Intracellular H+ ion signalling and control in the heart
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.
Our overall aim is to elucidate the integrated control of pHi within the heart, in both health and disease. This includes mapping H+i signalling in subcellular organelles of the cardiac myocyte, such as mitochondria, and the sarcoplasmic reticulum, imaging local pHi microdomain dynamics within the cytoplasm, and tracking H+ ion movements across the sarcolemma on transporters such as Na+/H+ exchange. We plan to image pHi in larger structures of the heart, such as the vascularised myocardium, the conduction system, and eventually the whole organ, in an attempt to discover how pHi regulation contributes to normal cardiac physiology and how this becomes remodelled in disease states. Throughout all our work we investigate how pHi changes impact on other ionic signalling systems in the heart, such as those for Ca2+ & Na+.
Our current objectives:
- To characterise fully the remodelling of pHi regulation in maladaptive hypertrophy and heart failure
- To investigate how common stresses that lead to maladaptive hypertrophy and its progression to heart failure cause alterations in the expression and localisation of pH regulatory proteins and other accessory components.
- To understand how these changes in pH regulation alter intracellular Ca2+ signalling
- To explore pharmacological approaches for therapeutically intervening in the dysregulation of pH homeostasis. Such an approach may ultimately inform the effective treatment of maladaptive hypertrophy and heart failure.
Work with us
We will shortly be seeking to employ an additional research technician and post-doctoral research assistant.
We welcome enquiries from prospective PhD students and post-docs to discuss available projects and funding opportunities. We are a member of the BHF Centre of Research Excellence and a member of the BHF non-clinical DPhil programme at Oxford. We are also a member of the OXION programme, which offers PhD studentships and training fellowships, and we maintain teaching links with the Oxford Doctoral Training Centre.
In addition to our main programme of work on H+ ion control and signalling in cardiac hypertrophy and heart failure, we maintain an interest in related areas. These include the structure and function of pH regulatory transport proteins, and the regulation of H+ permeation through gap junctions. We welcome enquiries from anyone interested in pursuing research in these or similar areas.
Linescan of calcium wave in adult rat ventricular myocyte loaded with fluo-3 (time on y axis 1 s)
HeLa cells with membrane (WGA) and nuclear (DAPI) staining
Neonatal rat ventricular myocyte monolayer with pHi-sensitive dye (SNARF-1)