affiliations

• Position

  Research Associate

  Company

  Department of Cardiology, Wales Heart Research Institute, School of Medicine, Cardiff University

  Duration

  2007 - 2010

  Further information

City:

Caerdydd, Wales, United Kingdom

Hub:

Cardiff-Swansea

The sarcoplasmic reticulum Ca2+ -release channel provides a regulated pathway for the release of the Ca2+ that initiates contraction following excitation of the cardiac muscle cell with each action potential. The overall aim of the laboratory is to characterise the functional properties of the sarcoplasmic reticulum Ca2+-release channel (also known as the ryanodine receptor or RyR) and relate these properties to the structure of the channel protein. These investigations continue to reveal details of the mechanisms and structures underlying the function of this pivotal membrane protein in the normal myocardium and in pathophysiological states such as heart failure. To achieve our aims we use biophysical, molecular biological, biochemical and structural approaches.

Structures and mechanisms involved in cation translocation and discrimination in the cardiac sarcoplasmic reticulum calcium-release channel.
The contractile state of cardiac muscle is dependent upon the level of Ca2+ in the cytosol. On excitation, a small increase in cytosolic Ca2+ occurs as the result of an influx through sarcolemmal Ca2+ channels. This influx is not sufficient to raise cytosolic Ca2+ to a level at which contraction occurs but acts as a trigger for the release of additional Ca2+ from an intracellular store, the sarcoplasmic reticulum (SR). The pathway for Ca2+-induced Ca2+ release is provided by a membrane protein called the Ca2+-release channel (also known as the ryanodine receptor (RyR)). We have established that the efficiency of the SR Ca2+-release system is underpinned by enormous rates of cation translocation in this very unusual channel. In the current project we are using a combination of approaches to identify the structures and mechanisms governing ion movement and discrimination in the RyR channel. We are characterising the function of individual wild type and mutant channels. The design of mutants and the interpretation of data are enhanced by molecular dynamics simulations in a recently developed analogy model of the channel pore.