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Mol Pain. 2008; 4: 1.
Published online Jan 2, 2008. doi:  10.1186/1744-8069-4-1
PMCID: PMC2262064
Mutation I136V alters electrophysiological properties of the NaV1.7 channel in a family with onset of erythromelalgia in the second decade
Xiaoyang Cheng,1,2,3 Sulayman D Dib-Hajj,1,2,3 Lynda Tyrrell,1,2,3 and Stephen G Waxmancorresponding author1,2,3
1Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510, USA
2Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, USA
3Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516, USA
corresponding authorCorresponding author.
Xiaoyang Cheng: xiaoyang.cheng/at/yale.edu; Sulayman D Dib-Hajj: sulayman.dib-hajj/at/yale.edu; Lynda Tyrrell: lynda.tyrrell/at/yale.edu; Stephen G Waxman: stephen.waxman/at/yale.edu
Received September 18, 2007; Accepted January 2, 2008.
Background
Primary erythromelalgia is an autosomal dominant pain disorder characterized by burning pain and skin redness in the extremities, with onset of symptoms during the first decade in the families whose mutations have been physiologically studied to date. Several mutations of voltage-gated Na+ channel NaV1.7 have been linked with primary erythromelalgia. Recently, a new substitution NaV1.7/I136V has been reported in a Taiwanese family, in which pain appeared at later ages (9–22 years, with onset at 17 years of age or later in 5 of 7 family members), with relatively slow progression (8–10 years) to involvement of the hands. The proband reported onset of symptoms first in his feet at the age of 11, which then progressed to his hands at the age of 19. The new mutation is located in transmembrane segment 1 (S1) of domain I (DI) in contrast to all NaV1.7 mutations reported to date, which have been localized in the voltage sensor S4, the linker joining segments S4 and S5 or pore-lining segments S5 and S6 in DI, II and III.
Results
In this study, we characterized the gating and kinetic properties of I136V mutant channels in HEK293 cells using whole-cell patch clamp. I136V shifts the voltage-dependence of activation by -5.7 mV, a smaller shift in activation than the other erythromelalgia mutations that have been characterized. I136V also decreases the deactivation rate, and generates larger ramp currents.
Conclusion
The I136V substitution in NaV1.7 alters channel gating and kinetic properties. Each of these changes may contribute to increased excitability of nociceptive dorsal root ganglion neurons, which underlies pain in erythromelalgia. The smaller shift in voltage-dependence of activation of NaV1.7, compared to the other reported cases of inherited erythromelalgia, may contribute to the later age of onset and slower progression of the symptoms reported in association with this mutation.
Voltage-gated Na+ channels are heteromeric protein complexes, consisting of a pore-forming α subunit and auxiliary β subunits [1]. Nine α subunits (NaV1.1–NaV1.9) have been reported to date, and have been shown to be expressed in a tissue-specific manner [2]. Each α subunit is composed of four homologous domains (DI-DIV), with each domain consisting of six transmembrane segments (S1–S6), with S4 acting as a voltage-sensor and S5 and S6 lining the pore [1]. Voltage-gated Na+ channels are essential for the production of action potentials and are thus pivotal for excitability of neurons, myocytes, and neuroendocrine cells [2]. Mutations of voltage-gated Na+ channels have been linked to a number of human diseases including epilepsy, periodic paralysis, cardiac disorders, and pain disorders [3-7].
Primary erythromelalgia is a rare, inherited, autosomal dominant disorder, characterized by intermittent burning pain in the extremities and skin redness of the affected areas. Episodes can be triggered by warm stimuli or mild exercise [8]. The onset of symptoms varies from childhood, adolescence, to adulthood [9], with onset of pain most commonly occurring during the first decade of life. Primary erythromelalgia has been linked to mutations in SCN9A, the gene that encodes voltage-gated sodium channel NaV1.7 [10]. NaV1.7 is preferentially expressed in nociceptive dorsal root ganglia (DRG) neurons and sympathetic ganglia neurons [11-14], and it produces a fast-activating and -inactivating TTX-sensitive (TTX-S) current with a slow recovery from inactivation [12,15]. NaV1.7 also exhibits slow kinetics of closed-state inactivation, which enables it to respond to small, slow depolarizing inputs and boost subthreshold depolarizations [15]. Thus, gain-of-function mutations of the NaV1.7 channel might be expected to contribute to the hyperexcitability of nociceptive neurons which underlies chronic pain in patients with erythromelagia.
Nine mutations of NaV1.7 have been identified in patients with primary erythromelalgia, with eight of them, all from families with onset in childhood (≤ 10 years of age), having been characterized by electrophysiological studies [16-22]. All eight mutations cause a hyperpolarizing shift in voltage dependence of activation in NaV1.7 channels. Slow deactivation kinetics and larger ramp currents were observed in all but the F1449V mutant channels [16-22]. The changes in the biophysical properties of mutant NaV1.7 are predicted to increase excitability of DRG neurons and thereby contribute to the pathophysiology of erythromelalgia. In fact, three of these mutations (F1449V, A863P, and L858H) have been studied using current clamp and shown to increase excitability of DRG neurons in culture [18,20,23].
Recently, a new erythromelalgia mutation of NaV1.7 was reported by Lee et al in a Taiwanese family, affecting family members of three generations [24], with a later age of onset. In this family, pain appeared first in the feet at ages varying from 9 to 22 years, with onset at ages ≥ 17 years in five of seven family members; pain was reported in the hands in one-half of the affected family members, 8–10 years later (C-C Yang and M-J Lee, personal communication). The clinical phenotype was unusual in that the proband reported onset of pain in feet at 11 years of age, later than in most of familial cases [16,18,21,22,25] and in the patients with de novo founder mutations that have been studied to date [19,20]. Genetic analysis identified a substitution of isoleucine 136 with valine (I136V) in NaV1.7 in all affected family members, but not in unaffected family members or control DNA [24]. This amino acid substitution is located in DIS1 of the NaV1.7 channel, in contrast to all NaV1.7 mutations reported to date, which have been localized in the voltage sensor S4, the linker joining segments S4 and S5 or pore-lining segments S5 and S6 in DI, II and III. Here, we investigate the effect of this mutation on biophysical properties of NaV1.7 channels.
I136V mutation produces lower threshold for activation, slower kinetics of fast inactivation, and larger window currents
Sodium currents were recorded from HEK293 cells stably expressing either wild type NaV1.7R or I136V mutant channels. Figure Figure1A1A shows representative families of inward Na+ current traces of wild type and I136V mutant channels. Cell capacitance was similar (p > 0.05) in cells that were transfected with NaV1.7R or with I136V mutant channels (NaV1.7R: 19.2 ± 0.6 pF, n = 40; I136V: 18.9 ± 0.5 pF, n = 43). Figure Figure1B1B shows the mean current-voltage relationship of wild-type and I136V channels, with no apparent difference of reversal potentials (NaV1.7R: 71.5 ± 0.5 mV; I136V: 70.3 ± 0.4 mV). However, currents generated by I136V mutant channels activated and reached the maximal amplitudes at more hyperpolarized potentials compared with wild type channels. Boltzmann fits of conductance show that the I136V mutation significantly shifted the midpoint of the activation curve in a hyperpolarizing direction (I136V: V1/2,act = -28.8 ± 0.5 mV, n = 43; NaV1.7R: -23.1 ± 0.7 mV, n = 40, p < 0.05, Figure Figure1C,1C, Table Table11).
Figure 1
Figure 1
I136V mutation alters voltage-dependent activation and steady-state fast inactivation of NaV1.7 channels. A, Representative family traces of Na+ currents from voltage-clamped HEK293 cells expressing either wild-type NaV1.7R (top) or I136V mutant (bottom) (more ...)
Table 1
Table 1
Electrophysiological properties of wild-type and I136V mutant NaV1.7 channels.
Activation kinetics, measured as time-to-peak, were similar between wild-type and I136V channels (Figure (Figure1D).1D). The kinetics of fast inactivation, which reflects the transition from the open to inactive state, were measured by fitting the decaying phase of Na+ currents in Figure Figure1A1A with single exponential functions. Because open state inactivation is coupled to activation state [26], the curve of inactivation kinetics of I136V mutant channels was shifted by 5.7 mV in a depolarizing direction (gray circles in Figure Figure1E)1E) to match the similar activation voltages of wild type channels. Analysis of the data shows that the I136V substitution leads to slower kinetics of fast inactivation.
Steady-state fast inactivation was tested with a series of 500-ms prepulses from -140 to -10 mV followed by a 20 ms test pulse at -10 mV. Although mutant channels showed less inactivation at -100 and -90 mV, no difference was observed in V1/2,fast inact between the two channels, probably because the inactivation curve of mutant channels is steeper than that of wild type channels (Figure (Figure1C,1C, Table Table1).1). Figure Figure1F1F shows the predicted window current which is defined by the overlap of activation and steady-state fast inactivation curves. I136V mutant channels are predicted to produce larger window currents than wild type channels, and thus are expected to lead to a more depolarized resting membrane potential in DRG neurons [20,23].
I136V mutant channels exhibit slower deactivation and enhanced steady-state slow inactivation
Similar to most NaV1.7 mutations that cause primary erythromelalgia, I136V mutation significantly decreases the deactivation rate of sodium currents at all tested deactivation potentials (Figure (Figure2A).2A). At -40 mV, the time constant of deactivation was 0.22 ± 0.02 ms (n = 17) for wild type channels and 0.94 ± 0.10 ms (n = 19) for I136V mutant channels. Slower deactivation has been suggested to contribute to neuronal excitability by prolonging responses after the cessation of a depolarizing stimulus [17].
Figure 2
Figure 2
I136V mutation alters deactivation and steady-state slow-inactivation. A, Time constants of channel deactivation. Cells were held at -100 mV and tail currents were generated by a brief 0.5-ms depolarization to -20 mV followed by a series of repolarizations (more ...)
Steady-state slow inactivation was enhanced in mutant channels (Figure (Figure2B).2B). The V1/2,slow inact was shifted by 8 mV in a hyperpolarizing direction, and the slope factor was significantly reduced when compared with wild type NaV1.7R channels. The fraction of I136V channels that are resistant to slow inactivation was reduced compared to wild type channels (Table (Table11).
I136V mutant channels recover faster from fast inactivation at -70 mV and generate larger ramp currents, compared to wild type channels
The ability of channels to recover from fast inactivation (repriming) may determine how fast a neuron can repetitively fire. Repriming kinetics of wild type and mutant channels were examined for a series of recovery periods at four different recovery potentials between prepulses and test pulses. I136V mutation does not change the repriming kinetics at -100, -90, and -80 mV, but significantly enhances the recovery at -70 mV (Figure (Figure3A3A).
Figure 3
Figure 3
I136V mutation alters recovery from fast-inactivation and increases currents elicited by slow ramp depolarizations. A, Cells were held at -100 mV, and fast-inactivation was initiated by a 20-ms depolarization to 0 mV, followed by a recovery period (2–300 (more ...)
The responses of wild type and mutant channels to slow ramp depolarizations were also tested. HEK293 cells expressing mutant channels produced larger ramp currents than cells expressing wild type channels (I136V: 0.79 ± 0.04%, n = 26; WT: 0.23 ± 0.02%, n = 19, p < 0.05). The I136V mutation also shifted the onset of the currents to more negative potentials (I136V: -48.0 ± 0.5 mV, n = 26; WT: -42.3 ± 0.9 mV, n = 19, p < 0.05).
In this study we investigated the gating properties of the I136V mutation of NaV17 channels, which has been linked to inherited primary erythromelalgia in a Taiwanese family reported by Lee et al [24]. Compared to wild-type channels, the I136V substitution leads to a hyperpolarizing shift of activation, slower deactivation kinetics, and larger ramp currents. The I136V mutation did not alter voltage-dependent steady-state fast-inactivation, but decreased the slope factor. The significant changes in the slopes of the activation and steady-state inactivation Boltzman fits might be due to altered allosteric interactions among the four voltage sensor domains. Mutant channels also reprimed faster than wild-type channels but only at a recovery voltage of -70 mV. These changes of the biophysical properties of NaV1.7 are expected to contribute to hyperexcitability of DRG neurons, which underlies painful symptoms of erythromelalgia.
I136V mutant channels significantly enhanced slow-inactivation which would be expected to reduce excitability of DRG neurons. However, enhanced slow inactivation has been reported in other erythromelalgia mutations, suggesting that enhanced voltage-dependence of NaV1.7 activation dominates over slow inactivation in these erythromelalgia mutations [17,21]. Computer simulations of the effect of mutant NaV1.7 channels in model DRG neurons have in fact shown that the hyperpolarized shift in the activation of channels is the key factor in inducing neuron hyperexcitability, whereas slow inactivation modulates the effect on the firing frequency of these neurons [22].
The location (DIS1) and conservative nature of the I136V substitution might account for the milder effect of this mutation on the channel gating properties. Among the eight erythromelalgia mutations characterized so far, four are located within the S4–S5 linkers of DI [21] or DII [17,19], one in DIS4 [16], one each in DIS6 [22] and DIIIS6 [18], and one in DIIS5 [20]. Considering the importance of these regions for channel function [1], it is not surprising that those mutations alter NaV1.7 activity. In contrast, I136V is located within DIS1, a segment which has not been shown to have a dominant effect in channel gating. Moreover, both Val and Ile are neutral, nonpolar branched amino acids which differ by a single methyl group in their side chain, and substitution of one residue by the other is generally not expected to cause significant change in protein function. However, a similarly conservative substitution of a serine with threonine (S241T) in the DI S4–S5 linker [27] has been proven to have a significant effect on channel activation, an effect which is likely caused by the larger side chain of the threonine residue compared to that of serine [21]. Thus, the I136V substitution might influence the packing of the S1 segment within the voltage sensor domain (S1–S4) [28] and this could lead to altered gating properties by favoring the open state of the channel.
The conservation of an isoleucine in DIS1 of most voltage-gated sodium and calcium channels is consistent with a role of this residue in channel function. A recent study identified a conserved motif (F-XXX-I-XXX-I-XX-N/S-XXX-M/L; the residue in boldface corresponds to I136 in NaV1.7) within S1 segments of most voltage-gated Na+ and Ca2+ channels [29]. However, NaV1.9 is an exception because the residue which corresponds to I136 in DIS1 is valine [30-32], similar to the mutant NaV1.7 from the Taiwanese family [24]. NaV1.9 activates at more hyperpolarized potentials compared to the other sodium channels [31,33], and while the S1 sequence of NaV1.9 carries additional amino acid changes compared to the other channels, it is possible that the equivalent residue of NaV1.7/I136 within NaV1.9 contributes to the hyperpolarized activation of this channel. Interestingly, M145T in DIS1 in NaV1.1 (which corresponds to the last conserved residue in the S1 consensus motif) has been linked to familial febrile seizures and the activation curve of the mutant NaV1.1 has been reported to shift by 10 mV in a depolarizing direction [34]. The opposite effects on voltage-dependence of channel activation of I136V and M145T could reflect a fundamental difference in the structure of the voltage sensor domain (S1–S4) as a consequence of conservative (I136V) and non-conservative (M145T) substitutions of key residues in S1.
The mutation I136V causes a smallest shift (-5.7 mV) in voltage-dependent activation compared to the other erythromelalgia mutations that have been studied to date [16-22]. The small shift induced by I136V is possibly related to the location of the mutation within DIS1 and the conservative nature of the substitution, but despite the reduced magnitude of the shift in I136V, it appears to be enough to contribute to the erythromelalgia symptoms. It is possible that the smaller shift in channel activation is a factor that contributes to the later onset and relatively slower progression of the symptoms from feet to hands in this family. This case may thus represent a correlation of genotype and phenotype in patients with primary erythromelalgia.
Recent studies have revealed an association between missense mutations within other parts of NaV1.7 and another painful neuropathy, paroxysmal extreme pain disorder (PEPD) [35], whereas nonsense mutations of NaV1.7 have been linked to channelopathy-associated congenital indifference to pain [36-38]. The identification and characterization of mutant NaV1.7 channels have begun to elucidate the molecular basis for positive symptoms (pain) and negative symptoms (indifference to pain) in patients carrying these mutations. The present results document another gain-of-function mutation of NaV1.7 that is associated with painful symptoms in humans, in a family with onset of erythromelalgia's symptoms in the second decade, and add to the data pointing to this channel as a target for therapeutic intervention for the treatment of chronic pain.
I136V mutation in DIS1 of NaV1.7 channels has been reported to cause primary erythromelalgia in a Taiwanese family, with onset of symptoms in the second decade. Electrophysiological study revealed a hyperpolarizing shift of the voltage-dependence of activation, decreased deactivation rate, and a larger response to slow ramp depolarization in mutant channels. All these changes could contribute to the development of primary erythromelalgia. The shift in activation is smaller when compared with other primary erythromelalgia mutations which present with pain at earlier ages, possibly due to the conservative nature of the substitution between isoleucine and valine and the location of this mutation in the DIS1 in NaV1.7. This study adds to the evidence for an essential role of NaV1.7 in the pain sensory pathway, and suggests that the extent of shift of voltage-dependence of activation of NaV1.7 may be a factor that is correlated with the rate of development of erythromelalgia symptoms.
Plasmids and stable cell lines
The TTX-resistant human NaV1.7R expression vector has been described previously [39]. The I136V substitution was introduced into NaV1.7R using the QuickChange XL site-directed mutagenesis kit (Stratagene, La Jolla, CA). Human embryonic kidney cells (HEK293) stably expressing either wild-type (NaV1.7R) or mutant (I136V) channels were generated as described before [21].
Electrophysiology
Whole-cell voltage-clamp recordings of HEK293 cells expressing either wild type NaV1.7R or I136V mutant channels were performed at room temperature (20–22°C) using an Axopatch 200 B amplifier (Axon Instruments, Foster City, CA). Fire-polished electrodes (0.6–1.3 MΩ) were fabricated from 1.6 mm outer diameter borosilicate glass micropipettes (World Precision Instruments, Sarasota, FL). The pipette potential was adjusted to zero before seal formation, and liquid junction potential was not corrected. Capacity transients were cancelled and voltage errors were minimized with 80–90% series resistance compensation. Currents were acquired with Clampex 9.2, 5 min after establishing whole-cell configuration, sampled at a rate of 50 or 100 kHz, and filtered at 10 kHz.
For current-voltage relationships, cells were held at -100 mV and stepped to a range of potentials (-80 to +60 mV in 5 mV increments) for 50 ms. Peak inward currents (I) were plotted as a function of depolarization potential to generate I-V curves. Activation curves were obtained by converting I to conductance (G) at each voltage (V) using the equation G = I/(V-Vrev), where Vrev is the reversal potential which was determined for each cell individually. Activation curves were then fit with Boltzmann function in the form of G = Gmax/{1 + exp[(V1/2,act-V)/k]}, where Gmax is the maximal sodium conductance, V1/2,act is the potential at which activation is half-maximal, V is the test potential, and k is the slope factor.
Steady-state fast inactivation was achieved with a series of 500-ms prepulses (-140 to 10 mV in 10 mV increments) and the remaining non-inactivated channels were activated by a 20 ms step depolarization to -10 mV. Steady-state slow inactivation was determined with 30 s prepulses ranging from -130 to +10 mV followed by a 100 ms hyperpolarization at -120 mV to remove fast inactivation. Remaining available channels were activated by a 20 ms test pulse to -10 mV. Peak inward currents obtained from steady-state fast inactivation and slow inactivation protocols were normalized with the maximal peak current (Imax) and fit with Boltzman functions:
I/Imax = 1/{1 + exp[(V - V1/2,inact)/k]}
for fast inactivation, and
I/Imax = Rin + (1 - Rin)/{1 + exp[(V - V1/2,inact)/k]}
for slow inactivation, where
V represents the inactivating prepulse potential, V1/2,inact represents the midpoint of inactivation curve, and Rin is the fraction of channels that are resistant to inactivation.
Deactivation was examined using a short (0.5 ms) depolarizing pulse to -20 mV followed by a 50 ms repolarizing pulse to potentials ranging from -100 to -40 mV with 5 mV increments. Deactivation kinetics was calculated by fitting the decaying currents with a single exponential function. Ramp currents were elicited with a slow depolarizing voltage ramp from -100 to +20 mV at a rate of 0.2 mV/ms. The absolute ramp current amplitude was normalized to the maximal peak current obtained by I-V protocol.
The pipette solution contained (in mM): 140 CsF, 10 NaCl, 1 EGTA, 10 dextrose, and 10 HEPES, pH 7.35 (adjusted with CsOH), and the osmolarity was adjusted to 307 mOsmol/L with sucrose. The extracellular bath solution contained (in mM): 140 NaCl, 3 KCl, 1 MgCl2, 1 CaCl2, 10 dextrose, 10 HEPES, pH 7.4 (adjusted with NaOH), and the osmolarity was adjusted to 311 mOsmol/L with sucrose. Tetrodotoxin (TTX, 300 nM) was added to the bath solution to block endogenous voltage-gated sodium currents in HEK293 cells, permitting currents from wild type NaV1.7R or I136V to be recorded in isolation.
Data Analysis
Data were analyzed using Clampfit 9.2 (Molecular Devices) and Origin 7.5 (Microcal Software, Northampton, MA), and presented as means ± SE. Statistical significance was determined by unpaired student's t tests.
Competing interests
The author(s) declare that they have no competing interests.
Authors' contributions
XC collected, analyzed and interpreted electrophysiological data. SDD-H participated in the experimental design and interpretation of the data. LT generated the mutant I136V construct and established the stable cell lines. SGW conceived the project, participated in the experimental design and interpretation. XC, SDD-H, and SGW participated in writing of the manuscript. All authors read and approved the final manuscript.
Acknowledgements
We thank Drs. Jin Sung Choi, Mark Estacion, Angelika Lampert, and Elaine Gilmore for valuable discussions, and Emmanuella M. Eastman and Bart Toftness for technical assistance. We are grateful to Drs. C-C Yang and M-J Lee for generously sharing unpublished information about the ages of onset of symptoms in this family. This work was supported in part by grants from the National Multiple Sclerosis Society and the Rehabilitation Research Service and Medical Research Service, Department of Veterans Affairs, and the Erythromelalgia Association. The Center for Neuroscience and Regeneration Research is a collaboration of the Paralyzed Veterans of America and the United Spinal Association with Yale University.
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