H+ ion activation and inactivation of the ventricular gap junction: a basis for spatial regulation of intracellular pH.
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.
Swietach
Pawel
P
The Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, UK.
Rossini
Alessandra
A
Spitzer
Kenneth W
KW
Vaughan-Jones
Richard D
RD
D000818:Animals; D001578:Benzopyrans / Q000493:pharmacokinetics; D018031:Connexin 43 / Q000378:metabolism; D017097:Electric Impedance; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D017629:Gap Junctions / Q000378:metabolism / Q000502:physiology*; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D006706:Homeostasis; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D010539:Permeability; D011522:Protons; D051381:Rats; D014018:Tissue Distribution
D001578:Benzopyrans; D018031:Connexin 43; D005456:Fluorescent Dyes; D007473:Ion Channels; D011522:Protons; C063917:SNARF dye