Trends in Neurosciences
ReviewNaN/Nav1.9: a sodium channel with unique properties
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)
Nomenclature of voltage-gated sodium channels
Neuron
(2000)From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels
Neuron
(2000)A single serine residue confers tetrodotoxin insensitivity on the rat sensory-neuron-specific sodium channel SNS
FEBS Lett.
(1997)Coding sequence, genomic organization, and conserved chromosomal localization of the mouse gene Scn11a encoding the sodium channel NaN
Genomics
(1999)Cloning and characterization of a mouse sensory neuron tetrodotoxin-resistant voltage-gated sodium channel gene, Scn10a
Genomics
(1997)Two tetrodotoxin-resistant sodium channels in human dorsal root ganglion neurons
FEBS Lett.
(1999)Identification of a novel human voltage-gated sodium channel α-subunit gene, SCN12A
Biochem. Biophys. Res. Commun.
(2000)Cloning and expression study of the mouse tetrodotoxin-resistant voltage-gated sodium channel α-subunit NaT/Scn11a
Biochem. Biophys. Res. Commun.
(2000)Diversity of expression of the sensory neuron-specific TTX-resistant voltage-gated sodium ion channels SNS and SNS2
Mol. Cell. Neurosci.
(2000)Direct interaction with contactin targets voltage-gated sodium channel Nav1.9/NaN to the cell membrane
J. Biol. Chem.
(2001)
Ionic currents in the somatic membrane of rat dorsal root ganglion neurons-I. Sodium currents
Neuroscience
Three types of sodium channels in adult rat dorsal root ganglion neurons
Brain Res.
Sodium currents of large (Aβ-type) adult cutaneous afferent dorsal root ganglion neurons display rapid recovery from inactivation before and after axotomy
Neuroscience
Differential role of GDNF and NGF in the maintenance of two TTX-resistant sodium channels in adult DRG neurons
Mol. Brain Res.
A single pulse of nerve growth factor triggers long-term neuronal excitability through sodium channel gene induction
Neuron
Amplification of EPSPs by axosomatic sodium channels in neocortical pyramidal neurons
Neuron
Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states
Pain
Fibroblast growth factor homologous factor 1B binds to the C terminus of the tetrodotoxin-resistant sodium channel rNav1.9a (NaN)
J. Biol. Chem.
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.
A cluster of hydrophobic amino acid residues required for fast Na+-channel inactivation
Proc. Natl. Acad. Sci. U. S. A.
A mutant of TTX-resistant cardiac sodium channels with TTX-sensitive properties
Science
Chromosomal mapping of muscle-expressed sodium channel genes in the mouse
Mouse Genome
Genetic mapping of the peripheral sodium channel genes, Scn9a and Scn10a, in the mouse
Mamm. Genome
Two sodium channels contribute to the TTX-R sodium current in primary sensory neurons
Nat. Neurosci.
Localization of the tetrodotoxin-resistant sodium channel NaN in nociceptors
NeuroReport
A novel persistent tetrodotoxin-resistant sodium current in SNS-null and wild-type small primary sensory neurons
J. Neurosci.
Sodium channels and pain
Proc. Natl. Acad. Sci. U. S. A.
Differential properties of tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels in rat dorsal root ganglion neurons
J. Neurosci.
Characterization of TTX-sensitive and TTX-resistant sodium currents in small cells from adult rat dorsal root ganglia
J. Physiol.
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