A Proton Leak Current through the Cardiac Sodium Channel Is Linked to Mixed Arrhythmia and the Dilated Cardiomyopathy Phenotype
Figure 3
Nav1.5/R219H exhibits a pH dependent current.
Panel (A) shows that varying the Ringer's extracellular pH (pHo) induced an inward current in Nav1.5/R219H–injected oocytes. An acidic Ringer's solution induced inward currents in an oocyte expressing the Nav1.5/R219H channel. The oocyte was held at −80 mV and a −140 mV test pulse was repeated every 2 s (only current responses at −140 mV are shown). The bottom panels show current traces of the experiment in (A). The inset shows the protocol, and the grey zone indicates where currents were measured as a mean of the current amplitude between 150 and 200 ms.(B) Effect of an acidic Ringer's solution in the presence of TTX in an oocyte expressing the Nav1.5/R219H mutant channel in a background in which the native cysteine in D1 had been replaced with a tyrosine (C373F) and in the presence of 1 µM TTX. This mutation in the pore region increases the TTX sensitivity of cardiac channels 60- to100-fold, as described previously [46]. (C) Currents recorded from a water-injected and oocyte expressing the Nav1.5/WT or Nav1.5/R219H channel. The oocytes were held at −80 mV and were pulsed to −140 mV. This protocol was repeated every 2 s as indicated in the inset (panel A). Acidic NMDG solutions induced a pH-dependent current in an oocyte expressing the Nav1.5/R219H channel in a C373F background in the presence of 1 µM TTX. This experiment was carried out in a Nav1.5 background in which the native cysteine in D1 was replaced with a tyrosine (C373F). (D) Acidic NMDG solutions induced a reversible current in an oocyte expressing the Nav1.5/R219H channel.