Contribution of Nav 1.8 sodium channels to action potential electrogenesis in DRG neurons

Muthukrishnan Renganathan, Theodore Cummins, Stephen G. Waxman

Research output: Contribution to journalArticle

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Abstract

C-type dorsal root ganglion (DRG) neurons can generate tetrodotoxin-resistant (TTX-R) sodium-dependent action potentials. However, multiple sodium channels 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 recordings to compare action potential electrogenesis in Nav 1.8 (+/+) and (-/-) small DRG neurons maintained for 2-8 h in vitro to examine the role of sodium channel Nav 1.8 (α-SNS) in action potential electrogenesis. Although there was no significant difference in resting membrane potential, input resistance, current threshold, or voltage threshold in Nav 1.8 (+/+) and (-/-) DRG neurons, there were significant differences in action potential electrogenesis. Most Nav 1.8 (+/+) neurons generate all-or-none action potentials, whereas most of Nav 1.8 (-/-) neurons produce smaller graded responses. The peak of the response was significantly reduced in Nav 1.8 (-/-) neurons [31.5 ± 2.2 (SE) mV] compared with Nav 1.8 (+/+) neurons (55.0 ± 4.3 mV). The maximum rise slope was 84.7 ± 11.2 mV/ms in Nav 1.8 (+/+) neurons, significantly faster than in Nav 1.8 (-/-) neurons where it was 47.2 ± 1.3 mV/ms. Calculations based on the action potential overshoot in Nav 1.8 (+/+) and (-/-) neurons, following blockade of Ca2+ currents, indicate that Nav1.8 contributes a substantial fraction (80-90%) of the inward membrane current that flows during the rising phase of the action potential. We found that fast TTX-sensitive Na+ channels can produce all-or-none action potentials in some Nav 1.8 (-/-) neurons but, presumably as a result of steady-state inactivation of these channels, electrogenesis in Nav 1.8 (-/-) neurons is more sensitive to membrane depolarization than in Nav 1.8 (+/+) neurons, and, in the absence of Nav 1.8, is attenuated with even modest depolarization. These observations indicate that Nav 1.8 contributes substantially to action potential electrogenesis in C-type DRG neurons.

Original languageEnglish (US)
Pages (from-to)629-640
Number of pages12
JournalJournal of Neurophysiology
Volume86
Issue number2
StatePublished - 2001
Externally publishedYes

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Sodium Channels
Spinal Ganglia
Action Potentials
Neurons
Tetrodotoxin
Membranes
Membrane Potentials

ASJC Scopus subject areas

  • Physiology
  • Neuroscience(all)

Cite this

Contribution of Nav 1.8 sodium channels to action potential electrogenesis in DRG neurons. / Renganathan, Muthukrishnan; Cummins, Theodore; Waxman, Stephen G.

In: Journal of Neurophysiology, Vol. 86, No. 2, 2001, p. 629-640.

Research output: Contribution to journalArticle

Renganathan, Muthukrishnan ; Cummins, Theodore ; Waxman, Stephen G. / Contribution of Nav 1.8 sodium channels to action potential electrogenesis in DRG neurons. In: Journal of Neurophysiology. 2001 ; Vol. 86, No. 2. pp. 629-640.
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abstract = "C-type dorsal root ganglion (DRG) neurons can generate tetrodotoxin-resistant (TTX-R) sodium-dependent action potentials. However, multiple sodium channels 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 recordings to compare action potential electrogenesis in Nav 1.8 (+/+) and (-/-) small DRG neurons maintained for 2-8 h in vitro to examine the role of sodium channel Nav 1.8 (α-SNS) in action potential electrogenesis. Although there was no significant difference in resting membrane potential, input resistance, current threshold, or voltage threshold in Nav 1.8 (+/+) and (-/-) DRG neurons, there were significant differences in action potential electrogenesis. Most Nav 1.8 (+/+) neurons generate all-or-none action potentials, whereas most of Nav 1.8 (-/-) neurons produce smaller graded responses. The peak of the response was significantly reduced in Nav 1.8 (-/-) neurons [31.5 ± 2.2 (SE) mV] compared with Nav 1.8 (+/+) neurons (55.0 ± 4.3 mV). The maximum rise slope was 84.7 ± 11.2 mV/ms in Nav 1.8 (+/+) neurons, significantly faster than in Nav 1.8 (-/-) neurons where it was 47.2 ± 1.3 mV/ms. Calculations based on the action potential overshoot in Nav 1.8 (+/+) and (-/-) neurons, following blockade of Ca2+ currents, indicate that Nav1.8 contributes a substantial fraction (80-90{\%}) of the inward membrane current that flows during the rising phase of the action potential. We found that fast TTX-sensitive Na+ channels can produce all-or-none action potentials in some Nav 1.8 (-/-) neurons but, presumably as a result of steady-state inactivation of these channels, electrogenesis in Nav 1.8 (-/-) neurons is more sensitive to membrane depolarization than in Nav 1.8 (+/+) neurons, and, in the absence of Nav 1.8, is attenuated with even modest depolarization. These observations indicate that Nav 1.8 contributes substantially to action potential electrogenesis in C-type DRG neurons.",
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N2 - C-type dorsal root ganglion (DRG) neurons can generate tetrodotoxin-resistant (TTX-R) sodium-dependent action potentials. However, multiple sodium channels 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 recordings to compare action potential electrogenesis in Nav 1.8 (+/+) and (-/-) small DRG neurons maintained for 2-8 h in vitro to examine the role of sodium channel Nav 1.8 (α-SNS) in action potential electrogenesis. Although there was no significant difference in resting membrane potential, input resistance, current threshold, or voltage threshold in Nav 1.8 (+/+) and (-/-) DRG neurons, there were significant differences in action potential electrogenesis. Most Nav 1.8 (+/+) neurons generate all-or-none action potentials, whereas most of Nav 1.8 (-/-) neurons produce smaller graded responses. The peak of the response was significantly reduced in Nav 1.8 (-/-) neurons [31.5 ± 2.2 (SE) mV] compared with Nav 1.8 (+/+) neurons (55.0 ± 4.3 mV). The maximum rise slope was 84.7 ± 11.2 mV/ms in Nav 1.8 (+/+) neurons, significantly faster than in Nav 1.8 (-/-) neurons where it was 47.2 ± 1.3 mV/ms. Calculations based on the action potential overshoot in Nav 1.8 (+/+) and (-/-) neurons, following blockade of Ca2+ currents, indicate that Nav1.8 contributes a substantial fraction (80-90%) of the inward membrane current that flows during the rising phase of the action potential. We found that fast TTX-sensitive Na+ channels can produce all-or-none action potentials in some Nav 1.8 (-/-) neurons but, presumably as a result of steady-state inactivation of these channels, electrogenesis in Nav 1.8 (-/-) neurons is more sensitive to membrane depolarization than in Nav 1.8 (+/+) neurons, and, in the absence of Nav 1.8, is attenuated with even modest depolarization. These observations indicate that Nav 1.8 contributes substantially to action potential electrogenesis in C-type DRG neurons.

AB - C-type dorsal root ganglion (DRG) neurons can generate tetrodotoxin-resistant (TTX-R) sodium-dependent action potentials. However, multiple sodium channels 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 recordings to compare action potential electrogenesis in Nav 1.8 (+/+) and (-/-) small DRG neurons maintained for 2-8 h in vitro to examine the role of sodium channel Nav 1.8 (α-SNS) in action potential electrogenesis. Although there was no significant difference in resting membrane potential, input resistance, current threshold, or voltage threshold in Nav 1.8 (+/+) and (-/-) DRG neurons, there were significant differences in action potential electrogenesis. Most Nav 1.8 (+/+) neurons generate all-or-none action potentials, whereas most of Nav 1.8 (-/-) neurons produce smaller graded responses. The peak of the response was significantly reduced in Nav 1.8 (-/-) neurons [31.5 ± 2.2 (SE) mV] compared with Nav 1.8 (+/+) neurons (55.0 ± 4.3 mV). The maximum rise slope was 84.7 ± 11.2 mV/ms in Nav 1.8 (+/+) neurons, significantly faster than in Nav 1.8 (-/-) neurons where it was 47.2 ± 1.3 mV/ms. Calculations based on the action potential overshoot in Nav 1.8 (+/+) and (-/-) neurons, following blockade of Ca2+ currents, indicate that Nav1.8 contributes a substantial fraction (80-90%) of the inward membrane current that flows during the rising phase of the action potential. We found that fast TTX-sensitive Na+ channels can produce all-or-none action potentials in some Nav 1.8 (-/-) neurons but, presumably as a result of steady-state inactivation of these channels, electrogenesis in Nav 1.8 (-/-) neurons is more sensitive to membrane depolarization than in Nav 1.8 (+/+) neurons, and, in the absence of Nav 1.8, is attenuated with even modest depolarization. These observations indicate that Nav 1.8 contributes substantially to action potential electrogenesis in C-type DRG neurons.

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