Enantioselectivity of 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) Atropisomers toward Ryanodine Receptors (RyRs) and Their Influences on Hippocampal Neuronal Networks.
Enantioselectivity of 2,2',3,5',6-Pentachlorobiphenyl (PCB 95) Atropisomers toward Ryanodine Receptors (RyRs) and Their Influences on Hippocampal Neuronal Networks.
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DOI：
10.1021/acs.est.7b04446
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发表时间：
2017-12-19
影响因子：
11.4
通讯作者：
Pessah IN
中科院分区：
文献类型：
--
作者：
Feng W;Zheng J;Robin G;Dong Y;Ichikawa M;Inoue Y;Mori T;Nakano T;Pessah IN
19种邻位取代的多氯联苯是手性的，在生态系统中发现具有对映体选择性富集性。它们对生物靶标的不同作用尚不清楚。多氯联苯95(2，2‘，3，5’，6-五氯联苯)是目前与环境相关的手性多氯联苯，是调节兰尼定受体(RyR)功能和钙信号转导的最有效的多氯联苯之一。用三手性高效液相色谱和圆二色谱分离并归属了对映体Ar和As。对富含RyR1的微粒体的研究表明，与AS-PCB95相比，Ar-PCB95的~gt；4倍效价(EC_(50)=0.20±0.05μM)，~1.3倍的[~3H]Ryanodine结合效率(Bmax=3.74±0.07μM)和~gt；3倍的钙外流速率(R=7.72±0.31nmoL/秒/mg)，而消旋体具有中等的活性。AR-PCB95对RyR2具有适度的选择性，并且对脑膜中的RyR异构体混合物的效力低于外消旋体。在发育的关键时期，海马神经元网络长期暴露于纳分子PCB95对同步钙振荡(SCO)的影响是不同的：RAC-PCB95增加和Ar-PCB95降低50 nM时的同步钙振荡频率，尽管后者的影响在较高浓度时是非单调的。AS-PCB95对20赫兹电脉冲序列的抑制反应影响最大。考虑到多氯联苯95在环境中的持久性，对RyRs的立体选择性和发展神经网络可能会澄清与多氯联苯对映异构体浓缩相关的健康风险。
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 (Bmax = 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.
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影响因子：
48
作者：
Grandjean, Philippe;Landrigan, Philip J.
通讯作者：
Landrigan, Philip J.
DOI：
10.1083/jcb.128.5.893
发表时间：
1995-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Giannini G;Conti A;Mammarella S;Scrobogna M;Sorrentino V
通讯作者：
Sorrentino V
影响因子：
2.8
作者：
Ghosh, Somiranjan;Murinova, Lubica;Dutta, Sisir K.
通讯作者：
Dutta, Sisir K.
影响因子：
11.4
作者：
BROWN, JF
通讯作者：
BROWN, JF
影响因子：
8.8
作者：
de Geus, HJ;Wester, PG;Brinkman, UAT
通讯作者：
Brinkman, UAT