Spatial aspects of intracellular pH regulation in heart muscle

Intracellular pH (pH_i) is an important modulator of cardiac function. Because it is readily influenced by metabolic processes, pH_i is controlled physiologically. Classical models of intracellular pH regulation comprise acid/base transport proteins expressed in the sarcolemma, acting in concert with intracellular buffers. These two processes are coupled via a diffusive movement of protons. Because intracellular H⁺ buffering is high, H_i⁺-diffusion occurs through a passive shuttling on intrinsic mobile buffers such as acetylated carnosine, anserine and homocarnosine: low molecular weight imidazole compounds. This mechanism is assisted by carbonic buffer, a system regulated biochemically by the enzyme carbonic anhydrase. H_i⁺-mobility via the buffer shuttles is low, and this can result in significant pH_i non-uniformity under conditions of high proton flux across the sarcolemma or within the cell. Spatial regulation of pH_i is complemented by passive H⁺ permeation between cells through gap junctions. This permeation is also mediated via protonated buffers. The control of pH_i is therefore dependent on carrier molecules that spatially shuttle protons within and between cells. In this review, we consider the physiological regulation of H_i⁺-mobility and permeation, and its relevance to pH_i-control in normal and pathophysiological states such as myocardial ischaemia, a clinical condition associated with severe intracellular acidosis.