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Open AccessArticle

Extremely Potent Block of Bacterial Voltage-Gated Sodium Channels by µ-Conotoxin PIIIA

1
Department of Physiology & Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
2
Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia
3
Department of Biochemistry, Brandeis University, Waltham, MA 0254-9110, USA
4
I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, Saint Petersburg 194223, Russia
5
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 4K1, Canada
*
Authors to whom correspondence should be addressed.
Mar. Drugs 2019, 17(9), 510; https://doi.org/10.3390/md17090510
Received: 11 July 2019 / Revised: 13 August 2019 / Accepted: 24 August 2019 / Published: 29 August 2019
(This article belongs to the Special Issue Toxins as Marine-Based Drug Discovery)
µ-Conotoxin PIIIA, in the sub-picomolar, range inhibits the archetypal bacterial sodium channel NaChBac (NavBh) in a voltage- and use-dependent manner. Peptide µ-conotoxins were first recognized as potent components of the venoms of fish-hunting cone snails that selectively inhibit voltage-gated skeletal muscle sodium channels, thus preventing muscle contraction. Intriguingly, computer simulations predicted that PIIIA binds to prokaryotic channel NavAb with much higher affinity than to fish (and other vertebrates) skeletal muscle sodium channel (Nav 1.4). Here, using whole-cell voltage clamp, we demonstrate that PIIIA inhibits NavBac mediated currents even more potently than predicted. From concentration-response data, with [PIIIA] varying more than 6 orders of magnitude (10−12 to 10−5 M), we estimated an IC50 = ~5 pM, maximal block of 0.95 and a Hill coefficient of 0.81 for the inhibition of peak currents. Inhibition was stronger at depolarized holding potentials and was modulated by the frequency and duration of the stimulation pulses. An important feature of the PIIIA action was acceleration of macroscopic inactivation. Docking of PIIIA in a NaChBac (NavBh) model revealed two interconvertible binding modes. In one mode, PIIIA sterically and electrostatically blocks the permeation pathway. In a second mode, apparent stabilization of the inactivated state was achieved by PIIIA binding between P2 helices and trans-membrane S5s from adjacent channel subunits, partially occluding the outer pore. Together, our experimental and computational results suggest that, besides blocking the channel-mediated currents by directly occluding the conducting pathway, PIIIA may also change the relative populations of conducting (activated) and non-conducting (inactivated) states. View Full-Text
Keywords: µ-conotoxin PIIIA; voltage-gated sodium channels; bacterial sodium channels, prokaryotic sodium channels (NavBacs); eukaryotic sodium channels (Nav1s); voltage- and use-dependent block µ-conotoxin PIIIA; voltage-gated sodium channels; bacterial sodium channels, prokaryotic sodium channels (NavBacs); eukaryotic sodium channels (Nav1s); voltage- and use-dependent block
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MDPI and ACS Style

Finol-Urdaneta, R.K.; McArthur, J.R.; Korkosh, V.S.; Huang, S.; McMaster, D.; Glavica, R.; Tikhonov, D.B.; Zhorov, B.S.; French, R.J. Extremely Potent Block of Bacterial Voltage-Gated Sodium Channels by µ-Conotoxin PIIIA. Mar. Drugs 2019, 17, 510.

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