Developmental Expression of the TTX-Resistant Voltage-Gated Sodium Channels Nav1.8 (SNS) and Nav1.9 (SNS2) in Primary Sensory Neurons

Abstract

The development of neuronal excitability involves the coordinated expression of different voltage-gated ion channels. We have characterized the expression of two sensory neuron-specific tetrodotoxin-resistant sodium channel α subunits, Na_v1. (SNS/PN3) and Na_v1.9 (SNS2/NaN), in developing rat lumbar dorsal root ganglia (DRGs). Expression of both Na_v1.8 and Na_v1.9 increases with age, beginning at embryonic day (E) 15 and E17, respectively, and reaching adult levels by postnatal day 7. Their distribution is restricted mainly to those subpopulations of primary sensory neurons in developing and adult DRGs that give rise to unmyelinated C-fibers (neurofilament 200 negative). Na_v1.8 is expressed in a higher proportion of neuronal profiles than Na_v1.9 at all stages during development, as in the adult. At E17, almost all Na_v1.8-expressing neurons also express the high-affinity NGF receptor TrkA, and only a small proportion bind to IB4, a marker for c-ret-expressing (glial-derived neurotrophic factor-responsive) neurons. Because IB4 binding neurons differentiate from TrkA neurons in the postnatal period, the proportion of Na_v1.8 cells that bind to IB4 increases, in parallel with a decrease in the proportion of Na_v1.8–TrkA co-expressing cells. In contrast, an equal number of Na_v1.9 cells bind IB4 and TrkA in embryonic life. The differential expression of Na_v1.8 and Na_v1.9 in late embryonic development, with their distinctive kinetic properties, may contribute to the development of spontaneous and stimulus-evoked excitability in small diameter primary sensory neurons in the perinatal period and the activity-dependent changes in differentiation they produce.