Physiological interactions between Nav1.7 and Nav1.8 sodium channels: a computer simulation study

We have examined the question of how the level of expression of sodium channel Na v 1.8 affects the function of dorsal root ganglion (DRG) neurons that also express Na v 1.7 channels and, conversely, how the level of expression of sodium channel Na v 1.7 affects the function of DRG neurons that also express Na v 1.8, using computer simulations. Our results demonstrate several previously undescribed effects of expression of Na v 1.7: 1) at potentials more negative than −50 mV, increasing Na v 1.7 expression reduces current threshold. 2) Na v 1.7 reduces, but does not eliminate, the dependence of action potential (AP) threshold on membrane potential. 3) In cells that express Na v 1.8, the presence of Na v 1.7 results in larger amplitude subthreshold oscillations and increases the frequency of repetitive firing. Our results also demonstrate multiple effects of expression of Na v 1.8: 1) dependence of current threshold on membrane potential is eliminated or reversed by expression of Na v 1.8 at ≥50% of normal values. 2) Expression of Na v 1.8 alone, in the absence of Na v 1.7, can support subthreshold oscillation. 3) Na v 1.8 is required for generation of overshooting APs, and its expression results in a prolonged AP with an inflection of the falling phase. 4) Increasing levels of expression of Na v 1.8 result in a reduction in the voltage threshold for AP generation. 5) Increasing levels of expression of Na v 1.8 result in an attenuation of Na v 1.7 current during activity evoked by sustained depolarization due, at least in part, to accumulation of fast inactivation by Na v 1.7 following the first AP. These results indicate that changes in the level of expression of Na v 1.7 and Na v 1.8 may provide a regulatory mechanism that tunes the excitability of small DRG neurons.