title: A gamut of undiscovered electrophysiological effects produced by Tityus serrulatus toxin 1 on NaV-type isoforms.
abstract: In the last decades, Ts1 has not only been the subject of many studies, it has also been considered as a very useful tool to investigate NaV channels and to explore the exact role of NaV channels in channelopathies. Ts1 is believed to modulate the activation process of NaV upon interaction at the neurotoxin binding site 4. Our aim was to carry out an in depth functional characterization of Ts1 on a wide array of Nav channels, in order to investigate its mechanism of action and to verify if Ts1 can indeed be considered as a prototype site 4 selective toxin, valid for all the Nav isoforms we know currently. Ts1 has been subjected to an in-depth functional investigation on 9 NaV isoforms expressed in Xenopus laevis oocytes. Ts1 does not only interfere with the activation process but also modulates the inactivation in a bell-shaped voltage-dependent matter. Furthermore, Ts1 altered the ion selectivity through insect NaV. without influencing the tetrodotoxin selectivity of the channels. Finally, Ts1 was also found to inhibit the sodium current through the cardiac Nav1.5 isoform. On the basis of the totally unexpected plethora of Nav modulations as induced by Ts1, we demonstrate that caution is required in interpretation the in vivo experiments when using Ts1. The electrophysiological characterization of Ts1 indeed shows that the general accepted contours of NaV binding sites are much more obscure than believed and that interpretation of NaV pharmacology upon toxin binding is more complex than believed thus far.
authors: Toxicology and Pharmacology, University of Leuven (KU Leuven), Campus Gasthuisberg, O&N2, PO Box 922, Herestraat 49, 3000 Leuven, Belgium.
authors: Steve
authors: S
authors: Peigneur
authors: Physics and Chemistry Department, Faculty of Pharmaceutical Sciences, Ribeirão Preto - USP, Ribeirão Preto, SP, Brazil.
authors: Camilla T
authors: CT
authors: Cologna
authors: Physics and Chemistry Department, Faculty of Pharmaceutical Sciences, Ribeirão Preto - USP, Ribeirão Preto, SP, Brazil.
authors: Caroline M
authors: CM
authors: Cremonez
authors: Toxicology and Pharmacology, University of Leuven (KU Leuven), Campus Gasthuisberg, O&N2, PO Box 922, Herestraat 49, 3000 Leuven, Belgium.
authors: Bea G
authors: BG
authors: Mille
authors: Physics and Chemistry Department, Faculty of Pharmaceutical Sciences, Ribeirão Preto - USP, Ribeirão Preto, SP, Brazil.
authors: Manuela B
authors: MB
authors: Pucca
authors: Toxicology and Pharmacology, University of Leuven (KU Leuven), Campus Gasthuisberg, O&N2, PO Box 922, Herestraat 49, 3000 Leuven, Belgium.
authors: Eva
authors: E
authors: Cuypers
authors: Physics and Chemistry Department, Faculty of Pharmaceutical Sciences, Ribeirão Preto - USP, Ribeirão Preto, SP, Brazil.
authors: Eliane C
authors: EC
authors: Arantes
authors: Toxicology and Pharmacology, University of Leuven (KU Leuven), Campus Gasthuisberg, O&N2, PO Box 922, Herestraat 49, 3000 Leuven, Belgium. Electronic address: jan.tytgat@pharm.kuleuven.be.
authors: Jan
authors: J
authors: Tytgat
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D006801:Humans; D019476:Insect Proteins / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D051379:Mice; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011487:Protein Conformation / Q000187:drug effects; D020033:Protein Isoforms; D051381:Rats; D012604:Scorpion Venoms / Q000378:metabolism / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology; D061566:Voltage-Gated Sodium Channels / Q000737:chemistry / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D019476:Insect Proteins; D049990:Membrane Transport Modulators; D020033:Protein Isoforms; D012604:Scorpion Venoms; D061566:Voltage-Gated Sodium Channels; C120263:scorpion toxin Ts1, Tityus; D013779:Tetrodotoxin; D012964:Sodium
keywords: Bell-shaped modulation; Binding site; Ion channel modulator; Scorpion toxin; Tityus serrulatus; Voltage-gated sodium channel