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(Circulation Research. 2007;100:1045.)
© 2007 American Heart Association, Inc.

Cellular Biology

H⁺ Ion Activation and Inactivation of the Ventricular Gap Junction

A Basis for Spatial Regulation of Intracellular pH

Pawel Swietach, Alessandra Rossini, Kenneth W. Spitzer, Richard D. Vaughan-Jones

From The Burdon Sanderson Cardiac Science Centre (P.S., A.R., R.D.V.-J.), Department of Physiology, Anatomy and Genetics, University of Oxford, UK; and The Nora Eccles Harrison Cardiovascular Research and Training Institute (K.W.S.), University of Utah, Salt Lake City.

Correspondence to Richard D. Vaughan-Jones, PhD, Burdon Sanderson Cardiac Science Center, University Laboratory of Physiology, Parks Rd, Oxford OX1 3PT, UK. E-mail richard.vaughan-jones{at}dpag.ox.ac.uk

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 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.

Key Words: connexin 43 • gap junction channel • intracellular pH • ventricular myocytes