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

2 Citations (Scopus)

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

Fingerprint

Malignant Hyperthermia
Ryanodine Receptor Calcium Release Channel
Hot Temperature
Sarcoplasmic Reticulum
Diamide
Muscle
Mutation
Genotype
Pest control
Excitation Contraction Coupling
Ryanodine
Muscles
Pest Control
Pharmacogenetics
Insecticides
chlorantranilipole
flubendiamide
Agriculture
Inbred C57BL Mouse
Ion Channels

Keywords

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

ASJC Scopus subject areas

  • Toxicology

Cite this

@article{948fe41303a14e09a1f489ab130c7843,
title = "Comparison of Chlorantraniliprole and Flubendiamide Activity Toward Wild-Type and Malignant Hyperthermia-Susceptible Ryanodine Receptors and Heat Stress Intolerance",
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 {\^a} ‰ R163C{\^a} 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.",
keywords = "chlorantraniliprole, diamides, flubendiamide, insecticides, malignant hyperthermia, ryanodine receptors",
author = "Truong, {Kim M.} and Pessah, {Isaac N}",
year = "2019",
month = "2",
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doi = "10.1093/toxsci/kfy256",
language = "English (US)",
volume = "167",
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T1 - Comparison of Chlorantraniliprole and Flubendiamide Activity Toward Wild-Type and Malignant Hyperthermia-Susceptible Ryanodine Receptors and Heat Stress Intolerance

AU - Truong, Kim M.

AU - Pessah, Isaac N

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

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KW - diamides

KW - flubendiamide

KW - insecticides

KW - malignant hyperthermia

KW - ryanodine receptors

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