A population of in silico models identifies the interplay between Nav 1.8 conductance and potassium currents as key in regulating human dorsal root ganglion neuron excitability

Abstract

Background: The Nav 1.8 sodium channel has a key role in generating repetitive action potentials in nociceptive human dorsal root ganglion neurons. Nav 1.8 is differentiated from other voltage-gated sodium channels by its unusually slow inactivation kinetics and depolarised voltage-dependence of activation. These features are particularly pronounced in the human Nav 1.8 channel and allow the channel to remain active during repolarisation. Gain-of-function mutations in Nav 1.8 have been linked to neuropathic pain and selective blockers of Nav 1.8 have been developed as potential new analgesics. However, it is not well understood how modulating the Nav 1.8 conductance alters neuronal excitability and how this depends on the balance of other ion channels expressed by nociceptive neurons. Methods: To investigate this, we developed a novel computational model of the human dorsal root ganglion neuron and used it to construct a population of models that mimicked inter-neuronal heterogeneity in ionic conductances and action potential morphology Results: By simulating changes to the Nav 1.8 conductance in the population of models, we found that moderately increasing the Nav 1.8 conductance led to increased firing rate, as expected, but increasing Nav 1.8 conductance beyond an inflection point caused firing rate to decrease. We found that the delayed rectifier and M-type potassium conductances were also critical for determining neuronal excitability. In particular, altering the delayed rectifier potassium conductance shifted the position of the Nav 1.8 inflection point and therefore the relationship between Nav 1.8 conductance and firing rate. Conclusions: Our results suggest that the effects of modulating Nav 1.8 in a nociceptive neuron can depend significantly on other conductances, particularly potassium conductances.