The pH dependence of late sodium current in large sensory neurons

The effects of altering extracellular pH on late Na+ currents were investigated in large dorsal root ganglion neurons from rats (100-300 g), using patch-clamp techniques. The late current amplitude was steeply dependent upon pH over a range which included normal physiological values: raising the pH from 7.3 to 8.3 approximately doubled the amplitude. Whole-cell late currents 60 ms after depolarization to - 30 mV were blocked with an apparent pKa of 6.96. The pH-dependent changes in current amplitude could not be accounted for by the effects of altered surface charge. In recordings of unitary Na+ currents from outside-out membrane patches, acidification promoted channel opening to a reduced conductance level, near one-half of its maximal value. Acidification to pH < 6.0 also changed the kinetics of the current recruited with the lowest threshold from non-inactivating to inactivating, with the elimination of late openings. We conclude that lowering pH from an initial alkaline or neutral value blocks late Na+ current by reducing the number of contributing channels while also reducing the single channel conductance. The pH dependence of late Na+ current helps to explain clinically relevant changes in neuronal excitability in response to small (i.e. < 1 unit) perturbations in extracellular pH.