Comparison of Chlorantraniliprole and Flubendiamide Activity Toward Wild-Type and Malignant Hyperthermia-Susceptible Ryanodine Receptors and Heat Stress Intolerance

Kim M. Truong, Isaac N Pessah

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Chlorantraniliprole (CP) and flubendiamide (FD) are widely used in agriculture globally to control lepidopteran pests. Both insecticides target ryanodine receptors (RyRs) and promote Ca 2+ leak from sarcoplasmic reticulum (SR) within insect skeletal muscle yet are purportedly devoid of activity toward mammalian RyR1 and muscle. RyRs are ion channels that regulate intracellular Ca 2+ release from SR during physiological excitation-contraction coupling. Mutations in RYR1 genes confer malignant hyperthermia susceptibility (MHS), a potentially lethal pharmacogenetic disorder in humans and animals. Compared with vehicle control, CP (10 μM) triggers a 65-fold higher rate of Ca 2+ efflux from Ca 2+-loaded mammalian WT-RyR1 SR vesicles, whereas FD (10 μM) produces negligible influence on Ca 2+ leak. We, therefore, compared whether CP or FD differentially influence patterns of high-Affinity [ 3 H]ryanodine ([ 3 H]Ry) binding to RyR1 isolated from muscle SR membranes prepared from adult C57BL/6J mice expressing WT, homozygous C-Terminal MHS mutation T4826I, or heterozygous N-Terminal MHS mutation R163C. Basal [ 3 H]Ry binding differed among genotypes with rank order T4826I â ‰ R163Câ 1/4WT, regardless of [Ca 2+ ] in the assay medium. Both CP and FD (0.01-100 μM) elicited concentration-dependent increase in [ 3 H]Ry binding, although CP showed greater efficacy regardless of genotype or [Ca 2+ ]. Exposure to CP (500 mg/kg; p.o) failed to shift intolerance to heat stress (38°C) characteristic of R163C and T4826I MHS mice, nor cause lethality in WT mice. Although nM-μM of either diamide is capable of differentially altering WT and MHS RyR1 conformation in vitro, human RyR1 mutations within putative diamide N-and C-Terminal interaction domains do not alter heat stress intolerance (HSI) in vivo.

Original languageEnglish (US)
Pages (from-to)509-523
Number of pages15
JournalToxicological Sciences
Volume167
Issue number2
DOIs
StatePublished - Feb 1 2019

Keywords

  • chlorantraniliprole
  • diamides
  • flubendiamide
  • insecticides
  • malignant hyperthermia
  • ryanodine receptors

ASJC Scopus subject areas

  • Toxicology

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