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Sodium channel toxin-resistance mutations do not govern batrachotoxin (BTX) autoresistance in poison birds and frogs

Fayal Abderemane-Ali, Nathan D. Rossen, Megan E. Kobiela, Robert A. Craig II, Catherine E. Garrison, View ORCID ProfileLauren A. O’Connell, J. Du Bois, John P. Dumbacher, View ORCID ProfileDaniel L. Minor Jr.
doi: https://doi.org/10.1101/2020.10.29.361212
Fayal Abderemane-Ali
1Cardiovascular Research Institute, University of California, San Francisco, California 93858-2330 USA
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Nathan D. Rossen
1Cardiovascular Research Institute, University of California, San Francisco, California 93858-2330 USA
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Megan E. Kobiela
2School of Biological Sciences, University of Nebraska – Lincoln, Lincoln, Nebraska 68588
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Robert A. Craig II
3Department of Chemistry, Stanford University, Stanford, CA 94305
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Catherine E. Garrison
3Department of Chemistry, Stanford University, Stanford, CA 94305
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Lauren A. O’Connell
4Department of Biology, Stanford University, Stanford, CA 94305
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J. Du Bois
3Department of Chemistry, Stanford University, Stanford, CA 94305
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John P. Dumbacher
5Institute for Biodiversity Science and Sustainability, California Academy of Sciences, San Francisco, CA 94118, USA
6Department of Biology, San Francisco State University, San Francisco, CA 94132, USA
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Daniel L. Minor Jr.
1Cardiovascular Research Institute, University of California, San Francisco, California 93858-2330 USA
7Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California, San Francisco, California 93858-2330 USA
8California Institute for Quantitative Biomedical Research, University of California, San Francisco, California 93858-2330 USA
9Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, California 93858-2330 USA
10Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 USA
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  • ORCID record for Daniel L. Minor Jr.
  • For correspondence: daniel.minor@ucsf.edu
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Abstract

Poisonous organisms carry small molecule toxins that alter voltage-gated sodium channel (Na✓) function. Among these, batrachotoxin (BTX) from Pitohui toxic birds and Phyllobates poison frogs, stands out because of its lethality and unusual effects on Nav function. How these toxin-bearing organisms avoid autointoxication remains poorly understood. In poison frogs, a Nav DIVS6 pore-forming helix N→T mutation has been proposed as the BTX resistance mechanism. Here, we show that this variant is absent from Pitohui and poison frog Navs, incurs a strong cost that compromises channel function, and fails to produce BTX-resistant channels when tested in the context of poison frog Navs. We further show that captive-raised poison frogs are BTX resistant, even though they bear BTX-sensitive Navs. Hence, our data refute the hypothesis that BTX autoresistance is rooted in Nav mutations and instead suggest that more generalizable mechanisms such as toxin sequestration act to protect BTX-bearing species from autointoxication.

Competing Interest Statement

J.D.B. is a cofounder and holds equity shares in SiteOne Therapeutics, Inc., a start-up company interested in developing subtype-selective modulators of sodium channels. The other authors declare no competing interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 29, 2020.
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Sodium channel toxin-resistance mutations do not govern batrachotoxin (BTX) autoresistance in poison birds and frogs
Fayal Abderemane-Ali, Nathan D. Rossen, Megan E. Kobiela, Robert A. Craig II, Catherine E. Garrison, Lauren A. O’Connell, J. Du Bois, John P. Dumbacher, Daniel L. Minor Jr.
bioRxiv 2020.10.29.361212; doi: https://doi.org/10.1101/2020.10.29.361212
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Sodium channel toxin-resistance mutations do not govern batrachotoxin (BTX) autoresistance in poison birds and frogs
Fayal Abderemane-Ali, Nathan D. Rossen, Megan E. Kobiela, Robert A. Craig II, Catherine E. Garrison, Lauren A. O’Connell, J. Du Bois, John P. Dumbacher, Daniel L. Minor Jr.
bioRxiv 2020.10.29.361212; doi: https://doi.org/10.1101/2020.10.29.361212

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