The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity
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-TR...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-01129-0 |
| _version_ | 1818752250456047616 |
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| author | Joshua S. Wingerd Christine A. Mozar Christine A. Ussing Swetha S. Murali Yanni K.-Y. Chin Ben Cristofori-Armstrong Thomas Durek John Gilchrist Christopher W. Vaughan Frank Bosmans David J. Adams Richard J. Lewis Paul F. Alewood Mehdi Mobli Macdonald J. Christie Lachlan D. Rash |
| author_facet | Joshua S. Wingerd Christine A. Mozar Christine A. Ussing Swetha S. Murali Yanni K.-Y. Chin Ben Cristofori-Armstrong Thomas Durek John Gilchrist Christopher W. Vaughan Frank Bosmans David J. Adams Richard J. Lewis Paul F. Alewood Mehdi Mobli Macdonald J. Christie Lachlan D. Rash |
| author_sort | Joshua S. Wingerd |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-18T04:48:29Z |
| format | Article |
| id | doaj.art-f33655e710d64fada2b711f3a0de8577 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-18T04:48:29Z |
| publishDate | 2017-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-f33655e710d64fada2b711f3a0de85772022-12-21T21:20:30ZengNature PortfolioScientific Reports2045-23222017-04-017111510.1038/s41598-017-01129-0The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivityJoshua S. Wingerd0Christine A. Mozar1Christine A. Ussing2Swetha S. Murali3Yanni K.-Y. Chin4Ben Cristofori-Armstrong5Thomas Durek6John Gilchrist7Christopher W. Vaughan8Frank Bosmans9David J. Adams10Richard J. Lewis11Paul F. Alewood12Mehdi Mobli13Macdonald J. Christie14Lachlan D. Rash15Institute for Molecular Bioscience, The University of QueenslandDiscipline of Pharmacology, University of SydneyInstitute for Molecular Bioscience, The University of QueenslandDiscipline of Pharmacology, University of SydneyInstitute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandDepartment of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of MedicinePain Management Research Institute, University of SydneyDepartment of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of MedicineIllawarra Health and Medical Research Institute, University of WollongongInstitute for Molecular Bioscience, The University of QueenslandInstitute for Molecular Bioscience, The University of QueenslandCentre for Advanced Imaging & School of Chemistry and Molecular Biosciences, The University of QueenslandDiscipline of Pharmacology, University of SydneyInstitute for Molecular Bioscience, The University of QueenslandAbstract 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.https://doi.org/10.1038/s41598-017-01129-0 |
| spellingShingle | Joshua S. Wingerd Christine A. Mozar Christine A. Ussing Swetha S. Murali Yanni K.-Y. Chin Ben Cristofori-Armstrong Thomas Durek John Gilchrist Christopher W. Vaughan Frank Bosmans David J. Adams Richard J. Lewis Paul F. Alewood Mehdi Mobli Macdonald J. Christie Lachlan D. Rash The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity Scientific Reports |
| title | The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity |
| title_full | The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity |
| title_fullStr | The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity |
| title_full_unstemmed | The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity |
| title_short | The tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity |
| title_sort | tarantula toxin β δ trtx pre1a highlights the importance of the s1 s2 voltage sensor region for sodium channel subtype selectivity |
| url | https://doi.org/10.1038/s41598-017-01129-0 |
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