Molecular basis of selective resistance of the bumblebee BiNav1 sodium channel to tau-fluvalinate

Edited by David L. Denlinger, Ohio State University, Columbus, OH, and approved October 23, 2017 (received for review June 29, 2017)
November 20, 2017
114 (49) 12922-12927

Significance

Voltage-gated sodium channels are targeted by pyrethroids, which make up one of the largest classes of insecticides used globally for controlling human disease vectors and agricultural pests. Various pyrethroids can exhibit widely different toxicities on insect species. Most notably, bees are highly sensitive to most pyrethroids, but are resistant to tau-fluvalinate, a highly selective pyrethroid used to control varroa mites in beehives worldwide. However, the mechanism underlying bumblebee resistance to tau-fluvalinate remains elusive. Using mutagenesis, computer modeling of pyrethroid-receptor sites, and phylogenetic clues of sodium channel sequences, we uncovered bee-specific sodium channel residues that underlie species-specific pyrethroid selectivity. This finding could spur future development of a new generation of safer pyrethroids that selectively target pests, but not beneficial species.

Abstract

Insecticides are widely used to control pests in agriculture and insect vectors that transmit human diseases. However, these chemicals can have a negative effect on nontarget, beneficial organisms including bees. Discovery and deployment of selective insecticides is a major mission of modern toxicology and pest management. Pyrethroids exert their toxic action by acting on insect voltage-gated sodium channels. Honeybees and bumblebees are highly sensitive to most pyrethroids, but are resistant to a particular pyrethroid, tau-fluvalinate (τ-FVL). Because of its unique selectivity, τ-FVL is widely used to control not only agricultural pests but also varroa mites, the principal ectoparasite of honeybees. However, the mechanism of bee resistance to τ-FVL largely remains elusive. In this study, we functionally characterized the sodium channel BiNav1–1 from the common eastern bumblebee (Bombus impatiens) in Xenopus oocytes and found that the BiNav1–1 channel is highly sensitive to six commonly used pyrethroids, but resistant to τ-FVL. Phylogenetic and mutational analyses revealed that three residues, which are conserved in sodium channels from 12 bee species, underlie resistance to τ-FVL or sensitivity to the other pyrethroids. Further computer modeling and mutagenesis uncovered four additional residues in the pyrethroid receptor sites that contribute to the unique selectivity of the bumblebee sodium channel to τ-FVL versus other pyrethroids. Our data contribute to understanding a long-standing enigma of selective pyrethroid toxicity in bees and may be used to guide future modification of pyrethroids to achieve highly selective control of pests with minimal effects on nontarget organisms.

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Acknowledgments

We thank Dr. Kris Silver (Kansas State University) and Dr. Henry Chung (Michigan State University) for critical review of this manuscript and Connor Grady for excellent technical assistance. We thank anonymous reviewers for their valuable comments. Computations were performed using the facilities of the Shared Hierarchical Academic Research Computing Network (SHARCNET, www.sharcnet.ca/my/front/). This study was supported by Grants GM057440 (to K.D. and B.S.Z.) and R01GM115475 (to K.D.) from the National Institutes of Health, Grant 17-15-01292 from the Russian Science Foundation (to B.S.Z.), and Grant 31201541 from the National Natural Science Foundation of China (to S.W.). S.W. was partially supported by the China Scholarship Council.

Supporting Information

Supporting Information (PDF)

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 114 | No. 49
December 5, 2017
PubMed: 29158414

Classifications

Submission history

Published online: November 20, 2017
Published in issue: December 5, 2017

Keywords

  1. sodium channel
  2. pyrethroids
  3. tau-fluvalinate
  4. bees
  5. pyrethroid receptor site

Acknowledgments

We thank Dr. Kris Silver (Kansas State University) and Dr. Henry Chung (Michigan State University) for critical review of this manuscript and Connor Grady for excellent technical assistance. We thank anonymous reviewers for their valuable comments. Computations were performed using the facilities of the Shared Hierarchical Academic Research Computing Network (SHARCNET, www.sharcnet.ca/my/front/). This study was supported by Grants GM057440 (to K.D. and B.S.Z.) and R01GM115475 (to K.D.) from the National Institutes of Health, Grant 17-15-01292 from the Russian Science Foundation (to B.S.Z.), and Grant 31201541 from the National Natural Science Foundation of China (to S.W.). S.W. was partially supported by the China Scholarship Council.

Notes

This article is a PNAS Direct Submission.
Database deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. KY123916).

Authors

Affiliations

Shaoying Wu
College of Plant Protection, Henan Agricultural University, Zhengzhou, Henan, 450002, China;
Department of Entomology, Michigan State University, East Lansing, MI 48824;
Yoshiko Nomura
Department of Entomology, Michigan State University, East Lansing, MI 48824;
Genetics Program, Michigan State University, East Lansing, MI 48824;
Neuroscience Program, Michigan State University, East Lansing, MI 48824;
Yuzhe Du
Department of Entomology, Michigan State University, East Lansing, MI 48824;
Genetics Program, Michigan State University, East Lansing, MI 48824;
Neuroscience Program, Michigan State University, East Lansing, MI 48824;
Present address: US Department of Agriculture–Agricultural Research Service, Biological Control of Pest Research Unit, Stoneville, MS 38776.
Boris S. Zhorov
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada;
Sechenov Institute of Evolutionary Physiology & Biochemistry, Russian Academy of Sciences, 194356, St. Petersburg, Russia;
Institute of Molecular Biology and Genetics, Almazov Federal Heart, Blood and Endocrinology Centre, 197341, St. Petersburg, Russia
Department of Entomology, Michigan State University, East Lansing, MI 48824;
Genetics Program, Michigan State University, East Lansing, MI 48824;
Neuroscience Program, Michigan State University, East Lansing, MI 48824;

Notes

2
To whom correspondence should be addressed. Email: [email protected].
Author contributions: B.S.Z. and K.D. designed research; S.W., Y.N., Y.D., and B.S.Z. performed research; S.W., Y.D., B.S.Z., and K.D. analyzed data; and B.S.Z. and K.D. wrote the paper.

Competing Interests

The authors declare no conflict of interest.

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    Molecular basis of selective resistance of the bumblebee BiNav1 sodium channel to tau-fluvalinate
    Proceedings of the National Academy of Sciences
    • Vol. 114
    • No. 49
    • pp. 12839-E10605

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