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...
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Nature Portfolio
2017
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oai:doaj.org-article:f33655e710d64fada2b711f3a0de85772021-12-02T12:30:46ZThe tarantula toxin β/δ-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity10.1038/s41598-017-01129-02045-2322https://doaj.org/article/f33655e710d64fada2b711f3a0de85772017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01129-0https://doaj.org/toc/2045-2322Abstract 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.Joshua S. WingerdChristine A. MozarChristine A. UssingSwetha S. MuraliYanni K.-Y. ChinBen Cristofori-ArmstrongThomas DurekJohn GilchristChristopher W. VaughanFrank BosmansDavid J. AdamsRichard J. LewisPaul F. AlewoodMehdi MobliMacdonald J. ChristieLachlan D. RashNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017) |
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Medicine R Science Q 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 |
| 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. |
| format |
article |
| 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 |
| title |
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_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_sort |
tarantula toxin β/δ-trtx-pre1a highlights the importance of the s1-s2 voltage-sensor region for sodium channel subtype selectivity |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/f33655e710d64fada2b711f3a0de8577 |
| work_keys_str_mv |
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