The role of calcium as an intracellular second messenger in cells
My research interests are concerned with the kinetics of intracellular phenomena and particularly those that link events on the surface membrane of a cell to a physiological response, so called ‘second messengers’.
Thickening of the heart muscle, or hypertrophy, is one of the strongest predictors of the future risk of sudden cardiac death or heart failure. In one inherited form of cardiac hypertrophy (hypertrophic cardiomyopathy: HCM) thickening of the heart muscle has been shown to arise from mutations in the proteins that generate force during muscle cell contraction. We are analysing how these mutations alter the ability of the heart to contract and contrasting these changes with those caused by mutations in the same genes that are known to bring out another common cause of heart failure (dilated cardiomyopathy : DCM).
My research interests are concerned with the kinetics of intracellular phenomena and particularly those that link events on the surface membrane of a cell to a physiological response, so called ‘second messengers’. We observed that a minute and rapid change in free calcium ion (see Figure, blue trace - free calcium and black trace - force) was the prime linking event in skeletal muscle, as well as in other motile and non-motile cells using the aequorin luminescence technique. The obvious importance of calcium led to the development of methods for activating rapidly muscle cells and culminated in the use of time-resolved X-ray diffraction, as well as laser flash photolysis of photolabile caged calcium and caged calcium chelators, designed by others, but first used by my group to examine activation and deactivation processes in these cells. This work has been extended to the myocardium, where fatigue, calcium sensitizers and disease states are seen to affect directly the working of the heart, in systems where now the cell membrane cannot be a confounding influence.
Inherited cardiomyopathies provide the opportunity to dissect causal pathways in heart muscle disease. Our studies of molecular mechanisms in both HCM and DCM have led us to refine and test our hypothesis by developing further in vitro assays to investigate HCM caused by sarcomeric protein mutations and by comparing findings with those caused by DCM, where the phenotype is very different.
Studies of recombinant proteins will be complemented with analyses in human myocardial cardiomyopathy (DCM) and single myocyte studies and we will use our established and proposed in vitro techniques to test the hypothesis that different mutations produce fundamentally different effects to trigger these divergent remodelling pathways. Pathogenic mechanisms revealed in HCM and DCM are expected to be relevant to acquired conditions in which the role of abnormalities such as energy compromise has remained contentious in the absence of genetic evidence of causality.