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Three Peptide Modulators of the Human Voltage-Gated Sodium Channel 1.7, an Important Analgesic Target, from the Venom of an Australian Tarantula.
Toxins (Basel). 2015 Jun 30; 7(7):2494-513.T

Abstract

Voltage-gated sodium (NaV) channels are responsible for propagating action potentials in excitable cells. NaV1.7 plays a crucial role in the human pain signalling pathway and it is an important therapeutic target for treatment of chronic pain. Numerous spider venom peptides have been shown to modulate the activity of NaV channels and these peptides represent a rich source of research tools and therapeutic lead molecules. The aim of this study was to determine the diversity of NaV1.7-active peptides in the venom of an Australian Phlogius sp. tarantula and to characterise their potency and subtype selectivity. We isolated three novel peptides, μ-TRTX-Phlo1a, -Phlo1b and -Phlo2a, that inhibit human NaV1.7 (hNaV1.7). Phlo1a and Phlo1b are 35-residue peptides that differ by one amino acid and belong in NaSpTx family 2. The partial sequence of Phlo2a revealed extensive similarity with ProTx-II from NaSpTx family 3. Phlo1a and Phlo1b inhibit hNaV1.7 with IC50 values of 459 and 360 nM, respectively, with only minor inhibitory activity on rat NaV1.2 and hNaV1.5. Although similarly potent at hNaV1.7 (IC50 333 nM), Phlo2a was less selective, as it also potently inhibited rNaV1.2 and hNaV1.5. All three peptides cause a depolarising shift in the voltage-dependence of hNaV1.7 activation.

Authors+Show Affiliations

The University of Queensland, Institute for Molecular Bioscience, St Lucia, Queensland 4072, Australia. chun.chow@uqconnect.edu.au.The University of Queensland, Institute for Molecular Bioscience, St Lucia, Queensland 4072, Australia. b.cristoforiarmstrong@uq.edu.au.The University of Queensland, Institute for Molecular Bioscience, St Lucia, Queensland 4072, Australia. e.undheim@imb.uq.edu.au.The University of Queensland, Institute for Molecular Bioscience, St Lucia, Queensland 4072, Australia. glenn.king@imb.uq.edu.au.The University of Queensland, Institute for Molecular Bioscience, St Lucia, Queensland 4072, Australia. l.rash@uq.edu.au.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26134258

Citation

Chow, Chun Yuen, et al. "Three Peptide Modulators of the Human Voltage-Gated Sodium Channel 1.7, an Important Analgesic Target, From the Venom of an Australian Tarantula." Toxins, vol. 7, no. 7, 2015, pp. 2494-513.
Chow CY, Cristofori-Armstrong B, Undheim EA, et al. Three Peptide Modulators of the Human Voltage-Gated Sodium Channel 1.7, an Important Analgesic Target, from the Venom of an Australian Tarantula. Toxins (Basel). 2015;7(7):2494-513.
Chow, C. Y., Cristofori-Armstrong, B., Undheim, E. A., King, G. F., & Rash, L. D. (2015). Three Peptide Modulators of the Human Voltage-Gated Sodium Channel 1.7, an Important Analgesic Target, from the Venom of an Australian Tarantula. Toxins, 7(7), 2494-513. https://doi.org/10.3390/toxins7072494
Chow CY, et al. Three Peptide Modulators of the Human Voltage-Gated Sodium Channel 1.7, an Important Analgesic Target, From the Venom of an Australian Tarantula. Toxins (Basel). 2015 Jun 30;7(7):2494-513. PubMed PMID: 26134258.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Three Peptide Modulators of the Human Voltage-Gated Sodium Channel 1.7, an Important Analgesic Target, from the Venom of an Australian Tarantula. AU - Chow,Chun Yuen, AU - Cristofori-Armstrong,Ben, AU - Undheim,Eivind A B, AU - King,Glenn F, AU - Rash,Lachlan D, Y1 - 2015/06/30/ PY - 2015/04/15/received PY - 2015/06/19/revised PY - 2015/06/24/accepted PY - 2015/7/3/entrez PY - 2015/7/3/pubmed PY - 2016/4/14/medline KW - NaV1.7 KW - Phlogius sp. KW - ion channel KW - mass spectrometry KW - spider venom KW - two-electrode voltage clamp electrophysiology KW - venom peptide KW - voltage-gated sodium channel SP - 2494 EP - 513 JF - Toxins JO - Toxins (Basel) VL - 7 IS - 7 N2 - Voltage-gated sodium (NaV) channels are responsible for propagating action potentials in excitable cells. NaV1.7 plays a crucial role in the human pain signalling pathway and it is an important therapeutic target for treatment of chronic pain. Numerous spider venom peptides have been shown to modulate the activity of NaV channels and these peptides represent a rich source of research tools and therapeutic lead molecules. The aim of this study was to determine the diversity of NaV1.7-active peptides in the venom of an Australian Phlogius sp. tarantula and to characterise their potency and subtype selectivity. We isolated three novel peptides, μ-TRTX-Phlo1a, -Phlo1b and -Phlo2a, that inhibit human NaV1.7 (hNaV1.7). Phlo1a and Phlo1b are 35-residue peptides that differ by one amino acid and belong in NaSpTx family 2. The partial sequence of Phlo2a revealed extensive similarity with ProTx-II from NaSpTx family 3. Phlo1a and Phlo1b inhibit hNaV1.7 with IC50 values of 459 and 360 nM, respectively, with only minor inhibitory activity on rat NaV1.2 and hNaV1.5. Although similarly potent at hNaV1.7 (IC50 333 nM), Phlo2a was less selective, as it also potently inhibited rNaV1.2 and hNaV1.5. All three peptides cause a depolarising shift in the voltage-dependence of hNaV1.7 activation. SN - 2072-6651 UR - https://www.unboundmedicine.com/medline/citation/26134258/Three_Peptide_Modulators_of_the_Human_Voltage_Gated_Sodium_Channel_1_7_an_Important_Analgesic_Target_from_the_Venom_of_an_Australian_Tarantula_ L2 - http://www.mdpi.com/resolver?pii=toxins7072494 DB - PRIME DP - Unbound Medicine ER -