Identification and characterization of ProTx-III [μ-TRTX-Tp1a], a new voltage-gated sodium channel inhibitor from venom of the tarantula Thrixopelma pruriens

Cardoso, Fernanda C., Deka, Zoltan, Rosengren, K. Johan, Erickson, Andelain, Vetter, Irina, Deuis, Jennifer R., Herzig, Volker, Alewood, Paul F., King, Glenn F. and Lewis, Richard J. (2015) Identification and characterization of ProTx-III [μ-TRTX-Tp1a], a new voltage-gated sodium channel inhibitor from venom of the tarantula Thrixopelma pruriens. Molecular Pharmacology, 88 2: 291-303. doi:10.1124/mol.115.098178


Author Cardoso, Fernanda C.
Deka, Zoltan
Rosengren, K. Johan
Erickson, Andelain
Vetter, Irina
Deuis, Jennifer R.
Herzig, Volker
Alewood, Paul F.
King, Glenn F.
Lewis, Richard J.
Title Identification and characterization of ProTx-III [μ-TRTX-Tp1a], a new voltage-gated sodium channel inhibitor from venom of the tarantula Thrixopelma pruriens
Formatted title
Identification and characterization of ProTx-III [μ-TRTX-Tp1a], a new voltage-gated sodium channel inhibitor from venom of the tarantula Thrixopelma pruriens
Journal name Molecular Pharmacology   Check publisher's open access policy
ISSN 0026-895X
1521-0111
Publication date 2015-08
Sub-type Article (original research)
DOI 10.1124/mol.115.098178
Open Access Status DOI
Volume 88
Issue 2
Start page 291
End page 303
Total pages 11
Place of publication Bethesda, MD, United States
Publisher American Society for Pharmacology and Experimental Therapeutics
Collection year 2016
Language eng
Formatted abstract
Spider venoms are a rich source of ion channel modulators with therapeutic potential. Given the analgesic potential of subtype-selective inhibitors of voltage-gated sodium (NaV) channels, we screened spider venoms for inhibitors of human NaV1.7 (hNaV1.7) using a high-throughput fluorescent assay. Here, we describe the discovery of a novel NaV1.7 inhibitor, μ-TRTX-Tp1a (Tp1a), isolated from the venom of the Peruvian green-velvet tarantula Thrixopelma pruriens. Recombinant and synthetic forms of this 33-residue peptide preferentially inhibited hNaV1.7 > hNaV1.6 > hNaV1.2 > hNaV1.1 > hNaV1.3 channels in fluorescent assays. NaV1.7 inhibition was diminished (IC50 11.5 nM) and the association rate decreased for the C-terminal acid form of Tp1a compared with the native amidated form (IC50 2.1 nM), suggesting that the peptide C terminus contributes to its interaction with hNaV1.7. Tp1a had no effect on human voltage-gated calcium channels or nicotinic acetylcholine receptors at 5 μM. Unlike most spider toxins that modulate NaV channels, Tp1a inhibited hNaV1.7 without significantly altering the voltage dependence of activation or inactivation. Tp1a proved to be analgesic by reversing spontaneous pain induced in mice by intraplantar injection in OD1, a scorpion toxin that potentiates hNaV1.7. The structure of Tp1a as determined using NMR spectroscopy revealed a classic inhibitor cystine knot (ICK) motif. The molecular surface of Tp1a presents a hydrophobic patch surrounded by positively charged residues, with subtle differences from other ICK spider toxins that might contribute to its different pharmacological profile. Tp1a may help guide the development of more selective and potent hNaV1.7 inhibitors for treatment of chronic pain.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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Created: Thu, 25 Jun 2015, 14:23:59 EST by Fernanda Caldas Cardoso on behalf of Institute for Molecular Bioscience