Abstract
Kv7.4 channel subunits are expressed in central auditory pathways and in inner ear sensory hair cells, skeletal and smooth muscle cells. Openers of Kv7.4 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 Kv7.4 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 Kv7.4 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 Kv7.4 channels. AaTXKβ(2-64) also activated Kv7.3, Kv7.2/3, and Kv7.5/3 channels, whereas homomeric Kv1.1, Kv7.1, and Kv7.2 channels were unaffected. We anticipate that these results might prove useful to unravel novel biological roles of AaTXKβ(2-64)-sensitive Kv7 channels, and to develop novel pharmacological tools allowing subtype-selective targeting of Kv7 channels.
- The American Society for Pharmacology and Experimental Therapeutics