The theme to my research career has been the use of electrophysiolological techniques to measure ion channel function. I use kinetic models of channel gating and conductance to unravel and identify the complex mechanisms that control ion channels. Since 1992 my research has focused on the ion channels regulating the Ca2+ release from intracellular stores (ER/SR). This work has uncovered new mechanisms for activation of ryanodine receptor (RyR) calcium release channels by Ca2+ Mg2+ and ATP and produced the first quantitative theory of luminal Ca2+ control of RyR2. These developments lead to our first understanding of the link molecular defects in muscle and the symptoms of cardiac muscle disorders such as CPVT. This work culminated in the discovery of the first anti-arrhythmia drug therapy targeted to cardiac calcium release channels. My recent research aims to better understand how the properties of single RyR2 channels are linked to contraction and rhythmicity in the heart. To this end, I use develop 3D computer models of the cardiac dyad that simulate the time-course of Ca2+ sparks, Ca2+ blinks and Ca2+ spark restitution. This work has identified the first plausible negative-regulation mechanism for SR calcium release that counters the inherently regenerative process of calcium induced calcium release. Thus providing an explanation for the control of excitation-contraction coupling by the surface membrane.
Abstracts this author is presenting: