1. The Tarantula Toxin ω-Avsp1a Specifically Inhibits Human Ca V 3.1 and Ca V 3.3 via the Extracellular S3-S4 Loop of the Domain 1 Voltage-Sensor.
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Herzig, Volker, Chen, Yong-Cyuan, Chin, Yanni K.-Y., Dekan, Zoltan, Chang, Yu-Wang, Yu, Hui-Ming, Alewood, Paul F., Chen, Chien-Chang, and King, Glenn F.
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SPIDER venom ,TARANTULAS ,CALCIUM channels ,PREVENTIVE medicine ,TOXINS ,BINDING sites - Abstract
Inhibition of T-type calcium channels (Ca
V 3) 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 CaV 3. However, subtype-specific CaV 3 inhibitors for therapeutic purposes or for studying the physiological roles of CaV 3 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 CaV 3.1 and CaV 3.3, but only 25% of CaV 3.2 currents. In order to investigate the toxin binding site, we generated a range of chimeric channels from the less sensitive CaV 3.2 and more sensitive CaV 3.3. Our results suggest that domain-1 of CaV 3.3 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. [ABSTRACT FROM AUTHOR]- Published
- 2022
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