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Abstract
BackgroundSmall neurons of the dorsal root ganglion (DRG) express five of the nine known voltage-gated sodium channels. Each channel has unique biophysical characteristics which determine how it contributes to the generation of action potentials (AP). To better understand how AP amplitude is maintained in nociceptive DRG neurons and their centrally projecting axons, which are subjected to depolarization within the dorsal horn, we investigated the dependence of AP amplitude on membrane potential, and how that dependence is altered by the presence or absence of sodium channel Nav1.8.ResultsIn small neurons cultured from wild type (WT) adult mouse DRG, AP amplitude decreases as the membrane potential is depolarized from -90 mV to -30 mV. The decrease in amplitude is best fit by two Boltzmann equations, having V1/2 values of -73 and -37 mV. These values are similar to the V1/2 values for steady-state fast inactivation of tetrodotoxin-sensitive (TTX-s) sodium channels, and the tetrodotoxin-resistant (TTX-r) Nav1.8 sodium channel, respectively. Addition of TTX eliminates the more hyperpolarized V1/2 component and leads to increasing AP amplitude for holding potentials of -90 to -60 mV. This increase is substantially reduced by the addition of potassium channel blockers. In neurons from Nav1.8(-/-) mice, the voltage-dependent decrease in AP amplitude is characterized by a single Boltzmann equation with a V1/2 value of -55 mV, suggesting a shift in the steady-state fast inactivation properties of TTX-s sodium channels. Transfection of Nav1.8(-/-) DRG neurons with DNA encoding Nav1.8 results in a membrane potential-dependent decrease in AP amplitude that recapitulates WT properties.ConclusionWe conclude that the presence of Nav1.8 allows AP amplitude to be maintained in DRG neurons and their centrally projecting axons even when depolarized within the dorsal horn.
Highlights
Small neurons of the dorsal root ganglion (DRG) express five of the nine known voltage-gated sodium channels
The more hyperpolarized V1/2 is consistent with the voltage-dependence of steady-state fast inactivation that is characteristic of the TTX-s sodium channels present in small DRG neurons (V1/2's of -64 to -75 mV), while the more depolarized V1/2 is consistent with a contribution from TTX-r channels, which have fast inactivation V1/2's of -30 to -45 mV [6,7,9,10,11,12,13]
We have shown that the action potentials (AP) amplitude of small DRG neurons decreases as a function of membrane depolarization, and that this relationship is best fit with two Boltzmann components
Summary
Small neurons of the dorsal root ganglion (DRG) express five of the nine known voltage-gated sodium channels. Molecular Pain 2007, 3:12 http://www.molecularpain.com/content/3/1/12 spinal cord dorsal horn It is well-established that extracellular potassium levels ([K+]o) within the dorsal horn can rise significantly as a result of neuronal activity induced by many stimuli including peripheral injury and noxious stimuli [1]; these changes in [K+]o can, in turn, lead to depolarization which can inactivate sodium channels, producing conduction block of neurons and neuronal processes such as axons and their terminals [2,3,4]. Some forms of peripherally induced pain have a persistent quality, suggesting that the nociceptive afferent barrage can be maintained even in the face of this depolarization This raises the possibility that the membranes of nociceptive DRG neurons and their centrally projecting axons are constructed so as to permit the conduction of action potentials even when depolarized. Nav1.7 channels have a relatively slow rate of inactivation from the closed state, which allows them to produce inward current in response to slow depolarizations
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