The Tarantula Toxin ω-Avsp1a Specifically Inhibits Human CaV3.1 and CaV3.3 via the Extracellular S3-S4 Loop of the Domain 1 Voltage-Sensor

Volker Herzig; Yong-Cyung Chen; Yanni K Y Chin; Zoltan Dekan; Yu-Wang Chang; Hui-Ming Yu; Paul F Alewood; Chien-Chang Chen; Glenn F King

doi:10.3390/biomedicines10051066

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The Tarantula Toxin ω-Avsp1a Specifically Inhibits Human CaV3.1 and CaV3.3 via the Extracellular S3-S4 Loop of the Domain 1 Voltage-Sensor

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The Tarantula Toxin ω-Avsp1a Specifically Inhibits Human CaV3.1 and CaV3.3 via the Extracellular S3-S4 Loop of the Domain 1 Voltage-Sensor

Volker Herzig, Yong-Cyung Chen, Yanni K Y Chin, Zoltan Dekan, Yu-Wang Chang, Hui-Ming Yu, Paul F Alewood, Chien-Chang Chen and Glenn F King

Biomedicines, Vol.10(5), pp.1-17

2022

DOI: https://doi.org/10.3390/biomedicines10051066

PMCID: PMC9138389

PMID: 35625803

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Abstract

voltage-gated calcium channel

Cav3 subtype

T-type

venom peptide synthesis

theraphosid spider

tarantula

peptide structure

Inhibition of T-type calcium channels (CaV3) prevents development of diseases related to cardiovascular and nerve systems. Further, knockout animal studies have revealed that some diseases are mediated by specific subtypes of CaV3. However, subtype-specific CaV3 inhibitors for therapeutic purposes or for studying the physiological roles of CaV3 subtypes are missing. To bridge this gap, we employed our spider venom library and uncovered that Avicularia spec. (“Amazonas Purple”, Peru) tarantula venom inhibited specific T-type CaV channel subtypes. By using chromatographic and mass-spectrometric techniques, we isolated and sequenced the active toxin ω-Avsp1a, a C-terminally amidated 36 residue peptide with a molecular weight of 4224.91 Da, which comprised the major peak in the venom. Both native (4.1 μM) and synthetic ω-Avsp1a (10 μM) inhibited 90% of CaV3.1 and CaV3.3, but only 25% of CaV3.2 currents. In order to investigate the toxin binding site, we generated a range of chimeric channels from the less sensitive CaV3.2 and more sensitive CaV3.3. Our results suggest that domain-1 of CaV3.3 is important for the inhibitory effect of ω-Avsp1a on T-type calcium channels. Further studies revealed that a leucine of T-type calcium channels is crucial for the inhibitory effect of ω-Avsp1a.

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Title: The Tarantula Toxin ω-Avsp1a Specifically Inhibits Human CaV3.1 and CaV3.3 via the Extracellular S3-S4 Loop of the Domain 1 Voltage-Sensor
Authors: Volker Herzig (Author) - University of the Sunshine Coast, Queensland, School of Science, Technology and Engineering
Yong-Cyung Chen (Author) - Academia Sinica
Yanni K Y Chin (Author) - The University of Queensland
Zoltan Dekan (Author) - The University of Queensland
Yu-Wang Chang (Author) - Academia Sinica
Hui-Ming Yu (Author) - Academia Sinica
Paul F Alewood (Author) - The University of Queensland
Chien-Chang Chen (Author) - Academia Sinica
Glenn F King (Author) - The University of Queensland
Publication details: Biomedicines, Vol.10(5), pp.1-17
Publisher: MDPI AG
Date published: 2022
DOI: 10.3390/biomedicines10051066
ISSN: 2227-9059
PMID: 35625803; PMC9138389
Copyright note: Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Organisation Unit: University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
Language: English
Record Identifier: 99635579102621
Output Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Biochemistry & Molecular Biology; Medicine, Research & Experimental; Pharmacology & Pharmacy

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