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 (pH_i) 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 pH_i 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 pH_i/[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 pH_i-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 pH_i with [Ca²⁺]_i (e.g. functional coupling between NHE and Na⁺/Ca²⁺ exchange [NCX]). Pathophysiologically, pH_i falls during myocardial ischaemia. Experimentally, pH_i 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 pH_i-sensitive. Mitochondria play a major role in setting diastolic [Ca²⁺]. Mitochondrial Ca²⁺-release is evoked by low pH_i, 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 pH_i 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 pH_i-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 pH_i inhibits these transporters and lengthens the CaT. In summary, the effect of pH_i on CaTs depends on the state of mitochondria, SR load and Ca²⁺-transporters.

References:

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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