1. Importance of pH regulation; techniques used
Intracellular pH is a powerful modulator of cell function. In the heart, it is normally maintained at a value close to 7.20, equivalent to a cytoplasmic H+ concentration of ~60 nM. Changes from this value, by as little as 10 nM, significantly modulate other cellular processes, such as intracellular Ca2+ signalling, electrical excitation, and contraction. Since H+ ions are generated liberally as end products of respiration, intracellular H+ signalling provides important coupling between metabolism and the biochemical, electrical and mechanical activity of cardiac myocytes. Changes of H+i by 10 nM or more occur physiologically, for example, during changes of heart rate and cardiac workload. The homeostatic regulation of [H+]i (i.e. pHi) is thus fundamental to the maintenance of normal cardiac performance. Dysregulation of H+ signalling and its control has now been implicated in major clinical pathologies including myocardial ischaemia/reperfusion, arrhythmia, maladaptive hypertrophy, and heart failure.
We investigate this using a combination of real-time epifluorescence and confocal ionic imaging (H+, Ca2+, Na+, Mg2+), pharmacological inhibition, mapping of protein expression and localisation, genetic manipulation, and computational modelling. Experiments employ enzymatically isolated cardiac myocytes, cell culture systems and animal models, including those for cardiac hypertrophy and heart failure.