title: Subtype-selective activation of K(v)7 channels by AaTXKβ₂₋₆₄, a novel toxin variant from the Androctonus australis scorpion venom.
abstract: K(v)7.4 channel subunits are expressed in central auditory pathways and in inner ear sensory hair cells and skeletal and smooth muscle cells. Openers of K(v)7.4 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(v)7.4 channels from the venom of the North African scorpion Androctonus australis (Aa). We report the isolation and functional characterization of AaTXKβ₂₋₆₄, a novel variant of AaTXKβ₁₋₆₄, in a high-performance liquid chromatography fraction from Aa venom (named P8), which acts as the first peptide activator of K(v)7.4 channels. In particular, in both Xenopus oocytes and mammalian Chinese hamster ovary cells, AaTXKβ₂₋₆₄, but not AaTXKβ₁₋₆₄, hyperpolarized the threshold voltage of current activation and increased the maximal currents of heterologously expressed K(v)7.4 channels. AaTXKβ₂₋₆₄ also activated K(v)7.3, K(v)7.2/3, and K(v)7.5/3 channels, whereas homomeric K(v)1.1, K(v)7.1, and K(v)7.2 channels were unaffected. We anticipate that these results may prove useful in unraveling the novel biologic roles of AaTXKβ₂₋₆₄-sensitive K(v)7 channels and developing novel pharmacologic tools that allow subtype-selective targeting of K(v)7 channels.
authors.affiliation: Laboratoire des Venins et Molécules Thérapeutiques, Institut Pasteur de Tunis, Université Tunis-El Manar, Tunis-Belvédère, Tunisia (Z.L., M.E.A., R.B.); Division of Pharmacology, Department of Neuroscience, University of Naples Federico II, Naples, Italy (F.M., M.T.); Department of Chemical Sciences, University of Naples Federico II, Naples, Italy (A.P., A.A., G.M.); Department of Medicine and Health Science, University of Molise, Campobasso, Italy (M.T.); and Unidad de Biofísica, Consejo Superior de Investigaciones Cientificas, Universidad del Pais Vasco, Leioa, Spain (M.T.).
authors.forename: Zied
authors.initials: Z
authors.lastname: Landoulsi
authors.forename: Francesco
authors.initials: F
authors.lastname: Miceli
authors.forename: Angelo
authors.initials: A
authors.lastname: Palmese
authors.forename: Angela
authors.initials: A
authors.lastname: Amoresano
authors.forename: Gennaro
authors.initials: G
authors.lastname: Marino
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Ayeb
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taglialatela
authors.forename: Rym
authors.initials: R
authors.lastname: Benkhalifa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D051656:KCNQ Potassium Channels / Q000187:drug effects*; D008969:Molecular Sequence Data; D012604:Scorpion Venoms / Q000032:analysis / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014982:Xenopus laevis
chemical_list: D051656:KCNQ Potassium Channels; C117367:KCNQ4 protein, human; D012604:Scorpion Venoms