Toad toxin-resistant snake (Thamnophis elegans) expresses high levels of mutant Na+/K+-ATPase mRNA in cardiac muscle

Gene. 2017 May 30;614:21-25. doi: 10.1016/j.gene.2017.02.028. Epub 2017 Feb 27.


Toads are chemically defended by bufadienolides, which are lethal to most predators. These toxins exert their lethal effects by binding to and disabling the Na+/K+-ATPases of cell membranes. Many species of snakes exhibit resistance to the effects of bufadienolides due to target-site insensitivity of the Na+/K+-ATPase. Mutations that confer resistance have previously been identified in ATP1a3, the gene that codes for the Na+/K+-ATPase α-3 paralog. We have found that this mutant gene is expressed at a significantly elevated level in heart tissue compared to gut, kidney, and liver of the bufadienolide-resistant snake, Thamnophis elegans. Furthermore, we found that exposure to bufadienolides elicits a significant increase in the expression levels of ATP1a3 in the heart, but not in the kidneys, liver, or gut 1h after exposure. We suggest that upregulation of ATP1a3 in the heart plays an important role in the physiological processes involved in tolerance of bufadienolides among genetically resistant snakes.

Keywords: Bufadienolides; Gene expression; Na(+)/K(+)-ATPase; Snakes; Toxin resistance.

MeSH terms

  • Animals
  • Bufanolides / toxicity
  • Cardiotonic Agents / toxicity
  • Colubridae / genetics*
  • Drug Resistance / drug effects
  • Drug Resistance / genetics
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / genetics*
  • Intestine, Small / enzymology
  • Intestine, Small / metabolism
  • Kidney / enzymology
  • Kidney / metabolism
  • Liver / enzymology
  • Liver / metabolism
  • Male
  • Mutant Proteins / genetics*
  • Mutant Proteins / metabolism
  • Mutation*
  • Myocardium / enzymology
  • Myocardium / metabolism*
  • Organ Specificity / drug effects
  • Organ Specificity / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sodium-Potassium-Exchanging ATPase / genetics*
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Up-Regulation / drug effects


  • Bufanolides
  • Cardiotonic Agents
  • Mutant Proteins
  • RNA, Messenger
  • Sodium-Potassium-Exchanging ATPase