Identification of sodium channel toxins from marine cone snails of the subgenera Textilia and Afonsoconus

• Published in: Cellular and molecular life sciences : CMLS Vol. 80; no. 10; p. 287
• Main Authors: McMahon, Kirsten L., O’Brien, Henrik, Schroeder, Christina I., Deuis, Jennifer R., Venkatachalam, Dhananjeyan, Huang, Di, Green, Brad R., Bandyopadhyay, Pradip K., Li, Qing, Yandell, Mark, Safavi-Hemami, Helena, Olivera, Baldomero M., Vetter, Irina, Robinson, Samuel D.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.10.2023; Springer Nature B.V
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Channel gating; Channels; Conotoxins; Conus; Deoxyribonucleic acid; DNA; Gastropoda; Gene sequencing; genus; humans; Life Sciences; Membrane proteins; Mollusks; Nervous system; Nucleotide sequence; Original; Original Article; Peptides; sequence analysis; Snails; Sodium; sodium channels; Sodium channels (voltage-gated); species; Synthetic peptides; Toxins; Venom gland; venoms; Historical DNA; Conotoxin; µ-conotoxin; Voltage-gated sodium channel
• ISSN: 1420-682X; 1420-9071; 1420-9071
• DOI: 10.1007/s00018-023-04935-0

Voltage-gated sodium (Na V ) channels are transmembrane proteins that play a critical role in electrical signaling in the nervous system and other excitable tissues. µ-Conotoxins are peptide toxins from the venoms of marine cone snails (genus Conus ) that block Na V channels with nanomolar potency. Most species of the subgenera Textilia and Afonsoconus are difficult to acquire; therefore, their venoms have yet to be comprehensively interrogated for µ-conotoxins. The goal of this study was to find new µ-conotoxins from species of the subgenera Textilia and Afonsoconus and investigate their selectivity at human Na V channels. Using RNA-seq of the venom gland of Conus ( Textilia ) bullatus, we identified 12 µ-conotoxin (or µ-conotoxin-like) sequences. Based on these sequences we designed primers which we used to identify additional µ-conotoxin sequences from DNA extracted from historical specimens of species from Textilia and Afonsoconus . We synthesized six of these µ-conotoxins and tested their activity on human Na V 1.1–Na V 1.8. Five of the six synthetic peptides were potent blockers of human Na V channels. Of these, two peptides (BuIIIB and BuIIIE) were potent blockers of hNa V 1.3. Three of the peptides (BuIIIB, BuIIIE and AdIIIA) had submicromolar activity at hNa V 1.7. This study serves as an example of the identification of new peptide toxins from historical DNA and provides new insights into structure–activity relationships of µ-conotoxins with activity at hNa V 1.3 and hNa V 1.7.