Related Experiment Video

Updated: Jun 6, 2026

Crystal Structure of the N-terminal Domain of Ryanodine Receptor from Plutella xylostella
11:31

Crystal Structure of the N-terminal Domain of Ryanodine Receptor from Plutella xylostella

Published on: November 30, 2018

Para- and ortho-substitutions are key determinants of polybrominated diphenyl ether activity toward ryanodine

Kyung Ho Kim1, Diptiman D Bose, Atefeh Ghogha

  • 1Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, Davis, California 95616, USA. npessah@ucdavis.edu

Environmental Health Perspectives
|November 26, 2010
PubMed
Abstract

Insights

Polybrominated diphenyl ethers (PBDEs) disrupt calcium signaling by modulating ryanodine receptors (RyRs). Specific chemical structures of PBDEs determine their neurotoxic effects, offering a potential tool for risk assessment.

Area of Science:

  • Environmental Science
  • Toxicology
  • Neuroscience

Background:

  • Polybrominated diphenyl ethers (PBDEs) are flame retardants that accumulate in the body.
  • PBDEs are known to cause neurotoxicity through calcium ion (Ca(2+)) signaling disruption.
  • The precise mechanisms underlying PBDE-induced neurotoxicity remain unclear.

Purpose of the Study:

  • To investigate the structure-activity relationship (SAR) of PBDEs and their metabolites on ryanodine receptors (RyRs).
  • To determine if RyR modulation by PBDEs correlates with neurotoxicity.
  • To elucidate the specific mechanisms of PBDE-mediated Ca(2+) dysregulation.

Main Methods:

  • Analysis of [3H]ryanodine binding to RyRs.
  • Measurement of microsomal Ca(2+) fluxes and cellular Ca(2+) homeostasis.
  • Assessment of neurotoxicity in cortical neuron cultures.
  • Utilized HEK293 cells expressing RyR1 or RyR2.

Main Results:

  • PBDEs with specific bromine substitution patterns (e.g., BDE-49) activated RyR1 and RyR2 more effectively than others (e.g., BDE-47).
  • Hydroxylated metabolites (e.g., 6-OH-BDE-47) showed biphasic modulation of RyRs.
  • BDE-49 sensitized Ca(2+) flux, while BDE-47 had minimal effect, and this differential activity predicted neurotoxicity.

Conclusions:

  • PBDEs are potent modulators of RyR1 and RyR2, with activity dictated by their chemical structure.
  • The ortho and para positions of bromine substituents are critical for determining PBDE congener activity at RyRs.
  • RyR modulation by PBDEs represents a convergent molecular target, useful for predicting and assessing the neurotoxicity of PBDEs and related compounds.

More Related Videos

Functional Characterization of Endogenously Expressed Human RYR1 Variants07:59

Functional Characterization of Endogenously Expressed Human RYR1 Variants

Published on: June 9, 2021

Genetic and Biochemical Approaches for In Vivo and In Vitro Assessment of Protein Oligomerization: The Ryanodine Receptor Case Study12:43

Genetic and Biochemical Approaches for In Vivo and In Vitro Assessment of Protein Oligomerization: The Ryanodine Receptor Case Study

Published on: July 27, 2016

Related Concept Videos

ortho–para-Directing Activators: –CH3, –OH, –⁠NH2, –OCH301:11

ortho–para-Directing Activators: –CH3, –OH, –⁠NH2, –OCH3

All ortho–para directors, excluding halogens, are activating groups. These groups donate electrons to the ring, making the ring carbons electron-rich. Consequently, the reactivity of the aromatic ring towards electrophilic substitution increases. For instance, the nitration of anisole is about 10,000 times faster than the nitration of benzene. The electron-donating effect of the methoxy group in anisole activates the ortho and para positions on the ring and stabilizes the corresponding...
ortho–para-Directing Deactivators: Halogens01:24

ortho–para-Directing Deactivators: Halogens

Halogens are ortho–para directors. They are more electronegative than carbon. Therefore, as ring substituents, they can withdraw electrons through the inductive effect and deactivate the aromatic ring towards electrophilic substitution. Halogens also have an electron-donating resonance effect on the ring, which influences the orientation of the incoming electrophile. If an electrophile attacks at the ortho or the para position, the halogen donates electrons and stabilizes the intermediate...
Directing Effect of Substituents: ortho–para-Directing Groups01:14

Directing Effect of Substituents: ortho–para-Directing Groups

Ortho–para directors are substituent groups attached to the benzene ring and direct the addition of an electrophile to the positions ortho or para to the substituent. All electron-donating groups are considered ortho–para directors. They donate electrons to the ring and make the ring more electron-rich. The ring is therefore susceptible to the addition of electrophiles. Substituents such as amino, hydroxy, or alkoxy, containing lone pairs on the atom adjacent to the ring, donate electrons...
meta-Directing Deactivators: –NO2, –CN, –CHO, –⁠CO2R, –COR, –CO2H01:13

meta-Directing Deactivators: –NO2, –CN, –CHO, –⁠CO2R, –COR, –CO2H

All meta-directing substituents are deactivating groups. These substituents withdraw electrons from the aromatic ring, making the ring less reactive toward electrophilic substitution. For example, the nitration of nitrobenzene is 100,000 times slower than that of benzene because of the deactivating effect of the nitro group. The first step in an electrophilic aromatic substitution is the addition of an electrophile to form a resonance-stabilized carbocation. The energy diagrams for the...
Nucleophilic Aromatic Substitution: Addition–Elimination (SNAr)01:30

Nucleophilic Aromatic Substitution: Addition–Elimination (SNAr)

Nucleophilic substitution in aromatic compounds is feasible in substrates bearing strong electron-withdrawing substituents positioned ortho or para to the leaving group. The reaction proceeds via two steps: the addition of the nucleophile and the elimination of the leaving group.
The reaction begins with an attack of the nucleophile on the carbon that holds the leaving group. This results in the delocalization of the π electrons over the ring carbons. The resonance interaction between the...
Adrenergic Agonists: Chemistry and Structure-Activity Relationship01:16

Adrenergic Agonists: Chemistry and Structure-Activity Relationship

Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of the aromatic...