Enantiomeric specificity of (-)-2,2',3,3',6,6'-hexachlorobiphenyl toward ryanodine receptor types 1 and 2

Isaac N Pessah; Hans-Joachim Lehmler; Larry W Robertson; Claudio F Perez; Elaine Cabrales; Diptiman D Bose; Wei Feng

doi:10.1021/tx800328u

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Enantiomeric specificity of (-)-2,2',3,3',6,6'-hexachlorobiphenyl toward ryanodine receptor types 1 and 2

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Open access

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Enantiomeric specificity of (-)-2,2',3,3',6,6'-hexachlorobiphenyl toward ryanodine receptor types 1 and 2

Isaac N Pessah, Hans-Joachim Lehmler, Larry W Robertson, Claudio F Perez, Elaine Cabrales, Diptiman D Bose and Wei Feng

Chemical research in toxicology, Vol.22(1), pp.201-207

01/2009

DOI: 10.1021/tx800328u

PMCID: PMC2662366

PMID: 18954145

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Abstract

Polychlorinated biphenyls (PCBs) with unsymmetrical chlorine substitutions and multiple orthosubstitutions that restrict rotation around the biphenyl bond may exist in two stable enantiomeric forms.Stereospecific binding and functional modification of specific biological signaling targets have not been previously described for PCB atropisomers. We report that (-)-2,2',3,3',6,6'-hexachlorobiphenyl [(-)-PCB 136] enhances the binding of [3H]ryanodine to high-affinity sites on ryanodine receptors type 1(RyR1) and type 2 (RyR2) (EC50 values ~0.95 microM), whereas (+)-PCB 136 is inactive at < or =10 microM.(-)-PCB 136 induces a rapid release of Ca2+ from microsomal vesicles by selective sensitization of RyRs, an effect not antagonized by (+)-PCB 136. (-)-PCB 136 (500nM) enhances the activity of reconstituted RyR1 channels 3-fold by stabilizing the open and destabilizing the closed conformational states. The enantiomeric specificity is also demonstrated in intact HEK 293 cells expressing RyR1 where exposure to (-)-PCB 136 (100 nM; 12 h) sensitizes responses to caffeine, whereas (+)-PCB 136 does not. These data show enantiomeric specificity of (-)-PCB 136 toward a broadly expressed family of microsomal Ca2+ channels that may extend to other chiral noncoplanar PCBs and related structures.Evidence for enantioselective enrichment of PCBs in biological tissues that express RyR1 and RyR2channels may provide new mechanistic leads about their toxicological impacts on human health

Cell Line

Rabbits

Animals

Polychlorinated Biphenyls - chemistry

Polychlorinated Biphenyls - toxicity

Stereoisomerism

Humans

Ryanodine Receptor Calcium Release Channel - metabolism

Mice

Sarcoplasmic Reticulum - metabolism

Details

Title: Subtitle: Enantiomeric specificity of (-)-2,2',3,3',6,6'-hexachlorobiphenyl toward ryanodine receptor types 1 and 2
Creators: Isaac N Pessah - Department of VM, Molecular Biosciences and UC Davis Center for Children's Environmental Health, University of California, One Shields Avenue, Davis, California 95616, USA. inpessah@ucdavis.edu
Hans-Joachim Lehmler
Larry W Robertson
Claudio F Perez
Elaine Cabrales
Diptiman D Bose
Wei Feng
Resource Type: Journal article
Publication Details: Chemical research in toxicology, Vol.22(1), pp.201-207
DOI: 10.1021/tx800328u
PMID: 18954145
PMCID: PMC2662366
NLM abbreviation: Chem Res Toxicol
ISSN: 0893-228X
eISSN: 1520-5010
Publisher: United States
Grant note: P01 ES011269-060003 / NIEHS NIH HHS P42 ES013661 / NIEHS NIH HHS P01 ES011269 / NIEHS NIH HHS 1P01 ES11269 / NIEHS NIH HHS 5P42 ES04699 / NIEHS NIH HHS P30 ES005707 / NIEHS NIH HHS P42 ES004699 / NIEHS NIH HHS P01 ES011269-06 / NIEHS NIH HHS K25 ES012475 / NIEHS NIH HHS P30 ES05707 / NIEHS NIH HHS ES12475 / NIEHS NIH HHS P01 ES011269-070003 / NIEHS NIH HHS R01 ES014901 / NIEHS NIH HHS
Language: English
Date published: 01/2009
Academic Unit: Occupational and Environmental Health; Iowa Neuroscience Institute; Iowa Superfund Research Program
Record Identifier: 9984001096702771

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