Subtype-selective activation of K_v7 channels by AaTXKβ_(2-64), a novel toxin variant from the Androctonus australis Scorpion venom

K_v7.4 channel subunits are expressed in central auditory pathways and in inner ear sensory hair cells and skeletal and smooth muscle cells. Openers of K_v7.4 channels have been suggested to improve hearing loss, systemic or pulmonary arterial hypertension, urinary incontinence, gastrointestinal and neuropsychiatric diseases, and skeletal muscle disorders. Scorpion venoms are a large source of peptides active on K⁺ channels. Therefore, we have optimized a combined purification/screening procedure to identify specific modulator(s) of K_v7.4 channels from the venom of the North African scorpion Androctonus australis (Aa). We report the isolation and functional characterization of AaTXKβ_(2-64), a novel variant of AaTXKβ_(1-64), in a high-performance liquid chromatography fraction from Aa venom (named P8), which acts as the first peptide activator of K_v7.4 channels. In particular, in both Xenopus oocytes and mammalian Chinese hamster ovary cells, AaTXKβ_(2-64), but not AaTXKβ_(1-64), hyperpolarized the threshold voltage of current activation and increased the maximal currents of heterologously expressed K _v7.4 channels. AaTXKβ_(2-64) also activated K _v7.3, K_v7.2/3, and K_v7.5/3 channels, whereas homomeric K_v1.1, K_v7.1, and K_v7.2 channels were unaffected. We anticipate that these results may prove useful in unraveling the novel biologic roles of AaTXKβ_(2-64)-sensitive K_v7 channels and developing novel pharmacologic tools that allow subtype-selective targeting of K_v7 channels.