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Intracellular H+ ion signalling and control in the heart

Confocal images of adult rat ventricular myocytes with A. membrane staining (ANEPPS) B. calcium wave (fluo-3) C. pHi gradient (SNARF-1)
Confocal images of adult rat ventricular myocytes with A. membrane staining (ANEPPS) B. calcium wave (fluo-3) C. pHi gradient (SNARF-1)

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.

Our team

  • Richard Vaughan-Jones
    Richard Vaughan-Jones

    Professor of Cellular Physiology

  • Kerrie Ford
    Kerrie Ford

    Postdoctoral Research Scientist

  • Chela Nunez Alonso

    Research Technician

  • Mark Richards

    Postdoctoral Research Scientist

Selected publications

Related research themes