Department of Pharmacology, The University of Michigan, Ann Arbor, Michigan 48109-0632
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ABSTRACT |
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Voltage-gated sodium channel -subunits have been shown
to be key mediators of the pathophysiology of pain. The present review considers the role of sodium channel auxiliary
-subunits in channel modulation, channel protein expression levels, and interactions with
extracellular matrix and cytoskeletal signaling molecules. Although
-subunits have not yet been directly implicated in pain mechanisms,
their intimate association with and ability to regulate
-subunits
predicts that they may be a viable target for therapeutic intervention
in the future. It is proposed that multifunctional sodium channel
-subunits provide a critical link between extracellular and
intracellular signaling molecules and thus have the ability to fine
tune channel activity and electrical excitability.
cell adhesion molecules; extracellular matrix
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INTRODUCTION |
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ABNORMAL EXPRESSION of voltage-gated sodium channels in
primary sensory neurons [dorsal root ganglion (DRG) neurons and
trigeminal neurons] is thought to contribute to the molecular
pathophysiology of pain. A number of review articles have appeared
recently that describe the role of sodium channel -subunits,
especially the TTX-insensitive channels PN3/SNS (SCN10A) and NaN/SNS2
(SCN11A), in the molecular basis of pain (4, 8, 19, 23, 25, 36, 37). It
is important to remember that sodium channels are heterotrimeric
structures composed of a central, pore-containing
-subunit and two
auxiliary subunits: a noncovalently associated
1-subunit (or its
splice-variant isoform
1A) and a disulfide-linked
2-subunit,
which do not form the pore but play critical roles in channel gating,
voltage dependence of activation and inactivation, channel protein
expression levels, and interaction with other signaling molecules such
as extracellular matrix and the cytoskeleton (3, 10, 16). This article
examines recent advances in our understanding of sodium channel
auxiliary
-subunit function. In the future, specific modulation of
-subunit expression may result in the ability to fine tune sodium
channel activity in localized tissues, much like a rheostat, such that
pain sensations can be managed without serious side effects.
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MOLECULAR CLONING AND FUNCTIONAL EXPRESSION OF SODIUM CHANNEL
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1 (36 kDa),
1A (45 kDa), and
2 (33 kDa) are transmembrane
proteins with type I topology (11, 12, 16). All three molecules contain
extracellular immunoglobulin domains that are structurally homologous
to the V-set of the immunoglobulin superfamily that includes cell
adhesion molecules (CAMs) (9). Sequence analysis of
2 revealed that
its extracellular domain contains an immunoglobulin fold and an
extended region with similarity to the CAM contactin (12). Two distinct
regions of the extracellular domain of contactin have >40% amino
acid sequence identity with sodium channel
2-subunits. Subsequent
analysis of the extracellular domains of
1 and
1A showed a
similar homology to the CAM myelin Po (9). It was proposed
that
-subunits may function as CAMs as well as modulators of channel
kinetics and plasma membrane expression levels.
Coexpression of 1-subunits with brain [SCN1A (32), SCN2A (11),
SCN3A (24), and SCN8A (31)] or skeletal muscle [SCN4A (30)]
-subunits in Xenopus oocytes increased the size
of the peak sodium current, accelerated its inactivation, and shifted the voltage dependence of inactivation to more negative membrane potentials, indicating that
1 is crucial in the assembly,
expression, and functional modulation of the rat brain sodium channel
heterotrimeric complex. Coexpression of SCN2A
- and
1-subunits in
mammalian cells increased the level of sodium channels at the plasma
membrane two- to fourfold as determined from
[3H]saxitoxin binding but did not affect the
dissociation constant for saxitoxin (13). Coexpression of
1-subunits
in these cells also shifted the voltage dependence of sodium channel
inactivation to more negative membrane potentials by 10-12 mV and
shifted the voltage dependence of channel activation to more negative
membrane potentials by 2-11 mV (13). Interestingly,
1 does not
appear to modulate all sodium channel
-subunits. Most important for this discussion is the observation that SNS/PN3
-subunits are not
affected by coexpression of
1 (26, 33). These results suggest that
other
1-like subunits may be present in sensory neurons. To begin to
answer this question, a splice variant of
1,
1A, was recently
identified in DRG, as described below. Its functional effects on
the TTX-resistant sodium channels have not yet been determined.
Coexpression of 2 with
-subunits in Xenopus oocytes
caused an increase in functional expression of sodium channels, an
increase in the fraction of
-subunits gating in a fast mode, and a
small negative shift in the voltage dependence of channel inactivation, similar to the effects observed for
1 (12). Expression of higher levels of
2 also caused a fourfold increase in the capacitance of
the Xenopus oocyte, which resulted primarily from an increase in the number and surface area of the plasma membrane microvilli. Interestingly, this
2-subunit-mediated increase in membrane
capacitance did not depend on coexpression of
. The sequence
similarity of
2-subunits to contactin, their ability to expand the
cell surface membrane, and their appearance in developing neurons and
axons suggested that they may modulate cell surface expression and
function of sodium channels during neurogenesis and synaptogenesis
(12).
Association of neuronal - and
2-subunits is a late event in
sodium channel biosynthesis (29). In primary cultures of rat embryonic
brain neurons, a large, metabolically stable, intracellular pool of
newly synthesized "free"
-subunits (not disulfide-linked to
2-subunits) could be detected.
-Subunits disulfide-linked to
2-subunits were found preferentially at the cell surface. This
intracellular pool of
-subunits was found to be available to serve
as a source of precursors to form functional cell surface sodium
channels. It was proposed that association with
2 could be a
rate-limiting step in regulation of the cell surface density and
localization of sodium channels in developing neurons. Because high-affinity
-subunit antibodies were not available at the time of
these studies, the association of
and
1 was not described. However, more recent data have shown that
1-subunit expression is a
critical regulator of sodium channel density in the plasma membrane of
transfected cells (13). Thus an important function of
-subunits may
be to direct, promote, and/or stabilize sodium channel
-subunit
localization in the plasma membrane. In the future, tight regulation of
-subunit expression might serve as a therapeutic mechanism to
control sodium channel density and thus electrical excitability of
targeted neurons in pain pathways.
1 is expressed only after birth in the developing brain (24, 27).
However, the developmental time course of
1 expression in rat
forebrain showed multiple size bands at earlier time points (20). These
immunoreactive bands were also present in adrenal gland, heart, and
skeletal muscle. In an attempt to identify
1-subunit isoforms, a rat
adrenal cDNA library was screened with a probe specific to the coding
region of
1. A cDNA clone was isolated that contained identity to
1 at the 5' end followed by a novel 3' region. This
1
isoform,
1A, was found to be a splice variant of
1 that is the
result of the retention of intron 3 containing an in-frame stop codon
(16). This alternate splicing event produces a novel carboxy terminus
that includes a transmembrane segment and short intracellular domain.
The developmental time course of
1A vs.
1 mRNA expression in rat
brain showed that
1A is expressed early in embryonic development.
Its expression declines to undetectable levels after birth, concurrent
with the expression of
1. Thus alternate splicing of
1 mRNA
appears to be developmentally regulated. Immunohistochemical analysis
of
1A expression showed that it is expressed in adult DRG, spinal
cord, and heart. Functional coexpression of SCN2A with
1A in
transfected Chinese hamster lung fibroblasts resulted in a 2.5-fold
increase in current density compared with cells expressing the
-subunit alone. [3H]saxitoxin binding
analysis confirmed these results. This increase in current density
reflected two distinct effects of
1A: 1) an increase in the
proportion of cells expressing detectable sodium currents and
2) an increase in the levels of functional sodium channels in
expressing cells. Increases in sodium channel expression with
1A are
similar to previous results obtained with the adult brain
1 isoform
in both mammalian cells (13) and Xenopus oocytes (11). These
observations are consistent with the hypothesis that
1- and
1A-subunits facilitate the expression of sodium channels and/or
stabilize channels in the plasma membrane. Sodium currents in
1A-expressing cell lines also exhibited subtle functional differences compared with the parent
-subunit-expressing cell line.
Inactivation curves in
1A-expressing cell lines were shifted to
slightly more positive potentials than inactivation curves for
alone. This finding differs from previous results showing that
coexpression of
and
1 in Chinese hamster lung cells shifts inactivation to potentials ~10 mV more negative than for cells expressing
alone. Apparently, differences between these two
-subunit isoforms in the putative transmembrane and intracellular segments are responsible for these differences in functional effects.
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SODIUM CHANNEL ![]() |
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Glial-derived extracellular matrix molecules, for example tenascin-C
(TN-C) and tenascin-R (TN-R), play important roles in cell interactions
in developing or injured neuronal cells, such as neuronal migration,
neuritogenesis, and neuronal regeneration (6, 28). The tenascins are
multifunctional molecules that can promote neurite outgrowth, inhibit
growth cone advance, and induce axonal defasciculation in vitro. Two
research groups, in separate experiments, showed that sodium channel
-subunits interact with TN-C (34) and TN-R (34, 38). The tenascins
were chosen as candidate molecules because they bind contactin, a CAM
with homology to sodium channel
2-subunits (34). Incubation of
purified sodium channels on microtiter plates coated with TN-C showed
saturable and specific binding. Glutathione-S-transferase (GST)
fusion proteins containing various domains of TN-C and TN-R were tested
for their ability to bind purified sodium channels or the recombinant
2-subunit extracellular domain. Both sodium channels and
2 bound
specifically to the fibronectin (FN) type III repeats 1-2, A, B,
and 6-8 of TN-C and FN type III repeats 1-2 and 6-8 of
TN-R. No binding was observed to the epidermal growth factor (EGF)-like
repeats or the fibrinogen (FG)-like domain of either molecule.
Transfected cells expressing
1 or
2 were repelled from TN-R
plated on a nitrocellulose substrate (38). The same TN-R GST fusion
proteins used in the first study were used to determine which domains
were responsible for the observed repulsion. Both the
1- and
2-expressing cell lines were strongly repelled by EGF-L
(cysteine-rich amino terminus of TN-R plus the EGF-like domains) but
adhered well to EGF-S (EGF-like domains only), FN 6-8, FG, and
GST, suggesting that the cysteine-rich amino-terminal domain of TN-R
may be involved in repulsion of
1- or
2-expressing cells. Cells
expressing
1-subunits alone initially adhered to the TN-R
recombinant domains FN 6-8 (as found in the first study for
2)
and EGF-S before repulsion. A mixture of EGF-L, EGF-S, and FN 6-8
fusion proteins added to the cell culture medium blocked the adhesion
of
1-expressing cells to the EGF-like or FN-like domains of TN-R in
a concentration-dependent manner.
-Subunit-mediated effects in
response to TN-R occurred in the absence of
-subunits, suggesting
that
-subunits can function as CAMs independently of the ion channel complex.
In two-electrode recordings in Xenopus oocytes, EGF-L fusion
protein produced a rapid increase in the amplitude of sodium currents.
EGF-L-mediated potentiation was observed in oocytes expressing the
SCN2A -subunit alone and in oocytes coexpressing SCN2A,
1-, and
2-subunits. In contrast, neither FN 6-8 fusion protein nor GST
affected sodium currents in oocytes, suggesting that potentiation is a
specific effect of the EGF-L domain of TN-R. EGF-L-mediated
potentiation was not accompanied by any detectable changes in the
voltage dependence of current activation or inactivation or in any
obvious effects on current time course.
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SODIUM CHANNEL ![]() |
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Cell adhesion molecules of the immunoglobulin superfamily interact
homophilically and heterophilically to transduce signals between
adjacent cells or adjacent axons, where they participate in axonal
fasciculation. For example, certain CAMs interact homophilically in a
trans mechanism to produce cellular aggregation (14). After homophilic binding, CAMs of the L1 family that have intracellular carboxy-terminal domains transduce signals resulting in the recruitment of ankyrin and spectrin to points of cell-cell contact.
Drosophila S2 cells are a classic model system in which
potential CAMs have been tested for these properties (1). S2 cells do
not express endogenous CAMs and grow as a suspension culture. cDNAs of
interest are then cloned into the S2 cell expression vector under the
control of an inducible Drosophila metallothionine promoter. On
induction of protein expression, S2 cells transfected with CAMs
aggregate. Immunocytochemical localization of endogenously expressed
ankyrin can then be performed to determine whether
trans-homophilic binding results in ankyrin recruitment to the
plasma membrane. The S2 cell model system has been used to investigate
whether sodium channel 1- and
2-subunits behave in a similar
manner. S2 cells transfected with
1 or
2 display homophilic
interactions (18). Immunocytochemical analysis of the cell aggregates
revealed recruitment of ankyrin to sites of cell-cell contact.
Coimmunoprecipitation experiments from rat brain membranes showed that
ankyrinG, which is expressed at mammalian nodes of Ranvier
and axon initial segments (17), and
1- or
2-subunits are
physically associated in mammalian neurons (J. D. Malhotra and L. L. Isom, unpublished observations). Thus sodium channel
-subunits
appear to behave like classic CAMs: they bind homophilically, recruit
ankyrin to points of cell-cell contact, and interact with extracellular
matrix molecules.
The intracellular domains of 1 and
2 are critical for ankyrin
recruitment. Truncation mutants lacking the intracellular carboxy-terminal domains of
1 and
2, respectively, were
transfected into S2 cells and the transfected cells were induced to
aggregate. Although both cell lines aggregated, ankyrin staining was
diffuse and not concentrated to points of cell-cell contact as in cells expressing full-length
-subunits (18). It was concluded that the
intracellular carboxy-terminal domains of
1 and
2 are necessary for trans-homophilic-mediated signal transduction to the cytoskeleton.
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SODIUM CHANNELS ARE MODULATED BY CONTACTIN |
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Because of its homology to 2-subunits, contactin was also
investigated as a possible modulator of sodium channels (15). Stable
coexpression of SCN2A and contactin in Chinese hamster lung cells had
no obvious effects on channel gating, voltage dependence, or expression
levels. However, coexpression of SCN2A, contactin, and
1 resulted in
a fourfold increase in [3H]saxitoxin binding
and current amplitude compared with coexpression of SCN2A and
1.
This effect was limited to sodium channel expression levels, since no
changes were observed in channel-gating kinetics or voltage dependence.
Contactin-mediated effects on sodium channel expression appeared to
require the presence of
1, perhaps through heterophilic cell
adhesive interactions. The distribution of sodium channels and
contactin was investigated in sciatic nerve using immunocytochemical
techniques. Although contactin and sodium channels were clearly
separated into paranodal and nodal regions, respectively, in adult
animals, it was found that during embryonic development as well as
during remyelination these molecules were colocalized. After nerve
injury, the interaction of sodium channel
-subunits and contactin
may play a key role in reformation of nodes of Ranvier and
reestablishment of saltatory conduction.
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SODIUM CHANNEL ![]() |
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In rat models of neuropathic pain, it has been shown that chronic
constrictive injury results in dynamic changes in the relative expression of sodium channel -subunits in the DRG as well as in the
spinal cord (36). In the Bennett and Xie model of neuropathic pain,
levels of
1 and
2 mRNA in the dorsal horn of the spinal cord are
differentially regulated as well (2). At 12-15 days after
neuropathy,
1 mRNA levels increased, whereas
2 mRNA levels decreased significantly within laminae I-II on the ipsilateral side of
the spinal cord relative to the contralateral side. In laminae II-IV,
1 mRNA levels remained constant and
2 levels again showed a small
but significant decrease. It was proposed that a functional
downregulation of
2-subunits may decrease the interaction of
-subunits with tenascins, thereby promoting axonal growth and
projection of neurons into the superficial laminae in which new
synaptic contacts could be initiated. It remains to be seen whether
-subunit protein levels correspond to the reported changes in mRNA
after neuronal injury. Future research must also include a correlation
of neurons in which
-subunit levels change with localized changes in
-subunit expression as well as with specific pain pathways.
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SODIUM CHANNEL ![]() |
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Protein kinase A (PKA) modulation of TTX-resistant sodium channels may
underlie the hyperalgesic responses of sensory neurons to agents such
as serotonin and PGE2 (5, 8). The action of these agents
can be mimicked by drugs that upregulate PKA phosphorylation of sodium
channels, such as forskolin and 8-bromo-cAMP (5, 8). SNS/PN3 channels
are phosphorylated by PKA, resulting in a time-dependent increase in
sodium current amplitude as well as a marked hyperpolarizing shift in
the current-voltage relationship, reducing the threshold for activation
(7). Interestingly, sodium channel 1- and
2-subunit mRNA levels
are upregulated in spinal cord astrocytes, B50 neuroblastoma cells,
optic nerve astrocytes, sciatic nerve astrocytes, and Schwann cells
after exposure to increased levels of cAMP (21, 22). Perhaps increases
in cAMP mediated by hyperalgesic agents can result in hyperexcitability via two mechanisms: phosphorylation of
-subunits and upregulation of
-subunit expression. Upregulation of
1 and
2 levels would be
expected to result in increased sodium current amplitude as well as
hyperpolarizing shifts in the voltage dependence of channel activation
and inactivation.
Neuronal sodium channel expression has been shown to be influenced by
nerve growth factor (NGF) (35). Changes in sodium channel expression in
DRG neurons after axotomy within the sciatic nerve have been shown to
be, in part, due to loss of access to peripheral pools of NGF (36).
Direct delivery of NGF to DRG cell bodies in vitro resulted in
downregulation of type III -subunits (SCN3A) and upregulation of
SNS/PN3 expression, thus partially preventing the redistribution of
sodium channels normally seen after axotomy (36). Sodium channel
1-subunit mRNA is upregulated in DRG neurons in NGF-containing
medium (39). Again, like the situation with cAMP, neurotrophins may
modulate sodium channel expression in DRG neurons via differential
effects on
- and
-subunits. Thus future research focusing on
methods of modulating
-subunit expression with neurotrophins in
selective neuronal cell bodies in the DRG may yield effective therapies
for pain.
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THERAPEUTIC IMPLICATIONS |
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In conclusion, sodium channel -subunits present a unique and
exciting experimental problem.
-Subunits participate in modulation of the voltage dependence of channel activation and inactivation, channel gating mode, and channel expression levels at the plasma membrane. Now we see that the
-subunits are members of the
immunoglobulin superfamily and play roles in cellular adhesion and
repulsion as well. Thus sodium channel
-subunits are multifunctional
proteins that present a number of possibilities for future
therapeutics. It may be possible to target
-subunit expression in
selective DRG or spinal cord neurons. Tight control of
-subunit
expression levels in certain classes of neurons may be one way of
regulating sodium current density and therefore hyperexcitability after
neuronal injury. Alternatively, site-directed mutagenesis of specific
residues in the immunoglobulin fold or the intracellular domains, or
rational drug design directed toward these regions, may make it
possible to regulate
-subunit-mediated interactions with
extracellular matrix, other CAMs, or cytoskeletal molecules. In this
way, one might gain control over sodium channel clustering, axonal
sprouting, or axonal fasciculation during remodeling events after nerve
injury. Sodium channel
-subunits may indeed be critical links
between the extra- and intracellular neuronal environments and may now provide insights into future therapeutic interventions for pain.
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FOOTNOTES |
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* First in a series of invited articles on Pathobiology of Visceral Pain: Molecular Mechanisms and Therapeutic Implications.
Address for reprint requests and other correspondence: L. L. Isom, Dept. of Pharmacology, The Univ. of Michigan, 1301 MSRB III, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0632 (E-mail: lisom{at}umich.edu).
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