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

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Enantioselectivity of 2,2′,3,5′,6-Pentachlorobiphenyl (PCB 95) Atropisomers toward Ryanodine Receptors (RyRs) and Their Influences on Hippocampal Neuronal Networks
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2017-11-28 00:00:00 , DOI: 10.1021/acs.est.7b04446
Wei Feng ₁ , Jing Zheng _{1,

2} , Gaëlle Robin ₁ , Yao Dong ₁ , Makoto Ichikawa ₃ , Yoshihisa Inoue ₃ , Tadashi Mori ₃ , Takeshi Nakano ₄ , Isaac N. Pessah ₁

Affiliation

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

中文翻译：

2,2'，3,5'，6-五氯联苯（PCB 95）阻转异构体对Ryanodine受体（RyRs）的对映选择性及其对海马神经元网络的影响

十九种邻位取代的多氯联苯是手性的，在生态系统中对映选择性丰富。他们对生物学目标的不同作用尚不清楚。PCB 95（2,2'，3,5'，6-五氯联苯），一种具有当前环境相关性的手性PCB，在修饰ryanodine受体（RyR）功能和Ca ²⁺信号传导方面最有效。使用三个手性柱HPLC和圆二色谱，分离PCB 95对映体，并指定R-和S -PCB 95。富含RyR1的微粒体的研究表明，在[ ^3]中，aR -PCB 95的效力大于4倍（EC ₅₀ = 0.20±0.05μM），功效约为1.3倍（B _max = 3.74±0.07μM）。H] Ryanodine结合，与aS -PCB 95相比，Ca ²⁺外排率高> 3倍（R = 7.72±0.31 nmol / sec / mg），而外消旋体具有中等活性。aR- PCB 95对RyR2的选择性适中，并且对脑膜中RyR同工型混合物的消旋性低于消旋体。在关键的发育时期，海马神经元网络对纳摩尔PCB 95的慢性暴露显示出对同步Ca ²⁺振荡（SCO）的不同影响：rac -PCB 95增加，而aR -PCB 95在50 nM时降低SCO频率，尽管后者的影响是浓度较高时非单调。作为-PCB95对抑制对20 Hz电脉冲序列的响应显示出最大的影响。考虑到PCB 95在环境中的持久性，对RyRs的立体选择性和神经网络的发育可能会澄清与PCB的对映异构体富集有关的健康风险。

更新日期：2017-11-29

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