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We have shown that pHi in heart is controlled at the level of each constituent myocyte.  Specialised ion transport proteins, expressed at the sarcolemma, move H+ or their ionic equivalent (OH-, HCO3-) into or out of the cell, thereby compensating for displacements of pHi.  Our laboratory was the first to identify functionally three of the principal transporters involved in pHi regulation, the Cl--HCO3- exchanger (Anion Exchanger, AE), the Na+-HCO3- cotransporter (NBC) and a Cl--OH- exchanger (CHE). All except CHE have now been cloned, and the basic kinetic characteristics of the four principal transporters, NHE, AE, NBC and CHE have been mapped out, particularly their dependence on intracellular and extracellular pH levels.  When inserted into a computational model these pH dependencies accurately predict the time course of response of whole cell pHi to acute intracellular or extracellular acid/base loads. 

It has become apparent that pHi is controlled locally within the cardiac cell. This is because intracellular proton mobility within cytoplasm is very low – more than 200 fold lower than proton mobility in water. Low H+ mobility is a direct consequence of the high levels of intracellular buffers, many of which are poorly mobile. As a result, localised intracellular acid or base loads can take many seconds to dissipate diffusively. We have established the mechanisms responsible for regulating proton mobility within the cardiac myocyte, including the role played by the CO2/HCO3- buffer system and the endogenous enzyme carbonic anhydrase. We have discovered that pHi is also regulated spatially within cardiac myocytes by means of diffusible carrier molecules (e.g. histidyl dipeptides: HDPs) that shuttle H+ throughout the cytoplasmic compartment, and couple it functionally to the sarcolemmal transport proteins. 

One implication of the low H+ mobility is that pHi can become spatially non-uniform, leading to the generation of pHi microdomains. We have investigated circumstances that lead to such spatial non-uniformity of pHi, such as stimulation of sarcolemmal acid transport or localised exposure of myocardial cells to membrane permeant weak acids or bases. A dramatic example of this is exposure of a ventricular cell to an extracellular gradient of pCO2, such as may occur across an ischaemic border zone in the myocardium. This leads to a major standing gradient of intracellular pH that can be as large as 1.0 pH unit.  

A further level of pHi control is afforded by the flow of H+-loaded HDPs through gap junctions that bridge between adjacent cells, thereby regulating the local spread of H+ ions within the myocardium.  We are investigating the gating of this cell-to-cell H+ traffic by both pHi and Ca2+i. Such gating is important to our understanding of acid spread within the heart, for example from ischaemic to non-ischaemic zones.