Abstract
Kv7.4 channel subunits are expressed in central auditory pathways and in inner ear sensory hair cells and 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, we have optimized a combined purification/screening procedure 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 a high-performance liquid chromatography fraction from Aa venom (named P8), which acts as the first peptide activator of Kv7.4 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 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 may prove useful in unraveling the novel biologic roles of AaTXKβ(2–64)-sensitive Kv7 channels and developing novel pharmacologic tools that allow subtype-selective targeting of Kv7 channels.
Footnotes
- Received August 2, 2013.
- Accepted September 9, 2013.
This work was supported by grants from the Pasteur Institute of Tunis, Ministry of Higher Education and Scientific Research [Tox11] (to R.B.); Telethon [GGP07125], the Fondazione San Paolo–IMI [Project Neuroscience], Regione Molise [Convenzione AIFA/Regione Molise], the Italian Ministry for Education and Research [PRIN 2009], Provincia di Avellino [2012] (to M.T.); Regione Campania 2013 [PON01_01802 and PON01_00117] (to A.A.); and a traineeship grant from the International Division of the Pasteur Institute [RIIP/EC/MAM/N 117/11] (to Z.L.).
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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