Spatial aspects of intracellular pH regulation in heart muscle

Intracellular pH (pHi) is an important modulator of cardiac function. Because it is readily influenced by metabolic processes, pHi 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, Hi+-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. Hi+-mobility via the buffer shuttles is low, and this can result in significant pHi non-uniformity under conditions of high proton flux across the sarcolemma or within the cell. Spatial regulation of pHi is complemented by passive H+ permeation between cells through gap junctions. This permeation is also mediated via protonated buffers. The control of pHi is therefore dependent on carrier molecules that spatially shuttle protons within and between cells. In this review, we consider the physiological regulation of Hi+-mobility and permeation, and its relevance to pHi-control in normal and pathophysiological states such as myocardial ischaemia, a clinical condition associated with severe intracellular acidosis.