Subtype-specific block of voltage-gated K⁺ channels by μ-conopeptides

The neurotoxic cone snail peptide μ-GIIIA specifically blocks skeletal muscle voltage-gated sodium (Na_V1.4) channels. The related conopeptides μ-PIIIA and μ-SIIIA, however, exhibit a wider activity spectrum by also inhibiting the neuronal Na_V channels Na_V1.2 and Na_V1.7. Here we demonstrate that those μ-conopeptides with a broader target range also antagonize select subtypes of voltage-gated potassium channels of the K_V1 family: μ-PIIIA and μ-SIIIA inhibited K_V1.1 and K_V1.6 channels in the nanomolar range, while being inactive on subtypes K_V1.2-1.5 and K_V2.1. Construction and electrophysiological evaluation of chimeras between K_V1.5 and K_V1.6 revealed that these toxins block K_V 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 μ-SIIIA and μ-PIIIA, thus, are not specific for Na_V channels, and the known structure of some K_V channel subtypes may provide access to structural insight into the molecular interaction between μ-conopeptides and their target channels.