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Open AccessArticle

Characterization of Synthetic Tf2 as a NaV1.3 Selective Pharmacological Probe

1
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia
2
Institute of Physiology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany
3
Research Training Group 2416 MultiSenses-MultiScales, RWTH Aachen University, 52074 Aachen, Germany
4
Research Training Group 2415 ME3T, RWTH Aachen University, 52074 Aachen, Germany
5
School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4102, Australia
*
Authors to whom correspondence should be addressed.
Biomedicines 2020, 8(6), 155; https://doi.org/10.3390/biomedicines8060155
Received: 15 May 2020 / Revised: 2 June 2020 / Accepted: 5 June 2020 / Published: 11 June 2020
(This article belongs to the Special Issue Animal Venoms–Curse or Cure?)
NaV1.3 is a subtype of the voltage-gated sodium channel family. It has been implicated in the pathogenesis of neuropathic pain, although the contribution of this channel to neuronal excitability is not well understood. Tf2, a β-scorpion toxin previously identified from the venom of Tityus fasciolatus, has been reported to selectively activate NaV1.3. Here, we describe the activity of synthetic Tf2 and assess its suitability as a pharmacological probe for NaV1.3. As described for the native toxin, synthetic Tf2 (1 µM) caused early channel opening, decreased the peak current, and shifted the voltage dependence of NaV1.3 activation in the hyperpolarizing direction by −11.3 mV, with no activity at NaV1.1, NaV1.2, and NaV1.4-NaV1.8. Additional activity was found at NaV1.9, tested using the hNav1.9_C4 chimera, where Tf2 (1 µM) shifted the voltage dependence of activation by −6.3 mV. In an attempt to convert Tf2 into an NaV1.3 inhibitor, we synthetized the analogue Tf2[S14R], a mutation previously described to remove the excitatory activity of related β-scorpion toxins. Indeed, Tf2[S14R](10 µM) had reduced excitatory activity at NaV1.3, although it still caused a small −5.8 mV shift in the voltage dependence of activation. Intraplantar injection of Tf2 (1 µM) in mice caused spontaneous flinching and swelling, which was not reduced by the NaV1.1/1.3 inhibitor ICA-121431 nor in NaV1.9-/- mice, suggesting off-target activity. In addition, despite a loss of excitatory activity, intraplantar injection of Tf2[S14R](10 µM) still caused swelling, providing strong evidence that Tf2 has additional off-target activity at one or more non-neuronal targets. Therefore, due to activity at NaV1.9 and other yet to be identified target(s), the use of Tf2 as a selective pharmacological probe may be limited. View Full-Text
Keywords: Tf2; sodium channel; NaV1.3; NaV1.9; scorpion; toxin Tf2; sodium channel; NaV1.3; NaV1.9; scorpion; toxin
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Israel, M.R.; Dash, T.S.; Bothe, S.N.; Robinson, S.D.; Deuis, J.R.; Craik, D.J.; Lampert, A.; Vetter, I.; Durek, T. Characterization of Synthetic Tf2 as a NaV1.3 Selective Pharmacological Probe. Biomedicines 2020, 8, 155.

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