ω-Grammotoxin-SIA inhibits voltage-gated Na+ channel currents.
| Autor: | Collaço RC; Department of Basic and Applied Medical Sciences, Molecular Physiology and Neurophysics Group, Ghent University, Ghent, Belgium., Van Petegem F; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada.; Life Sciences Institute, University of British Columbia , Vancouver, Canada., Bosmans F; Department of Basic and Applied Medical Sciences, Molecular Physiology and Neurophysics Group, Ghent University, Ghent, Belgium.; Faculty of Medicine and Pharmacy, Center for Neurosciences (C4N), Vrije Universiteit Brussel , Brussels, Belgium. |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of general physiology [J Gen Physiol] 2024 Oct 07; Vol. 156 (10). Date of Electronic Publication: 2024 Jul 23. |
| DOI: | 10.1085/jgp.202413563 |
| Abstrakt: | ω-Grammotoxin-SIA (GrTX-SIA) was originally isolated from the venom of the Chilean rose tarantula and demonstrated to function as a gating modifier of voltage-gated Ca2+ (CaV) channels. Later experiments revealed that GrTX-SIA could also inhibit voltage-gated K+ (KV) channel currents via a similar mechanism of action that involved binding to a conserved S3-S4 region in the voltage-sensing domains (VSDs). Since voltage-gated Na+ (NaV) channels contain homologous structural motifs, we hypothesized that GrTX-SIA could inhibit members of this ion channel family as well. Here, we show that GrTX-SIA can indeed impede the gating process of multiple NaV channel subtypes with NaV1.6 being the most susceptible target. Moreover, molecular docking of GrTX-SIA onto NaV1.6, supported by a p.E1607K mutation, revealed the voltage sensor in domain IV (VSDIV) as being a primary site of action. The biphasic manner in which current inhibition appeared to occur suggested a second, possibly lower-sensitivity binding locus, which was identified as VSDII by using KV2.1/NaV1.6 chimeric voltage-sensor constructs. Subsequently, the NaV1.6p.E782K/p.E838K (VSDII), NaV1.6p.E1607K (VSDIV), and particularly the combined VSDII/VSDIV mutant lost virtually all susceptibility to GrTX-SIA. Together with existing literature, our data suggest that GrTX-SIA recognizes modules in NaV channel VSDs that are conserved among ion channel families, thereby allowing it to act as a comprehensive ion channel gating modifier peptide. (© 2024 COLLAÇO et al.) |
| Databáze: | MEDLINE |
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