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Potent Modulation of the Voltage-Gated Sodium Channel Na_v1.7 by OD1, a Toxin from the Scorpion Odonthobuthus doriae

Laboratory of Toxicology, University of Leuven, Leuven, Belgium (C.M., E.C., J.T.); Department of Cell and Molecular Biology, Faculty of Science, University of Tehran, Tehran, Iran (M.A.); Department of Toxicology and Pharmacology, Jundishapour University of Medical Sciences, Ahvaz, Iran (A.J.); and Department of Toxicology and Pharmacology, Shaheed Beheshti University of Medical Science, Tehran, Iran (H.V.)

Voltage-gated sodium channels are essential for the propagation of action potentials in nociceptive neurons. Na_v1.7 is found in peripheral sensory and sympathetic neurons and involved in short-term and inflammatory pain. Na_v1.8 and Na_v1.3 are major players in nociception and neuropathic pain, respectively. In our effort to identify isoform-specific and high-affinity ligands for these channels, we investigated the effects of OD1, a scorpion toxin isolated from the venom of the scorpion Odonthobuthus doriae. Na_v1.3, Na_v1.7, and Na_v1.8 channels were coexpressed with ₁-subunits in Xenopus laevis oocytes. Na⁺ currents were recorded with the two-electrode voltage-clamp technique. OD1 modulates Na_v1.7 at low nanomolar concentrations: 1) fast inactivation is dramatically impaired, with an EC₅₀ value of 4.5 nM; 2) OD1 substantially increases the peak current at all voltages; and 3) OD1 induces a substantial persistent current. Na_v1.8 was not affected by concentrations up to 2 µM, whereas Na_v1.3 was sensitive only to concentrations higher than 100 nM. OD1 impairs the inactivation process of Na_v1.3 with an EC₅₀ value of 1127 nM. Finally, the effects of OD1 were compared with a classic -toxin, AahII from Androctonus australis Hector and a classic -like toxin, BmK M1 from Buthus martensii Karsch. At a concentration of 50 nM, both toxins affected Na_v1.7. Na_v1.3 was sensitive to AahII but not to BmK M1, whereas Na_v1.8 was affected by neither toxin. In conclusion, the present study shows that the scorpion toxin OD1 is a potent modulator of Na_v1.7, with a unique selectivity pattern.

Address correspondence to: J. Tytgat, Laboratory of Toxicology, University of Leuven, Onderwijs and Navorsing II, Herestraat 49 - Box 922, B-3000 Leuven, Belgium. E-mail: Jan.Tytgat{at}pharm.kuleuven.be