8.B.28 The Mu-Conotoxin (Mu-Conotoxin) Family
The neurotoxic cone snail peptide mu-GIIIA specifically blocks skeletal muscle voltage-gated sodium (NaV1.4; TC# 1.A.1.10.4) channels. The related conopeptides mu-PIIIA and mu-SIIIA, however, exhibit a wider activity spectrum by also inhibiting the neuronal NaV channels NaV1.2 and NaV1.7. Leipold et al. 2016 demonstrated that those mu-conopeptides with a broader target range also antagonize select subtypes of voltage-gated potassium channels of the KV1 family: mu-PIIIA and mu-SIIIA inhibited KV1.1 and KV1.6 channels in the nanomolar range, while being inactive on subtypes KV1.2-1.5 and KV2.1. Construction and electrophysiological evaluation of chimeras between KV1.5 and KV1.6 revealed that these toxins block KV channels involving their pore regions; the subtype specificity is determined in part by the sequence close to the selectivity filter but predominantly by the so-called turret domain, i.e. the extracellular loop connecting the pore with transmembrane segment S5. Conopeptides mu-SIIIA and mu- PIIIA, thus, are not specific for NaV channels (Leipold et al. 2016).
µ-Conotoxins are peptide toxins from the venoms of marine cone snails (genus Conus) that block NaV channels with nanomolar potency. Most species of the subgenera Textilia and Afonsoconus are difficult to acquire. McMahon et al. 2023 characterized new µ-conotoxins from species of the subgenera Textilia and Afonsoconus and investigated their selectivities for human NaV channels. Using RNA-seq of the venom gland of Conus (Textilia) bullatus, they identified 12 µ-conotoxin (or µ-conotoxin-like) sequences. Based on these sequences, primers were designed that were used to identify additional µ-conotoxin sequences from DNA extracted from historical specimens of species from Textilia and Afonsoconus. They synthesized six of these µ-conotoxins and tested their activity on human NaV1.1-NaV1.8. Five of the six synthetic peptides were potent blockers of human NaV channels. Of these, two peptides (BuIIIB and BuIIIE) were potent blockers of hNaV1.3. Three of the peptides (BuIIIB, BuIIIE and AdIIIA) had submicromolar activity on hNaV1.7 (McMahon et al. 2023).