Physiological interactions between Na(v)1.7 and Na(v)1.8 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.