title: Convergent Substitutions in a Sodium Channel Suggest Multiple Origins of Toxin Resistance in Poison Frogs.
abstract: Complex phenotypes typically have a correspondingly multifaceted genetic component. However, the genotype-phenotype association between chemical defense and resistance is often simple: genetic changes in the binding site of a toxin alter how it affects its target. Some toxic organisms, such as poison frogs (Anura: Dendrobatidae), have defensive alkaloids that disrupt the function of ion channels, proteins that are crucial for nerve and muscle activity. Using protein-docking models, we predict that three major classes of poison frog alkaloids (histrionicotoxins, pumiliotoxins, and batrachotoxins) bind to similar sites in the highly conserved inner pore of the muscle voltage-gated sodium channel, Nav1.4. We predict that poison frogs are somewhat resistant to these compounds because they have six types of amino acid replacements in the Nav1.4 inner pore that are absent in all other frogs except for a distantly related alkaloid-defended frog from Madagascar, Mantella aurantiaca. Protein-docking models and comparative phylogenetics support the role of these replacements in alkaloid resistance. Taking into account the four independent origins of chemical defense in Dendrobatidae, phylogenetic patterns of the amino acid replacements suggest that 1) alkaloid resistance in Nav1.4 evolved independently at least seven times in these frogs, 2) variation in resistance-conferring replacements is likely a result of differences in alkaloid exposure across species, and 3) functional constraint shapes the evolution of the Nav1.4 inner pore. Our study is the first to demonstrate the genetic basis of autoresistance in frogs with alkaloid defenses.
authors.affiliation: Department of Integrative Biology, University of Texas-Austin rdtarvin@gmail.com.
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Tarvin
authors.affiliation: Department of Zoology, Biodiversity Research Centre, University of British Columbia, Vancouver, Canada Department of Biology, Brigham Young University, Provo.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Santos
authors.affiliation: Center for Systems Biology, Harvard University.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: O'Connell
authors.affiliation: Department of Integrative Biology, University of Texas-Austin.
authors.forename: Harold H
authors.initials: HH
authors.lastname: Zakon
authors.affiliation: Department of Integrative Biology, University of Texas-Austin Biodiversity Collections, University of Texas-Austin.
authors.forename: David C
authors.initials: DC
authors.lastname: Cannatella
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D000664:Amphibian Venoms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001001:Anura / Q000235:genetics; D001496:Batrachotoxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D056726:Genetic Association Studies; D062105:Molecular Docking Simulation; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010802:Phylogeny; D011042:Poisons / Q000737:chemistry* / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism; D012867:Skin / Q000737:chemistry / Q000187:drug effects
chemical_list: D000470:Alkaloids; D000664:Amphibian Venoms; D001496:Batrachotoxins; D062553:NAV1.4 Voltage-Gated Sodium Channel; D011042:Poisons; D011804:Quinolines; C011093:pumiliotoxin C; C007948:histrionicotoxin
keywords: alkaloid docking; aposematism; autoresistance; chemical defense; functional constraint; voltage-gated sodium channels