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The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity.
Sci Rep. 2017 04 20; 7(1):974.SR

Abstract

Voltage-gated sodium (NaV) channels are essential for the transmission of pain signals in humans making them prime targets for the development of new analgesics. Spider venoms are a rich source of peptide modulators useful to study ion channel structure and function. Here we describe β/δ-TRTX-Pre1a, a 35-residue tarantula peptide that selectively interacts with neuronal NaV channels inhibiting peak current of hNaV1.1, rNaV1.2, hNaV1.6, and hNaV1.7 while concurrently inhibiting fast inactivation of hNaV1.1 and rNaV1.3. The DII and DIV S3-S4 loops of NaV channel voltage sensors are important for the interaction of Pre1a with NaV channels but cannot account for its unique subtype selectivity. Through analysis of the binding regions we ascertained that the variability of the S1-S2 loops between NaV channels contributes substantially to the selectivity profile observed for Pre1a, particularly with regards to fast inactivation. A serine residue on the DIV S2 helix was found to be sufficient to explain Pre1a's potent and selective inhibitory effect on the fast inactivation process of NaV1.1 and 1.3. This work highlights that interactions with both S1-S2 and S3-S4 of NaV channels may be necessary for functional modulation, and that targeting the diverse S1-S2 region within voltage-sensing domains provides an avenue to develop subtype selective tools.

Authors+Show Affiliations

Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, 4072, Australia.Discipline of Pharmacology, University of Sydney, Camperdown, NSW, 2006, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, 4072, Australia. Novo Nordisk A/S, Copenhagen Area, Capital Region, Denmark.Discipline of Pharmacology, University of Sydney, Camperdown, NSW, 2006, Australia. Harvard Medical School, Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, United States.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, 4072, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, 4072, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, 4072, Australia.Department of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA.Pain Management Research Institute, University of Sydney, St Leonards, NSW, 2006, Australia.Department of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA.Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, 2522, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, 4072, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, 4072, Australia.Centre for Advanced Imaging & School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, 4072, Australia.Discipline of Pharmacology, University of Sydney, Camperdown, NSW, 2006, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, 4072, Australia. l.rash@uq.edu.au. School of Biomedical Sciences, The University of Queensland, St Lucia, 4072, QLD, Australia. l.rash@uq.edu.au.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28428547

Citation

Wingerd, Joshua S., et al. "The Tarantula Toxin β/δ-TRTX-Pre1a Highlights the Importance of the S1-S2 Voltage-sensor Region for Sodium Channel Subtype Selectivity." Scientific Reports, vol. 7, no. 1, 2017, p. 974.
Wingerd JS, Mozar CA, Ussing CA, et al. The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity. Sci Rep. 2017;7(1):974.
Wingerd, J. S., Mozar, C. A., Ussing, C. A., Murali, S. S., Chin, Y. K., Cristofori-Armstrong, B., Durek, T., Gilchrist, J., Vaughan, C. W., Bosmans, F., Adams, D. J., Lewis, R. J., Alewood, P. F., Mobli, M., Christie, M. J., & Rash, L. D. (2017). The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity. Scientific Reports, 7(1), 974. https://doi.org/10.1038/s41598-017-01129-0
Wingerd JS, et al. The Tarantula Toxin β/δ-TRTX-Pre1a Highlights the Importance of the S1-S2 Voltage-sensor Region for Sodium Channel Subtype Selectivity. Sci Rep. 2017 04 20;7(1):974. PubMed PMID: 28428547.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity. AU - Wingerd,Joshua S, AU - Mozar,Christine A, AU - Ussing,Christine A, AU - Murali,Swetha S, AU - Chin,Yanni K-Y, AU - Cristofori-Armstrong,Ben, AU - Durek,Thomas, AU - Gilchrist,John, AU - Vaughan,Christopher W, AU - Bosmans,Frank, AU - Adams,David J, AU - Lewis,Richard J, AU - Alewood,Paul F, AU - Mobli,Mehdi, AU - Christie,Macdonald J, AU - Rash,Lachlan D, Y1 - 2017/04/20/ PY - 2016/12/14/received PY - 2017/03/27/accepted PY - 2017/4/22/entrez PY - 2017/4/22/pubmed PY - 2018/9/6/medline SP - 974 EP - 974 JF - Scientific reports JO - Sci Rep VL - 7 IS - 1 N2 - Voltage-gated sodium (NaV) channels are essential for the transmission of pain signals in humans making them prime targets for the development of new analgesics. Spider venoms are a rich source of peptide modulators useful to study ion channel structure and function. Here we describe β/δ-TRTX-Pre1a, a 35-residue tarantula peptide that selectively interacts with neuronal NaV channels inhibiting peak current of hNaV1.1, rNaV1.2, hNaV1.6, and hNaV1.7 while concurrently inhibiting fast inactivation of hNaV1.1 and rNaV1.3. The DII and DIV S3-S4 loops of NaV channel voltage sensors are important for the interaction of Pre1a with NaV channels but cannot account for its unique subtype selectivity. Through analysis of the binding regions we ascertained that the variability of the S1-S2 loops between NaV channels contributes substantially to the selectivity profile observed for Pre1a, particularly with regards to fast inactivation. A serine residue on the DIV S2 helix was found to be sufficient to explain Pre1a's potent and selective inhibitory effect on the fast inactivation process of NaV1.1 and 1.3. This work highlights that interactions with both S1-S2 and S3-S4 of NaV channels may be necessary for functional modulation, and that targeting the diverse S1-S2 region within voltage-sensing domains provides an avenue to develop subtype selective tools. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/28428547/The_tarantula_toxin_β/δ_TRTX_Pre1a_highlights_the_importance_of_the_S1_S2_voltage_sensor_region_for_sodium_channel_subtype_selectivity_ L2 - https://doi.org/10.1038/s41598-017-01129-0 DB - PRIME DP - Unbound Medicine ER -