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Next Article 
The Journal of Neuroscience, 1999, 19:RC43:1-6
RAPID COMMUNICATION
A Novel Persistent Tetrodotoxin-Resistant Sodium Current In
SNS-Null And Wild-Type Small Primary Sensory Neurons
Theodore R.
Cummins1, 2,
Sulayman D.
Dib-Hajj1, 2,
Joel A.
Black1, 2,
Armen N.
Akopian3,
John N.
Wood3, and
Stephen G.
Waxman1, 2
1 Department of Neurology and PVA/EPVA
Neuroscience Research Center, Yale Medical School, New Haven,
Connecticut 06510, 2 Rehabilitation Research Center,
Veterans Administration Connecticut Healthcare Center, West Haven,
Connecticut 06516, and 3 Department of Biology, University
College London, London WC1E 6BT, United Kingdom
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ABSTRACT |
TTX-resistant (TTX-R) sodium currents are preferentially expressed
in small C-type dorsal root ganglion (DRG) neurons, which include
nociceptive neurons. Two mRNAs that are predicted to encode TTX-R
sodium channels, SNS and NaN, are preferentially expressed in
C-type DRG cells. To determine whether there are multiple TTX-R currents in these cells, we used patch-clamp recordings to study sodium
currents in SNS-null mice and found a novel persistent voltage-dependent sodium current in small DRG neurons of both SNS-null
and wild-type mice. Like SNS currents, this current is highly
resistant to TTX (Ki = 39 ± 9 µM). In contrast to SNS currents, the threshold
for activation of this current is near  70 mV, the midpoint of
steady-state inactivation is 44 ± 1 mV, and the time constant
for inactivation is 43 ± 4 msec at 20 mV. The presence of this
current in SNS-null and wild-type mice demonstrates that a distinct
sodium channel isoform, which we suggest to be NaN, underlies this
persistent TTX-R current. Importantly, the hyperpolarized voltage-dependence of this current, the substantial overlap of its
activation and steady-state inactivation curves and its persistent nature suggest that this current is active near resting potential, where it may play an important role in regulating excitability of
primary sensory neurons.
Key words:
sodium current; persistent current; dorsal root ganglion; excitability; tetrodotoxin; sensory neuron
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INTRODUCTION |
Small
dorsal root ganglion (DRG) neurons (which include nociceptive cells)
are unusual in expressing tetrodotoxin-resistant (TTX-R) sodium
currents, in addition to the TTX-sensitive (TTX-S) sodium currents that
are present in many neurons (Kostyuk et al., 1981 ). Because of their
preferential expression in nociceptive neurons, the channels
responsible for these TTX-R currents are of special interest. One TTX-R
channel that has been cloned from DRG neurons, SNS (Akopian et al.,
1996; Sangameswaran et al., 1996), produces a slowly inactivating
sodium current ( inactivation, ~5 msec for
the peak current) with relatively depolarized voltage dependence of
activation and inactivation. A second sodium channel, NaN, with a
sequence predicting a TTX resistance similar to that of SNS, is also
preferentially expressed in small DRG neurons (Dib-Hajj et al., 1998,
1999; Tate et al., 1998).
A recent study on DRG neurons from SNS-null mutant mice demonstrated
only TTX-S sodium currents (Akopian et al., 1999). These findings were
unexpected in light of the presence of NaN transcript within these
cells. The present study revisits this issue and shows that DRG neurons
from SNS-null mice (Akopian et al., 1999) express a TTX-R sodium
current with novel properties. We also demonstrate that this TTX-R
current is present in small wild-type (WT) mouse DRG neurons.
The relatively hyperpolarized voltage dependence of activation and
inactivation of this current and its persistent nature suggest that it
contributes to setting the firing properties of small DRG neurons by
modulating their resting potentials and/or thresholds.
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MATERIALS AND METHODS |
Whole-cell patch-clamp recordings. DRG cultures from
L4 and L5 ganglia of WT and SNS-null mice (Akopian et al., 1999) were established as previously described (Cummins and Waxman, 1997). Sodium
currents were studied in small (18- to 27-µm-diameter) DRG neurons
after short-term culture (6-24 hr); at this time in culture, neurites
are not generally present. Whole-cell patch-clamp recordings were
conducted at room temperature (~21°C) using an EPC-9 amplifier and
the Pulse program (version 7.89). Fire-polished electrodes (0.8-1.5
M ) were fabricated from 1.7 mm capillary glass using a Sutter P-97
puller. The average cell capacitance was 21 ± 1 pF (mean ± SE; n = 55) for WT and 23 ± 1 pF
(n = 91) for SNS-null cells. The average access
resistance was 2.1 ± 0.1 M for WT and 2.0 ± 0.1 M for
SNS-null cells. Voltage errors were minimized using 80% series
resistance compensation. The maximum theoretical voltage error was
2 ± 1 mV for TTX-R sodium currents in SNS-null neurons; this and
the spherical nature of the cells provided nearly ideal
recording conditions. Linear leak subtraction was used for all
recordings. The pipette solution contained (in mM): 140 CsF, 1 EGTA, 10 NaCl, and 10 HEPES, pH
7.3. The standard bathing solution was (in mM)
140 NaCl, 3 KCl, 1 MgCl2, 1 CaCl2, 0.1 CdCl2,and 10 HEPES, pH 7.3. Cadmium was included to block calcium currents. The
osmolarity of all solutions was adjusted to 310 mOsm.
RT-PCR. Total cellular RNA was extracted from trigeminal
ganglia of each animal whose DRG neurons were studied to confirm the
SNS-null genotype and the presence of the expected NaN products (see
Fig. 3). First-strand cDNA synthesis and PCR were performed as
previously described (Dib-Hajj et al., 1998).
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RESULTS |
Whole-cell patch-clamp recordings demonstrate the presence of fast
and slow inactivating voltage-dependent inward currents from the
cultured DRG neurons of WT and SNS-null mice with a holding potential
of 120 mV (Fig. 1). In the presence of
250 nM TTX in the bathing solution, TTX-R inward currents
were recorded from 77% of small WT neurons (24 of 31) and 74% of
SNS-null neurons (37 of 50). However, the inward currents were
strikingly different in the two groups of cells. The majority of WT
neurons (18 of 31) showed slowly inactivating TTX-R currents (which
activated between 40 and 30 mV and resemble currents in
heterologously expressed SNS channels; see Akopian et al., 1996)
together with persistent TTX-R currents (which did not inactivate
during the 100 msec depolarization at negative test potentials).
Consistent with the conclusion that SNS encodes a slowly inactivating
channel (Akopian et al., 1996; Sangameswaran et al., 1996), SNS-null
neurons did not express the slowly inactivating TTX-R currents.
However, a persistent TTX-R current was clearly present in these cells (Fig. 1d), and the amplitude was as large as 11 nA. This
persistent current activated between 60 and 70 mV and peaked at
approximately 20 mV (peak amplitude, 5.0 ± 0.6 nA; peak
density, 235 ± 77 pA/pF; n = 22).
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Figure 1.
Multiple sodium currents are expressed in small
DRG neurons from WT and SNS-null mice. a, b,
Representative recordings from a holding potential of 120 mV. Calcium
currents were blocked with 100 µM cadmium in the bath
solution. c, d, TTX (250 nM) blocks the
fast-inactivating component. A persistent current is expressed in both
the WT (c) and SNS-null (d)
neurons, but the slowly inactivating component is seen only in the WT
neuron. e, f, When the neurons were held at 60 mV and
a 100 msec step to 120 mV preceded the test pulses, the persistent
current is not obvious in either WT (e) or
SNS-null (f) neurons. g,
Subtraction of the slowly inactivating component
(e) from the total TTX-R current
(c) reveals the persistent current in WT neurons.
h, The persistent current derived by this subtraction
process from WT neurons is similar to that recorded in SNS-null
neurons. Test potential is 60 mV, and traces are normalized for
comparison.
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Because the persistent TTX-R current was recorded with cadmium in the
bath and fluoride in the pipette solution, we suspected that it was a
sodium current. Whole-cell recordings of SNS-null cells in the presence
of low external calcium (10-50 µM) but high external
sodium (140 mM) demonstrated large persistent inward currents in 15 of 25 cells. Increasing external calcium from 50 µM to 1 mM did not increase the size of the
current (Fig. 2a; n = 4). Additionally, when the external medium
contained high calcium (1 mM) but zero sodium we
did not observe any inward currents activating at negative potentials
(n = 15). We could often observe small inward currents
that activated near 20 mV if cadmium was not included in the external
solution, but these high-voltage-activated currents could be blocked
with 50-100 µM cadmium and appear to be L-type
calcium currents. However, in four of six SNS-null cells tested, the
low-voltage-activated (LVA) persistent inward current was revealed in
the presence of cadmium when external sodium was increased from 0 to 50 mM (Fig. 2b). Based on these
experiments, we conclude that the LVA persistent current that we
observe in SNS-null neurons is indeed a sodium current.
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Figure 2.
SNS-null neurons express a TTX-R sodium current.
a, The current recorded from an SNS-null neuron in low
calcium (50 µM) was not altered by increasing calcium to
1 mM. Vtest = 30 mV. b,
In zero sodium (160 mM TEA) inward current is not elicited
by a step depolarization to 30 mV. Addition of 50 mM
sodium reveals the TTX-R current. c, The TTX-R current
in SNS-null neurons is resistant to high concentrations of TTX (10 µM). Vtest = 40 mV. d,
Activation and steady-state inactivation curves exhibit significant
overlap for the TTX-R current in SNS-null neurons. The interpulse
interval was 5 sec. Steady-state inactivation was measured with 500 msec prepulses. Vtest = 10 mV. e,
TTX-R persistent currents from an SNS-null neuron elicited with 2 sec step depolarizations to the voltage indicated. All recordings were
made with 250 nM TTX, 100 µM cadmium, and
Vhold = 120 mV.
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The LVA persistent sodium current is only marginally inhibited by 1 µM TTX (6 ± 5%; n = 6), and as
shown in Figure 2c, 10 µM TTX
inhibited this LVA sodium current in SNS-null neurons by ~20%
(estimated Ki, 39 ± 9 µM; n = 5). Thus, the LVA
current in DRG neurons is highly resistant to TTX, like SNS
(Ki, ~60 µM) (Akopian
et al., 1996) and unlike the cardiac TTX-R isoform
(Ki, ~1-2 µM; Satin et
al., 1992).
Although the TTX resistance of the current in SNS-null DRG neurons is
similar to that reported for SNS, its voltage dependence and kinetic
properties are quite distinct. As seen in Figure 1d, the
TTX-R currents in SNS-null neurons had extremely slow kinetics, with
inactivation = 43 ± 4 msec at 20 mV
(n = 18). These currents activated at hyperpolarized
potentials, with a threshold at approximately 70 mV and a midpoint of
activation of 47 ± 1 mV (n = 17). The overshoot
in the activation curve (Fig. 2d) could be attributable to
the presence of multiple TTX-R channels in SNS-null neurons. Alternatively, it could be attributable to a TTX-R channel with complex
behavior, such as one that has multiple open states or an inactivated
state from which recovery is ultraslow (ultraslow recovery from
inactivation is supported by data presented below). The voltage
dependence of steady-state inactivation was also fairly negative, with
a midpoint of 44 ± 1 mV (n = 10). The
considerable overlap between the activation and steady-state
inactivation curves (Fig. 2d) should generate persistent
window currents that are active near resting potential. Indeed, large
persistent currents were observed in the region of overlap when the
holding potential (Vhold) was 120 mV (Fig.
2e). The amplitude of the TTX-R persistent current measured
at 60 mV (Vhold = 120 mV) was 1.6 ± 0.5 nA for WT neurons (n = 17) and 1.7 ± 0.4 nA for SNS-null neurons (n = 22).
Based on the midpoint of steady-state inactivation, it might be
expected that large persistent TTX-R currents would also be readily
observed from a Vhold of 60 mV; however, when
the neurons were held at 60 mV and currents were elicited after a
brief hyperpolarizing prepulse (100 msec at 120 mV), the persistent
TTX-R current was not apparent in either WT (Fig. 1e) or
SNS-null (Fig. 1f) neurons. Under these conditions,
only the slowly inactivating TTX-R currents were observed in WT neurons
and, as previously reported by Akopian et al. (1999), who studied cells
with relatively depolarized holding potentials, there was no obvious
TTX-R current in SNS-null neurons. Consistent with this, we found a
prominent ultraslow inactivation of the LVA channels
(recovery = 16 ± 4 sec at 120 mV in
SNS-null neurons; n = 5). For SNS-null neurons that
expressed large TTX-R currents (peak amplitude = 8.0 ± 1.2 nA with Vhold of 120 mV), the peak amplitude
elicited after a 100 msec prepulse to 120 mV from a
Vhold of 60 mV was only 260 ± 57 pA
(n = 8), indicating that ~97% of the LVA TTX-R
channels are ultraslow-inactivated at 60 mV. We observed a similar
ultraslow inactivation for the LVA TTX-R current in WT neurons.
Because of the ultraslow inactivation of the LVA TTX-R currents,
subtraction of the slowly inactivating current recorded with Vhold = 60 mV from total TTX-R current would be
expected to yield the persistent current in WT neurons. In fact, an LVA
TTX-R current could be derived in this way in WT neurons (Fig.
1g) and closely matched the persistent current recorded in
SNS-null DRG neurons (Fig. 1h). Thus we can isolate LVA
TTX-R currents with similar properties in both WT and SNS-null DRG neurons.
The molecular identity of the novel persistent TTX-R current cannot be
positively determined at this time. However, transcripts for NaN, which
is predicted to encode a TTX-R channel, are present in WT and SNS-null
trigeminal ganglia (Fig. 3, lanes
1-4) and DRG neurons (data not shown). Residual SNS
transcript in SNS-null ganglia lacks the sequence encoded by exons 4 and 5 (Fig. 3, lanes 1-4), which truncates the
protein because of a reading frame shift in exon 6 (Akopian et al.,
1999). Therefore, we suggest that NaN underlies this novel TTX-R
persistent current.
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Figure 3.
RT-PCR products from DRG of WT (+/+) and SNS-null
(/) mutant mice. SNS and NaN products were co-amplified from WT
(lanes 1, 3), and SNS-null mutants
(lanes 2, 4). Two primer pairs,
Pr1 and Pr2, for SNS were previously described (Pr1, lanes
1, 2; Akopian et al., 1999; Pr2, lanes
3, 4; F1/R2; Dib-Hajj et al., 1998). The sizes
of SNS products from WT tissue using Pr1 and Pr2 are consistent with
the predicted lengths of 673 bp (nucleotides 100-772) and 482 bp
(nucleotides 594-1075), respectively. The smaller SNS product (denoted
by an asterisk in lane 2; 450 bp) from
SNS-null tissue is consistent with splicing exon 3 to exon 6 (Akopian
et al., 1999), whereas lack of SNS signal in lane 4 is
attributable to the replacement of F1-containing sequence by the
PGK-neo cassette in the null allele. Primers for mouse NaN
amplify nucleotides 708-995 (288 bp; lanes 1,
2) and 626-995 (370 bp; lanes 3,
4) (Dib-Hajj et al., 1999). Comparable levels of
glyceraldehyde-3-phosphate dehydrogenase were amplified from WT
(lane 5) and SNS-null mutants (lane
6) using primers that were previously described
(Dib-Hajj et al., 1998).
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DISCUSSION |
In this study we have identified and characterized a novel
persistent TTX-R sodium current in SNS-null and WT small-diameter DRG
neurons. Although previous studies have suggested the presence of
multiple TTX-R currents in DRG neurons, these currents have been either
slowly inactivating, with time constants of 3-8 msec (Rizzo et al.,
1994; Rush et al., 1998), or rapidly inactivating (time constants <2
msec; Scholz et al., 1998). TTX-R persistent currents have not been
previously identified. The persistent currents that have been reported
in large sensory neurons (Baker and Bostock, 1997) and other neuronal
cell types, e.g., cortical (Crill, 1996) and thalamocortical neurons
(Parri and Crunelli, 1998), are TTX-S. The persistent TTX-R current in
small sensory neurons thus appears to be a distinct sodium current, not
present in other types of neurons.
The kinetic properties of the LVA TTX-R persistent current that we
describe here are different from those of SNS currents. In contrast to
SNS currents, which activate at approximately 30 mV, the TTX-R
persistent current activated around resting potential (approximately
70 to 60 mV). This may have important functional implications,
because there are few channels of any kind that are active near resting
potential, so that even small persistent currents can have a
significant influence on excitability (Crill, 1996). Although the LVA
persistent current in SNS-null neurons was quite large when elicited
from hyperpolarized holding potentials, suggesting a relatively high
density of channels, it was greatly reduced near normal resting
potential (approximately 60 mV for small DRG neurons) by an apparent
ultraslow inactivation. Ultraslow inactivation decreased the amplitude
of the LVA TTX-R persistent current by >95% with
Vhold = 60 mV and should result in a low probability of opening of any single channel around resting potential. One possible advantage is that a large number of channels with a low
open probability might produce a small yet more consistent current than
a smaller number of channels with a higher probability of opening.
Based on the reduced amplitude observed when the cells are held near
resting potential, it is expected that the LVA TTX-R persistent current
will not play a prominent role in generating action potentials. On the
other hand, the properties of this current suggest that it may
contribute to setting the resting potential and to the modulation of
neuronal excitability close to resting potential. Persistent sodium
currents have been implicated in subthreshold oscillations (Kapoor et
al., 1997), in amplification of depolarizing inputs (Schwindt and
Crill, 1995), and in impulse initiation (Stafstrom et al., 1982). The
LVA TTX-R persistent current that we describe here might similarly be
expected to have important consequences on subthreshold electrogenesis
in small DRG neurons.
A previous study on SNS-null neurons (Akopian et al., 1999) did not
observe the persistent TTX-R currents that we describe here. Two
methodological differences may account for the failure of Akopian et
al. to detect this current: (1) Akopian et al. used depolarized holding
potentials, at which the LVA TTX-R persistent current is
slow-inactivated and thus not detectable; and (2) Akopian et al.
studied SNS-null neurons after 1-5 d in culture. Although we observed
large TTX-R currents in SNS-null neurons studied after <24 hr in
culture, these currents were greatly reduced in amplitude at longer
times in culture (data not shown).
DRG neurons are known to express at least six sodium channel
transcripts (Black et al., 1996; Dib-Hajj et al., 1998). Only two of
these, SNS and NaN, are predicted to encode TTX-R currents. DRG neurons
do not express mRNA for the TTX-R cardiac channel (Donahue, 1995; Black
et al., 1998; Akopian et al., 1999), and SNS-null neurons do not
express functional SNS channels. Because NaN transcript is present in
SNS-null DRG (Fig. 3) and is expressed preferentially in small sensory
neurons (Dib-Hajj et al., 1998), we suggest that the LVA TTX-R
persistent current that we describe here is produced by channels
encoded by NaN. Although the molecular identity of the channel that
produces the LVA TTX-R persistent current cannot be definitively
established at this time, the hypothesis that NaN underlies the LVA
TTX-R current in small DRG neurons is supported by data showing that
the loss of persistent currents in rat small DRG neurons after axotomy
(Cummins and Waxman, 1997) is accompanied by a decrease in NaN mRNA
levels (Dib-Hajj et al., 1998; Tate et al., 1998).
Patch-clamp studies on HEK293T cells transfected with recombinant NaN
(also referred to as SNS2) channels demonstrated a TTX-R sodium current with considerably faster kinetics
(inactivation = 1.3 msec at
approximately 20 mV) and a greater TTX sensitivity (Ki, ~1 µM)
than SNS (Tate et al., 1998). This is surprising because sodium
currents with a TTX Ki of 1-2
µM have never been described in DRG neurons.
Both SNS and NaN have a serine in the position (S356 in SNS and S355 in
NaN) that has been shown (Chen et al., 1992; Satin et al., 1992) to be
crucial for TTX resistance, and thus these two channels would be
expected to have similar Ki values for
TTX. Sivilotti et al. (1997) have demonstrated that mutation of SNS
S356 to phenylalanine changes the TTX
Ki to 8 nM,
suggesting that this serine residue alone confers the high TTX
resistance of SNS channels. Therefore, the high TTX resistance of the
LVA persistent current in SNS-null neurons is consistent with a channel isoform that has a serine at the TTX binding site.
The difference between the currents recorded in SNS-null DRG neurons
(this paper) and the HEK293T current ascribed to NaN by Tate et al.
(1998) raises several possibilities. (1) NaN could be differentially
processed or modulated in DRG and HEK293T cells. Skeletal muscle sodium
(SkM1) channels expressed in Xenopus oocytes can have
different kinetic properties from native SkM1 channels (Trimmer et al.,
1989), and thus differences between HEK293T cells and DRG neurons might
account for kinetic differences. However, SkM1, cardiac, and neuronal
sodium channels (including SNS) have essentially the same TTX
resistance in heterologous expression systems and native cells (Trimmer
et al., 1989; Chen et al., 1992; Akopian et al., 1996). Therefore, it
seems unlikely that NaN will have a different TTX resistance in DRG
neurons and HEK293 cells. (2) NaN might not underlie the LVA persistent
TTX-R current that is recorded in SNS-null and WT DRG neurons. If this
were the case, it would be expected that TTX-R currents such as those
described by Tate et al. (1998) should also be observed in the majority of small DRG neurons of SNS-null mice, because NaN transcript and
protein are observed in the majority of small DRG neurons (Dib-Hajj et
al., 1998; Tate et al., 1998). However, currents like those described
by Tate et al. (1998) are not observed in SNS-null neurons. (3) The
small current recorded in NaN-transfected HEK293T cells (Tate et al.,
1998) might not be encoded by NaN but could be an endogenous TTX-R
current that was observed in NaN-transfected HEK293T cells. This
possibility is supported by recordings showing small endogenous sodium
currents in nontransfected HEK293 cells with the same properties as
those ascribed to NaN channels by Tate et al. (Fig.
4). We observed small TTX-R currents in
four of five nontransfected HEK293 cells when
Vhold = 120 mV (peak amplitude = 505 ± 111 pA; n = 4). The properties of these endogenous
HEK293 TTX-R currents are strikingly similar to those of cloned cardiac
sodium channels (Chahine et al., 1996). Because currents with the
properties described by Tate et al. (1998) for NaN are not present in
SNS-null neurons but are present in nontransfected HEK293 cells, it is
likely that the currents reported by Tate et al. (1998) are endogenous
HEK293 currents.
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Figure 4.
Nontransfected HEK293 cells exhibit an endogenous
TTX-R current. a, Representative TTX-R currents recorded
from a nontransfected HEK293 cell (cell capacitance, 24 pF; access
resistance, 1.1 M). A single-exponential decay function fitted to
the inactivation phase of the peak current estimated that
inactivation = 1.2 msec. The bath solution
contained 200 nM TTX. b, Peak
current-voltage relationship for the currents shown in
a. The midpoint of activation was 42.4 ± 3.2 mV,
and the midpoint of steady-state inactivation was 88.4 ± 1.9 mV
for the endogenous TTX-R current in HEK293 cells (n = 4). Recordings were made 3-6 min after establishing the whole-cell
configuration. c, The endogenous TTX-R current in HEK293
cells is inhibited by TTX with a Ki of 1-2
µM.
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Our observations show that: (1) a distinct TTX-R sodium current is
expressed at high densities in small DRG neurons from SNS-null mice;
(2) this current has a hyperpolarized voltage dependence compared with
SNS; (3) this current is persistent at negative potentials close to
resting potential; and (4) this current is present in the majority of
small WT DRG neurons. These results provide strong evidence for the
presence of a distinct TTX-R sodium channel in addition to SNS, which
produces this persistent current in small DRG neurons. Irrespective of
the identity of the channel that produces it, it is likely that the
low-threshold, persistent TTX-R sodium current that we have identified
in SNS-null and WT neurons contributes to subthreshold electrogenesis
in C-type primary sensory neurons and affects the excitability of these neurons.
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FOOTNOTES |
Received Sept. 3, 1999; revised Oct. 6, 1999; accepted Oct. 8, 1999.
This work was supported in part by grants from the National Multiple
Sclerosis Society, the Medical Research Service and Rehabilitation Research Service, Department of Veterans Affairs (S.G.W.), and the
Wellcome Trust and Medical Research Council (J.N.W. and A.N.A.).
Correspondence should be addressed to Dr. Stephen G. Waxman, Yale
University School of Medicine, Department of Neurology, 707 LCI, 333 Cedar Street, New Haven, CT 06510. E-mail: Stephen.Waxman{at}Yale.Edu
This article is published in
The Journal of Neuroscience, Rapid Communications Section,
which publishes brief, peer-reviewed papers online, not in print. Rapid
Communications are posted online approximately one month earlier than
they would appear if printed. They are listed in the Table of Contents
of the next open issue of JNeurosci. Cite this article as:
JNeurosci, 1999, 19:RC43 (1-6). The
publication date is the date of posting online at
www.jneurosci.org.
| |
REFERENCES |
-
Akopian AN,
Sivilotti L,
Wood JN
(1996)
A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons.
Nature
379:257-262.
-
Akopian AN,
Souslova V,
England S,
Okuse K,
Ogata N,
Ure J,
Smith A,
Kerr BJ,
McMahon SB,
Boyce S,
Hill R,
Stanfa LC,
Dickenson AH,
Wood JN
(1999)
The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways.
Nat Neurosci
2:541-548.
-
Baker MD,
Bostock H
(1997)
Low-threshold, persistent sodium current in rat large dorsal root ganglion neurons in culture.
Neurophysiology
77:1503-1513.
-
Black JA,
Dib-Hajj S,
McNabola K,
Jeste S,
Rizzo MA,
Kocsis JD,
Waxman SG
(1996)
Spinal sensory neurons express multiple sodium channel a-subunit mRNAs.
Mol Brain Res
43:117-132.
-
Black JA,
Dib-Hajj S,
Cohen S,
Hinson AW,
Waxman SG
(1998)
Glial cells have heart: rH1 Na+ channel mRNA and protein in spinal cord astrocytes.
Glia
23:200-208.
-
Chahine M,
Deschene I,
Chen LQ,
Kallen RG
(1996)
Electrophysiological characteristics of cloned skeletal and cardiac muscle sodium channels.
Am J Physiol
271:H498-H506.
-
Chen LQ,
Chahine M,
Kallen RG,
Barchi RL,
Horn R
(1992)
Chimeric study of sodium channels from rat skeletal and cardiac muscle.
FEBS Lett
309:253-257.
-
Crill WE
(1996)
Persistent sodium currents in mammalian central neurons.
Annu Rev Physiol
58:349-362.
-
Cummins TR,
Waxman SG
(1997)
Down-regulation of TTX-resistant sodium currents and upregulation of a rapidly repriming TTX-sensitive sodium current in small spinal sensory neurons after nerve injury.
J Neurosci
17:3503-3514.
-
Dib-Hajj SD,
Tyrrell L,
Black JA,
Waxman SG
(1998)
NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy.
Proc Natl Acad Sci USA
95:8963-8968.
-
Dib-Hajj SD,
Tyrrell L,
Escayg A,
Wood PM,
Meisler MH,
Waxman SG
(1999)
Coding sequence, genomic organization and conserved chromosomal localization of the mouse gene Scn11a encoding the sodium channel NaN.
Genomics
59:309-318.
-
Donahue LM
(1995)
The tetrodotoxin-insensitive sodium current in rat dorsal root ganglia is unlikely to involve the expression of the tetrodotoxin-resistant sodium channel, SkM2.
Neurochem Res
20:713-717.
-
Kapoor R,
Li YG,
Smith KJ
(1997)
Slow sodium-dependent potential oscillations contribute to ectopic firing in mammalian demyelinated axons.
Brain
120:647-652.
-
Kostyuk PG,
Veselovsky NS,
Tsyndrenko AY
(1981)
Ionic currents in the somatic membrane of rat dorsal root ganglion neurons
 I. Sodium currents.
Neuroscience
6:2423-2430. -
Parri HR,
Crunelli V
(1998)
Sodium current in rat and cat thalamocortical neurons: role of a non-inactivating component in tonic and burst firing.
J Neurosci
18:854-867.
-
Rizzo MA,
Kocsis JD,
Waxman SG
(1994)
Slow sodium conductances of dorsal root ganglion neurons: intraneuronal homogeneity and interneuronal heterogeneity.
J Neurophysiol
72:2796-2815.
-
Rush AM,
Brau ME,
Elliott AA,
Elliott JR
(1998)
Electrophysiological properties of sodium current subtypes in small cells from adult rat dorsal root ganglia.
J Physiol (Lond)
511:771-789.
-
Sangameswaran L,
Delgado SG,
Fish LM,
Koch BD,
Jakeman LB,
Stewart GR,
Sze P,
Hunter JC,
Eglen RM,
Herman RC
(1996)
Structure and function of a novel voltage-gated tetrodotoxin-resistant sodium channel specific to sensory neurons.
J Biol Chem
271:5953-5956.
-
Satin J,
Kyle JW,
Chen M,
Bell P,
Cribbs LL,
Fozzard HA,
Rogart RB
(1992)
A mutant of TTX-resistant cardiac sodium channels with TTX-sensitive properties.
Science
256:1202-1205.
-
Scholz A,
Appel N,
Vogel W
(1998)
Two types of TTX-resistant and one TTX-sensitive Na+ channel in rat dorsal root ganglion neurons and their blockade by halothane.
Eur J Neurosci
10:2547-2556.
-
Schwindt PC,
Crill WE
(1995)
Amplification of synaptic current by persistent sodium conductance in apical dendrite of neocortical neurons.
J Neurophysiol
74:2220-2224.
-
Sivilotti L,
Okuse K,
Akopian AN,
Moss S,
Wood JN
(1997)
A single serine residue confers tetrodotoxin insensitivity on the rat sensory-neuron-specific sodium channel SNS.
FEBS Lett
409:49-52.
-
Stafstrom CE,
Schwindt PC,
Crill WE
(1982)
Negative slope conductance due to a persistent subthreshold sodium current in cat neocortical neurons in vitro.
Brain Res
236:221-226.
-
Tate S,
Benn S,
Hick C,
Trezise D,
John V,
Mannion RJ,
Costigan M,
Plumpton C,
Grose D,
Gladwell Z,
Kendall G,
Dale K,
Bountra C,
Woolf CJ
(1998)
Two sodium channels contribute to the TTX-R sodium current in primary sensory neurons.
Nat Neurosci
1:653-555.
-
Trimmer JS,
Cooperman SS,
Tomiko SA,
Zhou JY,
Crean SM,
Boyle MB,
Kallen RG,
Sheng ZH,
Barchi RL,
Sigworth FJ,
Goodman RH,
Agnew WS,
Mandel G
(1989)
Primary structure and functional expression of a mammalian skeletal muscle sodium channel.
Neuron
3:33-49.
Copyright © 0000 Society for Neuroscience 0270-6474/0/$05.00/0
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|
|
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|
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|
|
|
|
|
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|
|
|
|
|
|
|
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|
|
|
|
|
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[Full Text]
[PDF]
|
|
|
|
|
|
|
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7281 - 7292.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. T. Priest, B. A. Murphy, J. A. Lindia, C. Diaz, C. Abbadie, A. M. Ritter, P. Liberator, L. M. Iyer, S. F. Kash, M. G. Kohler, et al.
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102(26):
9382 - 9387.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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564(3):
803 - 815.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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J. Physiol.,
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564(2):
437 - 450.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Fukuda, T. Nakajima, P. C Viswanathan, and J. R Balser
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J. Physiol.,
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564(1):
21 - 31.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Beyak, N. Ramji, K. M. Krol, M. D. Kawaja, and S. J. Vanner
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Am J Physiol Gastrointest Liver Physiol,
October 1, 2004;
287(4):
G845 - G855.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. D Baker, S. Y Chandra, Y. Ding, S. G Waxman, and J. N Wood
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J. Physiol.,
April 15, 2003;
548(2):
373 - 382.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-j. Liu, S. D. Dib-Hajj, M. Renganathan, T. R. Cummins, and S. G. Waxman
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J. Biol. Chem.,
January 3, 2003;
278(2):
1029 - 1036.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. T. Blair and B. P. Bean
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J. Neurosci.,
December 1, 2002;
22(23):
10277 - 10290.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. W. Carr, S. Pianova, and J. A. Brock
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J. Gen. Physiol.,
August 26, 2002;
120(3):
395 - 405.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Zhou, G. Davar, and G. Strichartz
Endothelin-1 (ET-1) Selectively Enhances the Activation Gating of Slowly Inactivating Tetrodotoxin-Resistant Sodium Currents in Rat Sensory Neurons: A Mechanism for the Pain-Inducing Actions of ET-1
J. Neurosci.,
August 1, 2002;
22(15):
6325 - 6330.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
