Enantioselectivity of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers toward Ryanodine Receptors (RyRs) and Their Influences on Hippocampal Neuronal Networks

• DOI: 10.1021/acs.est.7b04446
• Publication Date: 2017-11-13T23:40:23Z
• Authors: Wei Feng; Jing Zheng; Gaëlle Robin; Yao Dong; Makoto Ichikawa; Yoshihisa Inoue; Tadashi Mori; Takeshi Nakano; Isaac N. Pessah
• Keywords: Atropisomer

Nineteen ortho-substituted PCBs are chiral and found enantioselectively enriched in ecosystems. Their differential actions on biological targets not understood. PCB 95 (2,2′,3,5′,6-pentachlorobiphenyl), a of current environmental relevance, is among the most potent toward modifying ryanodine receptors (RyR) function Ca2+ signaling. enantiomers separated assigned aR- aS-PCB using three chiral-column HPLC circular dichroism spectroscopy. Studies RyR1-enriched microsomes show aR-PCB with >4× greater potency (EC50 = 0.20 ± 0.05 μM), ∼ 1.3× higher efficacy (Bmax 3.74 0.07 μM) [3H]Ryanodine-binding >3× rates (R 7.72 0.31 nmol/sec/mg) efflux compared 95, whereas racemate has intermediate activity. modest selectivity for RyR2, lower than RyR isoform mixture brain membranes. Chronic exposure hippocampal neuronal networks to nanomolar during critical developmental period shows divergent influences synchronous oscillation (SCO): rac-PCB increasing decreasing SCO frequency at 50 nM, although latter's effects nonmonotonic concentration. aS-PCB95 greatest influence inhibiting responses 20 Hz electrical pulse trains. Considering persistence environment, stereoselectivity RyRs developing may clarify health risks associated enantioisomeric enrichment PCBs.