Nitric oxide blocks fast, slow, and persistent Na + channels in C-type DRG neurons by S-nitrosylation

M. Renganathan, Theodore Cummins, S. G. Waxman

Research output: Contribution to journalArticle

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Abstract

C-type dorsal root ganglion (DRG) neurons express three types of Na + currents: fast TTX-sensitive, slow TTX- resistant, and persistent TTX-resistant Na + currents. The nitric oxide (NO) donors papa-NONOate and S-nitroso-N-acetyl-DL-penicillamine inhibit all three types of Na + currents. The NO scavenger hemoglobin abolished the effects of papa-NONOate on Na + currents, indicating that NO or NO-related species inhibit these Na + currents. NO donor inhibition of all three types of Na + currents was reversed by washout. Incubation of neurons with 8-bromo cGMP, a membrane-permeable analogue of cGMP, and cG-PKI, an inhibitor of cGMP-dependent protein kinase, had no effect on papa-NONOate-mediated Na + current block, demonstrating that Na + current inhibition is independent of cGMP. Alkylation of free thiols with N-ethylmaleimide prevented the actions of papa-NONOate, suggesting that NO, or a related reactive nitrogen species, modifies sulfhydryl groups on Na + channels or a closely associated protein. Papa-NONOate-mediated block of Na + currents is not due to a hyperpolarizing shift in steady state voltage-dependent inactivation. The absence of NO-mediated enhancement of slow inactivation in fast and slow Na + channels indicates that NO does not inhibit fast and slow Na + channels by facilitating the transition to a slow inactivated state. These results demonstrate that inhibition of Na + currents is not due to the modulation of fast and slow sodium channel inactivation. Taken together, these results show that NO or NO-related products modify the sulfhydryl groups on Na + channels and inhibit Na + currents by blocking the channel conductance.

Original languageEnglish (US)
Pages (from-to)761-775
Number of pages15
JournalJournal of Neurophysiology
Volume87
Issue number2
StatePublished - 2002
Externally publishedYes

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Spinal Ganglia
Nitric Oxide
Neurons
Nitric Oxide Donors
Reactive Nitrogen Species
Cyclic GMP-Dependent Protein Kinases
Ethylmaleimide
Penicillamine
Sodium Channels
Alkylation
Sulfhydryl Compounds
Membranes
Proteins

ASJC Scopus subject areas

  • Physiology
  • Neuroscience(all)

Cite this

Nitric oxide blocks fast, slow, and persistent Na + channels in C-type DRG neurons by S-nitrosylation. / Renganathan, M.; Cummins, Theodore; Waxman, S. G.

In: Journal of Neurophysiology, Vol. 87, No. 2, 2002, p. 761-775.

Research output: Contribution to journalArticle

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N2 - C-type dorsal root ganglion (DRG) neurons express three types of Na + currents: fast TTX-sensitive, slow TTX- resistant, and persistent TTX-resistant Na + currents. The nitric oxide (NO) donors papa-NONOate and S-nitroso-N-acetyl-DL-penicillamine inhibit all three types of Na + currents. The NO scavenger hemoglobin abolished the effects of papa-NONOate on Na + currents, indicating that NO or NO-related species inhibit these Na + currents. NO donor inhibition of all three types of Na + currents was reversed by washout. Incubation of neurons with 8-bromo cGMP, a membrane-permeable analogue of cGMP, and cG-PKI, an inhibitor of cGMP-dependent protein kinase, had no effect on papa-NONOate-mediated Na + current block, demonstrating that Na + current inhibition is independent of cGMP. Alkylation of free thiols with N-ethylmaleimide prevented the actions of papa-NONOate, suggesting that NO, or a related reactive nitrogen species, modifies sulfhydryl groups on Na + channels or a closely associated protein. Papa-NONOate-mediated block of Na + currents is not due to a hyperpolarizing shift in steady state voltage-dependent inactivation. The absence of NO-mediated enhancement of slow inactivation in fast and slow Na + channels indicates that NO does not inhibit fast and slow Na + channels by facilitating the transition to a slow inactivated state. These results demonstrate that inhibition of Na + currents is not due to the modulation of fast and slow sodium channel inactivation. Taken together, these results show that NO or NO-related products modify the sulfhydryl groups on Na + channels and inhibit Na + currents by blocking the channel conductance.

AB - C-type dorsal root ganglion (DRG) neurons express three types of Na + currents: fast TTX-sensitive, slow TTX- resistant, and persistent TTX-resistant Na + currents. The nitric oxide (NO) donors papa-NONOate and S-nitroso-N-acetyl-DL-penicillamine inhibit all three types of Na + currents. The NO scavenger hemoglobin abolished the effects of papa-NONOate on Na + currents, indicating that NO or NO-related species inhibit these Na + currents. NO donor inhibition of all three types of Na + currents was reversed by washout. Incubation of neurons with 8-bromo cGMP, a membrane-permeable analogue of cGMP, and cG-PKI, an inhibitor of cGMP-dependent protein kinase, had no effect on papa-NONOate-mediated Na + current block, demonstrating that Na + current inhibition is independent of cGMP. Alkylation of free thiols with N-ethylmaleimide prevented the actions of papa-NONOate, suggesting that NO, or a related reactive nitrogen species, modifies sulfhydryl groups on Na + channels or a closely associated protein. Papa-NONOate-mediated block of Na + currents is not due to a hyperpolarizing shift in steady state voltage-dependent inactivation. The absence of NO-mediated enhancement of slow inactivation in fast and slow Na + channels indicates that NO does not inhibit fast and slow Na + channels by facilitating the transition to a slow inactivated state. These results demonstrate that inhibition of Na + currents is not due to the modulation of fast and slow sodium channel inactivation. Taken together, these results show that NO or NO-related products modify the sulfhydryl groups on Na + channels and inhibit Na + currents by blocking the channel conductance.

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