Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons

C-type dorsal root ganglion (DRG) neurons can generate tetrodotoxin-resista nt (TTX-R) sodium-dependent action potentials. However, multiple sodium cha nnels are expressed in these neurons, and the molecular identity of the TTX -R sodium channels that contribute to action potential production in these neurons has not been established. In this study, we used current-clamp reco rdings to compare action potential electrogenesis in Na(v)1.8 (+/+) and (-/ -) small DRG neurons maintained for 2-8 h in vitro to examine the role of s odium channel Na(v)1.8 (alpha -NS) in action potential electrogenesis. Alth ough there was no significant difference in resting membrane potential, inp ut resistance, current threshold, or voltage threshold in Na(v)1.8 (+/+) an d (-/-) DRG neurons, there were significant differences in action potential electrogenesis. Most Na(v)1.8 (+/+) neurons generate all-or-none action po tentials, whereas most of Na(v)1.8 (-/-) neurons produce smaller graded res ponses. The peak of the response was significantly reduced in Na(v)1.8 (-/- ) neurons [31.5 +/- 2.2 (SE) mV] compared with Na(v)1.8 (+/+) neurons (55.0 +/- 4.3 mV). The maximum rise slope was 84.7 +/- 11.2 mV/ms in Na(v)1.8 (/+) neurons, significantly faster than in Na(v)1.8 (-/-) neurons where it w as 47.2 +/- 1.3 mV/ms. Calculations based on the action potential overshoot in Na(v)1.8 (+/+) and (-/-) neurons, following blockade of Ca2+ currents, indicate that Na(v)1.8 contributes a substantial fraction (80-90%) of the i nward membrane current that flows during the rising phase of the action pot ential. We found that fast TTX-sensitive Na+ channels can produce all-or-no ne action potentials in some Na(v)1.8 (-/-) neurons but, presumably as a re sult of steady-state inactivation of these channels, electrogenesis in Na(v )1.8 (-/-) neurons is more sensitive to membrane depolarization than in Na( v)1.8 (+/+) neurons, and, in the absence of Na(v)1.8, is attenuated with ev en modest depolarization. These observations indicate that Na(v)1.8 contrib utes substantially to action potential electrogenesis in C-type DRG neurons .