Abstract

K_v7.4 channel subunits are expressed in central auditory pathways and in inner ear sensory hair cells, 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, a combined purification/screening procedure has been optimized in the present work 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 an HPLC fraction from the Aa venom (named P8), which acted as the first peptide activator of K_v7.4 channels. In particular, in both Xenopus oocytes and mammalian CHO cells, AaTXKβ_(2-64), but not AaTXKβ_(1-64), hyperpolarized the threshold voltage of current activation and increased the maximal currents of heterologoulsy-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 might prove useful to unravel novel biological roles of AaTXKβ_(2-64)-sensitive K_v7 channels, and to develop novel pharmacological tools allowing subtype-selective targeting of K_v7 channels.