Voltage-Gated Sodium Channel Modulation by a New Spider Toxin Ssp1a Isolated From an Australian Theraphosid
Dongol, Yashad, Choi, Phil M., Wilson, David T., Daly, Norelle L., Cardoso, Fernanda C., and Lewis, Richard J. (2021) Voltage-Gated Sodium Channel Modulation by a New Spider Toxin Ssp1a Isolated From an Australian Theraphosid. Frontiers in Pharmacology, 12. 795455.
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Abstract
Given the important role of voltage-gated sodium (NaV) channel-modulating spider toxins in elucidating the function, pharmacology, and mechanism of action of therapeutically relevant NaV channels, we screened the venom from Australian theraphosid species against the human pain target hNaV1.7. Using assay-guided fractionation, we isolated a 33-residue inhibitor cystine knot (ICK) peptide (Ssp1a) belonging to the NaSpTx1 family. Recombinant Ssp1a (rSsp1a) inhibited neuronal hNaV subtypes with a rank order of potency hNaV1.7 > 1.6 > 1.2 > 1.3 > 1.1. rSsp1a inhibited hNaV1.7, hNaV1.2 and hNaV1.3 without significantly altering the voltage-dependence of activation, inactivation, or delay in recovery from inactivation. However, rSsp1a demonstrated voltage-dependent inhibition at hNaV1.7 and rSsp1a-bound hNaV1.7 opened at extreme depolarizations, suggesting rSsp1a likely interacted with voltage-sensing domain II (VSD II) of hNaV1.7 to trap the channel in its resting state. Nuclear magnetic resonance spectroscopy revealed key structural features of Ssp1a, including an amphipathic surface with hydrophobic and charged patches shown by docking studies to comprise the interacting surface. This study provides the basis for future structure-function studies to guide the development of subtype selective inhibitors.
| Item ID: | 72819 |
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| Item Type: | Article (Research - C1) |
| ISSN: | 1663-9812 |
| Keywords: | ICK peptide, spider toxin, Ssp1a, venom peptide, voltage-gated sodium channel |
| Copyright Information: | © 2021 Dongol, Choi, Wilson, Daly, Cardoso and Lewis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Funders: | National Health and Medical Research Council (NHMRC), Australian Research Council (ARC) |
| Projects and Grants: | NHMRC Program Grant APP1072113, NHMRC Principal Research Fellowship APP1119056, NHMRC Ideas Grant APP1188959, ARC grant LE120100015, ARC Grant LE160100218 |
| Date Deposited: | 10 May 2022 02:08 |
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