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. 1998 Jul 21;95(15):8963-8.
doi: 10.1073/pnas.95.15.8963.

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

S D Dib-Hajj  1 , L Tyrrell, J A Black, S G Waxman
Affiliations

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

S D Dib-Hajj et al. Proc Natl Acad Sci U S A. .

Abstract

Although physiological and pharmacological evidence suggests the presence of multiple tetrodotoxin-resistant (TTX-R) Na channels in neurons of peripheral nervous system ganglia, only one, SNS/PN3, has been identified in these cells to date. We have identified and sequenced a novel Na channel alpha-subunit (NaN), predicted to be TTX-R and voltage-gated, that is expressed preferentially in sensory neurons within dorsal root ganglia (DRG) and trigeminal ganglia. The predicted amino acid sequence of NaN can be aligned with the predicted structure of known Na channel alpha-subunits; all relevant landmark sequences, including positively charged S4 and pore-lining SS1-SS2 segments, and the inactivation tripeptide IFM, are present at predicted positions. However, NaN exhibits only 42-53% similarity to other mammalian Na channels, including SNS/PN3, indicating that it is a novel channel, and suggesting that it may represent a third subfamily of Na channels. NaN transcript levels are reduced significantly 7 days post axotomy in DRG neurons, consistent with previous findings of a reduction in TTX-R Na currents. The preferential expression of NaN in DRG and trigeminal ganglia and the reduction of NaN mRNA levels in DRG after axonal injury suggest that NaN, together with SNS/PN3, may produce TTX-R currents in peripheral sensory neurons and may influence the generation of electrical activity in these cells.

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Figures

Figure 1
Figure 1
Restriction enzyme profile analysis of Na channel domain 1 RT-PCR products from DRG. “M” lanes contain the 100-bp ladder marker (Pharmacia). Lane 1 contains the amplification product from DRG cDNA. Lanes 2–9 show the result of cutting this DNA with EcoRV, EcoNI, AvaI, SphI, BamHI, AflII, XbaI, and EcoRI, which are specific to subunits αI, -II, -III, Na6, PN1, SNS/PN3, NaG, and NaN, respectively. The image was digitized by using gelbase 7500 system (Ultraviolet Products) and printed in black and white dye sublimation mode.
Figure 2
Figure 2
Predicted amino acid sequence of NaN. DI–DIV represent the four domains of Na channels, with the putative transmembrane segments underlined. The serine residue of DI-SS2 predicted to underlie the TTX-R phenotype (S355), the PKC phosphorylation site in L3 (T1321), and the tripeptide IFM in L3 involved in fast inactivation (40) are in bold and larger type, and are underlined.
Figure 3
Figure 3
Tissue distribution of NaN in adult rat by RT-PCR (A) and Northern blot analysis (B). (A) “M” lanes contain the 100-bp ladder marker (Pharmacia). Amplification product from DRG (lanes 1 and 16), trigeminal ganglia (lane 9), cerebral hemispheres (lane 2), and retina (lane 4) are consistent with a predicted size of 392 bp. No detectable signal is seen in cerebellum (lane 3), optic nerve (lane 5), spinal cord (lane 6), sciatic nerve (lane 7), superior cervical ganglia (lane 8), skeletal muscle (lane 10), cardiac muscle (lane 11), adrenal gland (lane 12), uterus (lane 13), liver (lane 14), kidney (lane 15), or water (lane 17). (B Upper) An antisense riboprobe hybridized specifically to a single transcript (about 6.5 kb) in poly(A)+ DRG RNA. No similar hybridization signal was seen in multiple-tissue Northern blot (CLONTECH) lanes containing poly(A)+ RNA from heart, brain, spleen, lung, liver, muscle, kidney, and testis. (B Lower) β-actin (1.6 kb and 2.0 kb) hybridization signal. Heart and muscle lanes show an actin signal at 1.6 kb, consistent with hybridization to the α- or γ-actin forms in these tissues (Boehringer Mannheim).
Figure 4
Figure 4
NaN mRNA expression in adult rat tissue by in situ hybridization. Strong hybridization signal for NaN mRNA is present in many small-diameter neurons within trigeminal ganglia (a) and DRG (b). Large-diameter neurons (arrow) generally lack NaN mRNA hybridization signal. DRG neurons hybridized with NaN sense riboprobe do not show signal above background (c). Hybridization signal for NaN mRNA is not present in cerebellum (d) or in liver, spinal cord, heart, kidney, and adrenal (not shown). (Bar = 50 μm.)
Figure 5
Figure 5
Analysis of NaN expression in control and axotomized DRG neurons by quantitative RT-PCR (a) and in situ hybridization (b and c). (a) A representative gel analysis of three independent coamplifications of NaN (392 bp) and GAPDH (666 bp) products from control (lanes 1, 3, and 5) and axotomized (lanes 2, 4, and 6) DRG. (b) NaN mRNA is expressed in many small neurons in control DRG. (c) At 7 dpa, NaN hybridization signal is attenuated, with only a few small neurons displaying hybridization signal. (Bar = 50 μm.)
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