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

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Polychlorinated biphenyls (PCBs) with unsymmetrical chlorine substitutions and multiple ortho-substitutions 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 [ 2H]ryanodine to high-affinity sites on ryanodine receptors type 1 (RyRl) and type 2 (RyR2) (EC 50 values ∼0.95 μM), whereas (+)-PCB 136 is inactive at ≤10 μM. (-)-PCB 136 induces a rapid release of Ca 2+ 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 Ca 2+ 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 RyR2 channels may provide new mechanistic leads about their toxicological impacts on human health.

Original languageEnglish (US)
Pages (from-to)201-207
Number of pages7
JournalChemical Research in Toxicology
Volume22
Issue number1
DOIs
StatePublished - Jan 2009

ASJC Scopus subject areas

  • Toxicology

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