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H(+) ions are powerful modulators of cardiac function, liberated during metabolic activity. Among their physiological effects is a chemical gating of cell-to-cell communication, caused by H(+)-mediated closure of connexin (Cx) channels at gap junctions. This protects surrounding tissue from the damaging effects of local intracellular acidosis. Cx proteins (largely Cx-43 in ventricle) form multimeric pores between cells, permitting translocation of ions and other solutes up to approximately 1 kDa. The channels are essential for electrical and metabolic coordination of a tissue. Here we demonstrate that, contrary to expectation, H(+) ions can induce an increase of gap-junctional permeability. This occurs during modest intracellular acid loads in myocyte pairs isolated from mammalian ventricle. We show that the increase in permeability allows a local rise of [H(+)](i) to dissipate into neighboring myocytes, thereby providing a mechanism for spatially regulating intracellular pH (pH(i)). During larger acid loads, the increased permeability is overridden by a more familiar H(+)-dependent inhibition (H(+) inactivation). This restricts cell-to-cell H(+) movement, while allowing sarcolemmal H(+) transporters such as Na(+)/H(+) exchange, to extrude the acid from the cell. The H(+) sensitivity of Cx channels therefore defines whether junctional or sarcolemmal mechanisms are selected locally for the removal of an acid load. The bell-shaped pH dependence of permeability suggests that, in addition to H(+) inactivation, an H(+) activation process regulates the ensemble of Cx channels open at the junction. As well as promoting spatial pH(i) regulation, H(+) activation of junctional permeability may link increased metabolic activity to improved myocardial coupling, the better to meet mechanical demand.

Original publication




Journal article


Circ Res

Publication Date





1045 - 1054


Animals, Benzopyrans, Connexin 43, Electric Impedance, Fluorescent Dyes, Gap Junctions, Guinea Pigs, Heart, Homeostasis, Hydrogen-Ion Concentration, Intracellular Membranes, Ion Channels, Models, Biological, Myocardium, Permeability, Protons, Rats, Tissue Distribution