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

ABSTRACT: 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_V1.1-Na_V1.8. 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_V1.3. Three of the peptides (BuIIIB, BuIIIE and AdIIIA) had submicromolar activity at hNa_V1.7. 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_V1.3 and hNa_V1.7.

SUBMITTER: McMahon KL 

PROVIDER: S-EPMC10492761 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature