Physiological interactions between NA _v1.7 and NA _v1.8 sodium channels: A computer simulation study

We have examined the question of how the level of expression of sodium channel Nav1.8 affects the function of dorsal root ganglion (DRG) neurons that also express Nav1.7 channels and, conversely, how the level of expression of sodium channel Nav1.7 affects the function of DRG neurons that also express Nav1.8, using computer simulations. Our results demonstrate several previously undescribed effects of expression of Nav1.7: 1) at potentials more negative than 50 mV, increasing Nav1.7 expression reduces current threshold. 2) Nav1.7 reduces, but does not eliminate, the dependence of action potential (AP) threshold on membrane potential. 3) In cells that express Nav1.8, the presence of Nav1.7 results in larger amplitude subthreshold oscillations and increases the frequency of repetitive firing. Our results also demonstrate multiple effects of expression of Nav1.8: 1) dependence of current threshold on membrane potential is eliminated or reversed by expression of Nav1.8 at 50% of normal values. 2) Expression of Nav1.8 alone, in the absence of Nav1.7, can support subthreshold oscillation. 3) Nav1.8 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 Nav1.8 result in a reduction in the voltage threshold for AP generation. 5) Increasing levels of expression of Nav1.8 result in an attenuation of Nav1.7 current during activity evoked by sustained depolarization due, at least in part, to accumulation of fast inactivation by Nav1.7 following the first AP. These results indicate that changes in the level of expression of Nav1.7 and Nav1.8 may provide a regulatory mechanism that tunes the excitability of small DRG neurons.