Interplay between pH, Ca, and E-C coupling at the cellular level

Pawel Swietach*, Kenneth W Spitzer, Richard D. Vaughan-Jones

Department of Physiology, Anatomy and Genetics, Oxford University, United Kingdom

*pawel.swietach@dpag.ox.ac.uk

Intracellular pH (pHi) is an important modulator of cardiac excitation-contraction coupling. The activity of virtually all proteins is subject to their protonation state, and therefore the effects of pHi on cell-function are often complex. An additional level of complexity is introduced by the slow mobility of H+ and Ca2+ ions inside cells, which may lead to pHi/[Ca2+]i non-uniformity. The interactions between H+ and Ca2+ ions can occur (i) at the level of common buffer molecules (e.g. troponin-C), (ii) by pHi-modulation of Ca2+-transporter activity (e.g. pH-sensitivity of SR Ca2+-ATPAse [SERCA]) or vice versa (e.g. Ca2+/calmodulin-modulation of Na+/H+ exchange, [NHE]), or (iii) through a third solute, such as intracellular Na+, linking pHi with [Ca2+]i (e.g. functional coupling between NHE and Na+/Ca2+ exchange [NCX]). Pathophysiologically, pHi falls during myocardial ischaemia. Experimentally, pHi can be reduced by membrane-permeable weak acids (e.g. acetic acid/acetate) or by UV-photolytic uncaging from membrane-permeable H+-donors (e.g. 2-nitrobenzaldehyde).

Ca2+-transients (CaT) in paced ventricular myocytes are pHi-sensitive. Mitochondria play a major role in setting diastolic [Ca2+]. Mitochondrial Ca2+-release is evoked by low pHi, and blocked by inhibitors, such as myxothiazol and FCCP. The SR [Ca2+] content is important in determining the peak systolic level. Total SR [Ca2+] content is dependent on cellular Ca2+ retention, and therefore the rate of Na+-driven Ca2+ extrusion by NCX. Physiologically, a fall in pHi stimulates Na+-driven acid-extrusion on transporters, such as NHE, with a consequent rise in [Na+]i. Inhibition of the [Na+]i rise (e.g. blocking NHE with cariporide) attenuates the pHi-evoked change in systolic [Ca2+]. The rate of Ca2+ recovery from systolic to diastolic levels is shaped by the activity of Ca2+ transporters, such as NCX and SERCA. Low pHi inhibits these transporters and lengthens the CaT. In summary, the effect of pHi on CaTs depends on the state of mitochondria, SR load and Ca2+-transporters.

References:

1.      Vaughan-Jones RD, Spitzer KW, Swietach P. (2009), "Intracellular pH regulation in heart", J Mol Cell Cardiol 46: 318-31

2.      Swietach P, Spitzer KW, Vaughan-Jones RD. (2007), "pH-Dependence of extrinsic and intrinsic H+-ion mobility in the rat ventricular myocyte, investigated using flash photolysis of a caged-H+ compound", Biophys J 92: 641-53

3.      Yamamoto T, Swietach P, Rossini A, Loh SH, Vaughan-Jones RD, Spitzer KW. (2005). "Functional diversity of electrogenic Na+-HCO3- cotransport in ventricular myocytes from rat, rabbit and guinea pig" J Physiol 562: 455-75