Review
NaN/Nav1.9: a sodium channel with unique properties

https://doi.org/10.1016/S0166-2236(02)02150-1Get rights and content

Abstract

The Nav1.9 Na+ channel (also known as NaN) is preferentially expressed in nociceptive neurons of the dorsal root ganglia (DRG) and trigeminal ganglia. Nav1.9 produces a persistent, tetrodotoxin-resistant current with wide overlap between activation and steady-state inactivation, and appears to modulate resting potential and to amplify small depolarizations. These unique properties indicate that Nav1.9 has significant effects on the electroresponsive properties of primary nociceptive neurons. Downregulation of Nav1.9, which results from a lack of peripheral glial cell-derived neurotrophic factor following peripheral axotomy, might retune DRG neurons and contribute to their hyperexcitability after nerve injury. Thus, Nav1.9 appears to play a key role in nociception and is an attractive target in the search for more effective treatments for pain.

Section snippets

Identification and cloning of Nav1.9

Nav1.9 was identified using a PCR-based assay [3]. It is formed of 1765 residues and contains all the hallmarks of Na+ channels, including the inactivation tripeptide Ile-Phe-Met [4] in L3 (Fig. 1). Nav1.9, like other Na+ channels, contains multiple predicted phosphorylation sites in the intracellular loops and N-glycosylation sites in the extracellular linkers. A serine in one of the pore-lining segments of domain 1 (D1/SS2) of Nav1.9 (Ser355; Fig. 1) is at an analogous position to Ser356 of Na

Restricted distribution of Nav1.9

Nav1.9 is found primarily within small sensory neurons (<30 μm diameter) of dorsal root ganglia (DRG) and trigeminal ganglia, but not in neurons and glia within the CNS, or in muscle (Fig. 2a). In situ hybridization demonstrates high concentrations of mRNA encoding Nav1.9 in ∼80% of small, but in only a few larger, DRG neurons (Fig. 2b). Similarly, immunocytochemical studies with Nav1.9-specific antibodies show high concentrations of Nav1.9 in small neurons from DRG (Fig. 2c). Low levels of

Nav1.9 produces a persistent, TTX-resistant Na+ current

In contrast to most CNS neurons, DRG neurons express multiple, voltage-dependent TTX-resistant and TTX-sensitive Na+ currents 21., 22., 23., 24., 25.. The fast-inactivating Na+ current in adult DRG neurons (Fig. 3a) is blocked by nanomolar concentrations of TTX. Even before the discovery of Nav1.9, multiple, distinct TTX-resistant Na+ currents, including both slowly inactivating 21., 22., 23., 24., 25. and persistent [26] currents, were reported in small DRG neurons. Nav1.8 produces the slowly

Nav1.9 in different species

Nav1.9 is among the few Na+ channels to be characterized both at the molecular and electrophysiological levels in tissues from humans, rats and mice. Human Nav1.9 is a 1792-residue polypeptide [11], compared to 1765 residues in rats [3] and mice [7]. Interestingly, whereas most of the divergent sequences in Nav1.9 are not associated with a specific attribute, substitution of a single residue within D2/S4 of human Nav1.9 (Fig. 4) does affect its properties [11]. The D2/S4 segment of human Nav

Changes in Nav1.9 levels after nerve injury

Transcription of Scn11a is downregulated in DRG neurons following transection of their axons within the sciatic nerve [3]. In parallel with this, the level of Nav1.9 is attenuated in axotomized DRG neurons (Fig. 5) [30]. Uninjured neurons in the ipsilateral (operated side) DRG do not exhibit a significant decrease in Nav1.9 immunofluorescence, which indicates that downregulation of the channel results from transection of peripheral axons [30].

Central and peripheral axotomy can have different

Effects of neurotrophins on the expression of Scn11a

Nerve growth factor (NGF) and glial-cell-derived neurotrophic factor(GDNF) have been shown to modulate Na+ channel gene expression 29., 44., 45., 46., 47., 48., 49.. To determine whether the gene expression in the levels of Nav1.9 channels in DRG neurons following peripheral axotomy might reflect loss of target-derived neurotrophic factors, DRGs were dissociated and studied after seven days culture in vitro (Fig. 6) [44]. After culture for seven days without added factors, the Nav1.9 level is

Effects of Nav1.9 on cell function

In the absence of drugs that specifically inhibit the Nav1.9 channel or Nav1.9-null mice, the contribution made by Nav1.9 to cell function cannot be studied directly. We have used computer simulations (Fig. 7a) that incorporate TTX-sensitive and TTX-resistant currents recorded from rat DRG neurons to investigate the contribution(s) of Nav1.9 current to neuronal excitability [35]. Interestingly, an ‘mh’ model fits the persistent TTX-resistant current (rather than the classical ‘m3h’ model which

Other properties and questions

Genetic and biochemical approaches are being used to identify proteins that interact with Nav1.9 and influence the localization and/or properties of the channel. Recently, we showed that contactin/F3 binds directly to Nav1.9 and increases the concentration of the channel at the cell surface (Fig. 2g,h) [18]. The two proteins colocalize on the somata of DRG neurons, along their axons and on nerve endings in the skin. The interaction of Nav1.9 with contactin recruits tenascin, an extracellular

Acknowledgements

We thank the members of our group for valuable discussions and Bart Toftness for technical assistance. This work is supported, in part, by grants from the National Multiple Sclerosis Society, and the Rehabilitation Research and Development Service and Medical Research Service, Dept of Veterans Affairs, and by gifts from the Paralyzed Veterans of America and Eastern Paralyzed Veterans Association.

References (61)

  • P.G. Kostyuk

    Ionic currents in the somatic membrane of rat dorsal root ganglion neurons-I. Sodium currents

    Neuroscience

    (1981)
  • J.M. Caffrey

    Three types of sodium channels in adult rat dorsal root ganglion neurons

    Brain Res.

    (1992)
  • B. Everill

    Sodium currents of large (Aβ-type) adult cutaneous afferent dorsal root ganglion neurons display rapid recovery from inactivation before and after axotomy

    Neuroscience

    (2001)
  • J. Fjell

    Differential role of GDNF and NGF in the maintenance of two TTX-resistant sodium channels in adult DRG neurons

    Mol. Brain Res.

    (1999)
  • J.J. Toledo-Aral

    A single pulse of nerve growth factor triggers long-term neuronal excitability through sodium channel gene induction

    Neuron

    (1995)
  • G. Stuart et al.

    Amplification of EPSPs by axosomatic sodium channels in neocortical pyramidal neurons

    Neuron

    (1995)
  • K. Coward

    Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states

    Pain

    (2000)
  • C. Liu

    Fibroblast growth factor homologous factor 1B binds to the C terminus of the tetrodotoxin-resistant sodium channel rNav1.9a (NaN)

    J. Biol. Chem.

    (2001)
  • S.D. Dib-Hajj

    NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy

    Proc. Natl. Acad. Sci. U. S. A.

    (1998)
  • J.W. West

    A cluster of hydrophobic amino acid residues required for fast Na+-channel inactivation

    Proc. Natl. Acad. Sci. U. S. A.

    (1992)
  • J. Satin

    A mutant of TTX-resistant cardiac sodium channels with TTX-sensitive properties

    Science

    (1992)
  • R. Klocke

    Chromosomal mapping of muscle-expressed sodium channel genes in the mouse

    Mouse Genome

    (1992)
  • C.A. Kozak et al.

    Genetic mapping of the peripheral sodium channel genes, Scn9a and Scn10a, in the mouse

    Mamm. Genome

    (1996)
  • S. Tate

    Two sodium channels contribute to the TTX-R sodium current in primary sensory neurons

    Nat. Neurosci.

    (1998)
  • J. Fjell

    Localization of the tetrodotoxin-resistant sodium channel NaN in nociceptors

    NeuroReport

    (2000)
  • T.R. Cummins

    A novel persistent tetrodotoxin-resistant sodium current in SNS-null and wild-type small primary sensory neurons

    J. Neurosci.

    (1999)
  • S.G. Waxman

    Sodium channels and pain

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • Lawson, S.N. et al. (2001) Sensory and electrophysiological properties of DRG neurones with NaN-like immunoreactivity...
  • M.L. Roy et al.

    Differential properties of tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels in rat dorsal root ganglion neurons

    J. Neurosci.

    (1992)
  • A.A. Elliott et al.

    Characterization of TTX-sensitive and TTX-resistant sodium currents in small cells from adult rat dorsal root ganglia

    J. Physiol.

    (1993)
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