title: beta-Scorpion toxin modifies gating transitions in all four voltage sensors of the sodium channel.
abstract: Several naturally occurring polypeptide neurotoxins target specific sites on the voltage-gated sodium channels. Of these, the gating modifier toxins alter the behavior of the sodium channels by stabilizing transient intermediate states in the channel gating pathway. Here we have used an integrated approach that combines electrophysiological and spectroscopic measurements to determine the structural rearrangements modified by the beta-scorpion toxin Ts1. Our data indicate that toxin binding to the channel is restricted to a single binding site on domain II voltage sensor. Analysis of Cole-Moore shifts suggests that the number of closed states in the activation sequence prior to channel opening is reduced in the presence of toxin. Measurements of charge-voltage relationships show that a fraction of the gating charge is immobilized in Ts1-modified channels. Interestingly, the charge-voltage relationship also shows an additional component at hyperpolarized potentials. Site-specific fluorescence measurements indicate that in presence of the toxin the voltage sensor of domain II remains trapped in the activated state. Furthermore, the binding of the toxin potentiates the activation of the other three voltage sensors of the sodium channel to more hyperpolarized potentials. These findings reveal how the binding of beta-scorpion toxin modifies channel function and provides insight into early gating transitions of sodium channels.
authors: Institute of Molecular Pediatric Sciences and Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
authors: Fabiana V
authors: FV
authors: Campos
authors: Baron
authors: B
authors: Chanda
authors: Paulo S L
authors: PS
authors: Beirão
authors: Francisco
authors: F
authors: Bezanilla
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D005260:Female; D019476:Insect Proteins / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D008954:Models, Biological; D009124:Muscle Proteins / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D009865:Oocytes; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051381:Rats; D012604:Scorpion Venoms / Q000494:pharmacology*; D015222:Sodium Channels / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D014981:Xenopus
chemical_list: D019476:Insect Proteins; D009124:Muscle Proteins; D009498:Neurotoxins; C466180:Scn4a protein, rat; D012604:Scorpion Venoms; D015222:Sodium Channels; C120263:scorpion toxin Ts1, Tityus
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