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Research ArticleArticle

Identification and Characterization of ProTx-III [μ-TRTX-Tp1a], a New Voltage-Gated Sodium Channel Inhibitor from Venom of the Tarantula Thrixopelma pruriens

Fernanda C. Cardoso, Zoltan Dekan, K. Johan Rosengren, Andelain Erickson, Irina Vetter, Jennifer R. Deuis, Volker Herzig, Paul F. Alewood, Glenn F. King and Richard J. Lewis
Molecular Pharmacology August 2015, 88 (2) 291-303; DOI: https://doi.org/10.1124/mol.115.098178
Fernanda C. Cardoso
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Zoltan Dekan
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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K. Johan Rosengren
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Andelain Erickson
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Irina Vetter
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Jennifer R. Deuis
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Volker Herzig
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Paul F. Alewood
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Glenn F. King
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Richard J. Lewis
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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    Fig. 1.

    Screening of T. pruriens spider venom against hNaV1.7 endogenously expressed in SH-SY5Y cells. Effect of venom from T. pruriens on hNaV1.7 showing 100 and 90% inhibition at 250 (●) and 25 (+) ng/μl, respectively, and loss of activity at 2.5 ng/μl (★). The positive control for hNaV1.7 activation was veratridine plus OD1 (×).

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    Fig. 2.

    Isolation of novel hNaV1.7 inhibitor from venom of the tarantula T. pruriens. (A) RP-HPLC fractionation of crude T. pruriens venom (1 mg) on a Phenomenex analytical C18 column using the gradient of solvent B indicated by the dashed line at a flow rate of 1 ml/min. Fractions were manually collected and screened for hNaV1.7 inhibition. Fractions found to inhibit hNaV1.7 are shaded dark gray. (B) Effect of RP-HPLC fractions on hNaV1.7 activity in SH-SY5Y cells as measured on a FLIPR. Fractions eluting at 26.9, 40.3, and 51.9 minutes potently inhibited hNaV1.7. The dominant masses found by matrix-assisted laser desorption/ionization–TOF analysis of each of the active fractions are indicated. Masses of 3984 and 3823 Da correspond to ProTx-I and ProTx-II, respectively. (C) Analytical RP-HPLC chromatogram and matrix-assisted laser desorption/ionization–TOF mass spectrum of RP-HPLC fraction 12 showing single peak and monoisotopic mass of 3799 Da that corresponds to Tp1a peptide.

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    Fig. 3.

    Determination of sequence of Tp1a and comparison with other spider toxins. (A) Determination of the amino acid sequence of Tp1a. The sequence of the first 31 amino acids was obtained by Edman degradation. The last two amino acids were determined using a combination of tandem mass spectrometry (MS nanospray) and amino acid analysis (AAA). (B) Alignment of Tp1a with spider venom peptides having at least 40% sequence identity. Identical residues are shown in bold and cysteines are gray. The percent identity relative to Tp1a and activity reported for each peptide is shown on the far right. Peptide sequences were obtained from the ArachnoServer database (www.arachnoserver.org) (Herzig et al., 2011). Asterisks denote C-terminal amidation. (C) Alignment of the sequence of Tp1a with those of ProTx-I (β/ω-TRTX-Tp1a) and ProTx-II (β/ω-TRTX-Tp2a), two NaV channel inhibitors previously isolated from the same venom.

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    Fig. 4.

    Production of recombinant Tp1a. (A) SDS-PAGE gel showing MBP-Tp1a fusion protein purified via nickel affinity chromatography (lane 1) and the efficiency of TEV protease cleavage of the fusion protein (∼50%) (lane 2). (B) RP-HPLC purification of cleaved recombinant rGly-Tp1a was performed using a Vydac 218TP C18 column with a two-step gradient of 5–50% solvent B over 45 minutes followed by 50–80% solvent B over 8 minutes. Matrix-assisted laser desorption/ionization–TOF mass spectrometry yielded a monoisotopic mass of 3858 Da, consistent with the calculated mass for rGly-Tp1a (3857.70).

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    Fig. 5.

    Comparison of native and synthetic Tp1a. Analytical RP-HPLC chromatograms of native amidated Tp1a (dashed trace), synthetic Tp1a-NH2 (gray trace), and coelution of synthetic Tp1a-NH2 and native Tp1a (black trace). RP-HPLC was performed on a Shimadzu LC20AT system using a Thermo Hypersil GOLD C18 column (2.1 × 100 mm; Thermo Fisher Scientific, Waltham, MA) heated at 40°C. Peptides were eluted using a gradient of 5–50% B over 45 minutes with a flow rate of 0.3 ml/min.

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    Fig. 6.

    Inhibition of hNaV1.7 by Tp1a. (A) Representative records of Na+ currents before (dashed traces) and after (black traces) addition of 2 nM native and synthetic Tp1a-NH2 or 10 nM recombinant and synthetic Tp1a-OH. Holding potential was –80 mV. (B) Concentration-response curves for inhibition of hNaV1.7 by native, recombinant, and synthetic acid and amidated Tp1a; the IC50 values calculated using I/Imax values and nonlinear regression were 2.1 ± 1.3 (n = 6), 9.5 ± 3.4 (n = 7), 11.5 ± 3.9 (n = 6), and 2.5 ± 0.8 (n = 6) nM (mean ± S.D.), respectively.

  • Fig. 7.
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    Fig. 7.

    Gating properties of Tp1a. Data (mean ± S.D., n = 3) for nTp1a (A), sTp1a-NH2 (B), sTp1a-OH (C), and rGly-Tp1a (D) are plotted as G/Gmax or I/Imax. Tp1a had no significant effect on the voltage dependence of steady-state activation or inactivation. Cells were held at –80 mV. Steady-state kinetics were estimated by currents elicited at 10-mV increments ranging from –110 to +80 mV. Conductance was calculated using G = I/(V–Vrev) in which I, V, and Vrev are the current value, membrane potential, and reverse potential, respectively. The voltage dependence of inactivation was estimated using a double-pulse protocol where currents were elicited by a 20-millisecond depolarizing potential of 0 mV following a 500-millisecond prepulse at potentials ranging from –130 to –10 mV with 10-mV increments. The ΔV1/2 for activation and inactivation were −8.89 and −7.24 mV for nTp1a (A), –5.1 and –5.1 mV for sTp1a-NH2 (B), –5.27 and –6.52 mV for sTp1a-OH (C), and –3.3 and –13.9 mV for rGly-Tp1a (D), respectively.

  • Fig. 8.
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    Fig. 8.

    On-rate of Tp1a inhibition of hNaV1.7. Measurement of on-rates for various forms of Tp1a. Na+ currents were recorded every 15 milliseconds soon after toxin addition. The calculated on-rates were 2.45, 1.63 × 103, and 2.01 × 103 minutes for nTp1a at 20, 2, and 0.2 nM, respectively (A); 2.28, 3.13 × 103, and 3.49 × 103 minutes for sTp1a-NH2 at 20, 2, and 0.2 nM, respectively (B); 3.15, 3.78 × 103, and 2.30 × 103 minutes for rGly-Tp1a at 150, 15, and 1.5 nM, respectively (C); and 2.40, 2.78 × 101, and 3.83 × 103 minutes for sTp1a-OH at 150, 15, and 1.5 nM, respectively (D).

  • Fig. 9.
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    Fig. 9.

    Off-rate of Tp1a and analogs at hNaV1.7. Tp1a was applied at 20 nM for nTp1a and sTp1a-NH2 and 150 nM for rGly-Tp1a and sTp1a-OH and incubated for 10 minutes before Na+ currents were measured every 10 minutes during saline washout. sTp1a-OH and rGly-Tp1a bound reversibly with off-rates of 53.5 and 47.7 minutes, respectively, whereas nTp1a and sTp1a-NH2 showed quasi-irreversible binding to hNaV1.7.

  • Fig. 10.
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    Fig. 10.

    Antinociceptive effects of Tp1a. (A) Intraplantar injection of the NaV1.7 activator OD1 (300 nM) led to rapid development of nocifensive behavior in mice that slowly declined over 40 minutes. This spontaneous pain behavior, measured by the number of paw lifts, licks, shakes, and flinches, was significantly attenuated in a concentration-dependent manner by coadministration of Tp1a when compared with vehicle control. (B) The reduction in spontaneous pain behavior persisted for 25 minutes after injection of the highest concentration of Tp1a (1 μM). Data are presented as the mean ± S.E.M. of 3–9 mice/group. Statistical significance was determined by analysis of variance with Dunnett’s post test; *P < 0.05 compared with control.

  • Fig. 11.
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    Fig. 11.

    3D structure of Tp1a. (A) Comparison of 1Hα chemical shifts for sTp1a-NH2 and sTp1a-OH, indicating that C-terminal amidation does not alter the 3D fold of Tp1a. (B) Ensemble of 20 structures chosen to represent the solution structure of Tp1a. Disulfide bonds are shown in yellow. (C) Schematic representation of Tp1a structure showing β-strands (magenta) and disulfide bonds (yellow). (D) Surface representation of the structures of Tp1a (left), μ-TRTX-Hhn1b (center), and μ-TRTX-Hs2a (right). Positively and negatively charged residues are highlighted in blue and red, respectively. Residues shown to be critical for inhibition of NaV1.7 include K27 and R29 for μ-TRTX-Hhn1b (Li et al., 2004) and K18, R26, and K32 for μ-TRTX-Hs2a (Minassian et al., 2013; Revell et al., 2013).

Tables

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    TABLE 1

    Kinetics of inhibition of hNaV1.7 by nTp1a, sTp1a-NH2, sTp1a-OH, and rGly-Tp1a

    Tp1a was applied at 0.2, 2, and 20 nM (nTp1a and sTp1a-NH2) or 1.5, 15, and 150 nM (sTp1a-OH and rGly-Tp1a), then sodium currents were measured. The kinetics of inhibition and recovery of inhibition were determined from the I/Imax as a function of time from traces shown in Fig. 8, fitted to a single exponential fit. Values are from at least three independent experiments (mean ± S.D.).

    ConcentrationKonKoffKd
    nM-1s−1s−1nM
    nTp1a
     0.2 nM4.1 ± 1.3 × 10−500
     2.0 nM5.1 ± 2.2 × 10−600
     20 nM3.4 ± 1.7 × 10−400
    sTp1a-NH2
     0.2 nM2.4 ± 0.5 × 10−500
     2.0 nM2.7 ± 1.2 × 10−600
     20 nM3.6 ± 0.6 × 10−400
    sTp1a-OH
     1.5 nM2.0 ± 0.2 × 10−4ND1.5 ± 0.1
     15 nM1.9 ± 0.4 × 10−5ND16.2 ± 0.3
     150 nM4.4 ± 1.7 × 10−53.1 ± 0.2 × 10−47.1 ± 0.5
    rGly-Tp1a
     1.5 nM2.3 ± 1.3 × 10−4ND1.5 ± 0.2
     15 nM2.3 ± 0.5 × 10−5ND15.13 ± 0.03
     150 nM2.2 ± 0.3 × 10−53.5 ± 0.5 × 10−415.84 ± 0.05
    • ND, not determined.

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    TABLE 2

    Tp1a activity on NaV channels evaluated by fluorescent imaging and electrophysiology represented as IC50 values

    For fluorescent assays, hNaV recombinant cell lines were incubated with rGly-Tp1a, sTp1a-NH2, or sTp1a-OH for 30 minutes followed by activation with veratridine/OD1. Fluorescent intensity was normalized against positive and negative controls and maximum response from 5-minute reading after NaV activation used for plotting the concentration-response curves. For electrophysiology assays, NaV recombinant cell lines held at –80 mV were incubated with rGly-Tp1a, sTp1a-OH, or sTp1a- NH2 for 5 minutes followed by a prepulse of –120 mV for 200 milliseconds and activation with a single pulse of 0 mV for 20 milliseconds. I/Imax values were used for plotting the concentration-response curves. Values are from at least three independent experiments (mean ± S.D.).

    ToxinhNaV1.1hNaV1.2hNaV1.3hNaV1.4hNaV1.5hNaV1.6hNaV1.7hNaV1.8
    Fluorescent imaging assay (μM)
     rGly-Tp1a2.8 ± 1.42.4 ± 0.413.7 ± 1.0>5>54.5 ± 1.31.12 ± 0.3>5
     sTp1a-OH1.5 ± 0.21.4 ± 0.712.1 ± 5.6>5>53.7 ± 1.11.5 ± 0.4>5
     sTp1a-NH20.5 ± 0.10.3 ± 0.10.9 ± 0.2>5>50.29 ± 0.050.22 ± 0.05>5
    Electrophysiology (nM)
     rGly-Tp1a60 ± 26ND21.9 ± 4.0ND>500ND9.5 ± 3.4ND
     sTp1a-OH101 ± 30ND41.3 ± 4.7ND>500ND11.5 ± 3.9ND
     sTp1a-NH211.3 ± 1.2ND11.5 ± 3.0ND>50ND2.5 ± 0.8ND
    • ND, not determined.

    • View popup
    TABLE 3

    Structural statistics for the ensemble of Tp1a structures

    NMR distance and dihedral statistics
     Distance constraints
      Total349
      Intraresidual (׀i-j׀ = 0)168
      Sequential (׀i-j׀ = 1)100
      Medium range (׀i-j׀ ≤ 4)36
      Long range (׀i-j׀ ≥ 5)45
     Hydrogen bonds (for 12 H-bonds)24
     Dihedral angles
      φ19
      χ118
    Structure statistics
     Violations
      Distance constraints (> 0.2 Å)0
      Dihedral angle constraints (> 2°)0
     Energies (kcal/mol, mean ± S.D.)
      Overall−1145 ± 36
      Bond13.4 ± 1.1
      Angles35.7 ± 2.8
      Improper12.4 ± 2.0
      vdw−155.0 ± 5.9
      NOE (experimental)0.068 ± 0.018
      cDih (experimental)0.13 ± 0.15
      Dihed150.6 ± 1.9
      Elec−1202 ± 42
     RMS deviation from idealized geometry
      Bond length (Å)0.0104 ± 0.00043
      Bond angles (°)1.08 ± 0.98
      Impropers (°)1.07 ± 0.96
     Average pairwise root mean square deviationa (Å)
      Heavy1.50 ± 0.30
      Backbone0.73 ± 0.25
     MOLPROBITY
      Clash score, all atomsb5.5 ± 3.2
      Poor rotamers0.8 ± 0.6
      Ramachandran favored (%)98.2 ± 2.3
      Ramachandran allowed (%)1.93 ± 2.31
      Ramachandran outliers (%)0 ± 0
      Molprobity score1.63 ± 0.34
      Molprobity score percentilec88.2 ± 8.7
      Cβ deviations, bad backbone bonds/angles0 ± 0
    • cDih, experimental dihedral angles; Dihed, dihedral angles; Elec, electrostatics; NOE, nuclear overhauser effect; RMS, root mean square; vdw, van der Waals.

    • ↵a Pairwise root mean square deviation from 20 refined structures over residues 2–29.

    • ↵b Number of steric overlaps (>0.4 Å) per 1000 atoms.

    • ↵c One hundred percent is the best among structures of comparable resolution, 0% is the worst.

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Molecular Pharmacology: 88 (2)
Molecular Pharmacology
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1 Aug 2015
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Research ArticleArticle

New Sodium Channel Inhibitor from Thrixopelma pruriens

Fernanda C. Cardoso, Zoltan Dekan, K. Johan Rosengren, Andelain Erickson, Irina Vetter, Jennifer R. Deuis, Volker Herzig, Paul F. Alewood, Glenn F. King and Richard J. Lewis
Molecular Pharmacology August 1, 2015, 88 (2) 291-303; DOI: https://doi.org/10.1124/mol.115.098178

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Research ArticleArticle

New Sodium Channel Inhibitor from Thrixopelma pruriens

Fernanda C. Cardoso, Zoltan Dekan, K. Johan Rosengren, Andelain Erickson, Irina Vetter, Jennifer R. Deuis, Volker Herzig, Paul F. Alewood, Glenn F. King and Richard J. Lewis
Molecular Pharmacology August 1, 2015, 88 (2) 291-303; DOI: https://doi.org/10.1124/mol.115.098178
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