8.B.28 The Mu-Conotoxin (Mu-Conotoxin) Family 

The neurotoxic cone snail peptide mu-GIIIA specifically blocks skeletal muscle voltage-gated sodium (Na_V1.4; 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 Na_V 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 Na_V 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 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 on hNa_V1.7 (McMahon et al. 2023).