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Abstract
A stringent structure-activity relationship among polychlorinated biphenyls (PCBs) possessing two or more ortho-chlorine substituents is observed for activation of ryanodine receptors in mammalian brain, revealing an arylhydrocarbon receptor-independent mechanism through which non-coplanar PCBs disrupt neuronal Ca2+ signaling. Of the congeners assayed, non-coplanar PCB 95 exhibits the highest potency (EC50 = 12-24 microM) toward activating high affinity [3H]ryanodine-binding in rat hippocampus, cerebellum, and cerebral cortex. Coplanar PCB 66 and PCB 126 have no ryanodine receptor activity in all brain regions examined. PCB 95 enhances [3H]ryanodine-binding affinity and capacity by significantly altering modulation by Ca2+ and Mg2+, thereby stabilizing a high affinity conformation of the ryanodine receptor. Ca2+ transport measurements using cortical microsomes reveal that PCB 95 discriminates between inositol 1,4,5-trisphosphate- and ryanodine-sensitive stores. PCB 95 selectively mobilizes Ca2+ from ryanodine-sensitive stores in a dose-dependent manner (EC50 = 3.5 microM) and is completely inhibited by ryanodine receptor blockers, whereas coplanar PCBs are inactive. These data demonstrate that ortho-substituted PCBs disrupt Ca2+ transport in central neurons by direct interaction with ryanodine receptors, showing high selectivity and specificity. Alteration of Ca2+ signaling mediated by ryanodine receptors in specific regions of the central nervous system may account, at least in part, for the significant impact of these agents toward neurodevelopment and neuroplasticity in mammals.
Highlights
Polychlorinated biphenyls (PCBs), polychlorinated dibenzop-dioxins and polychlorinated dibenzofurans are commonly known as halogenated aromatic hydrocarbons (HAHs), a family of persistent and widely dispersed environmental contaminants
We have provided evidence of the direct interaction between certain ortho-substituted PCB congeners and the ryanodine-sensitive Ca2ϩ channel complex (RyRs) localized on sarcoplasmic and endoplasmic reticulum (SR/ER) [22]
The present paper demonstrates for the first time a stringent structure-activity relationship among PCBs possessing two or more chlorine substitutions in the ortho positions for activation of ryanodine receptors (RyRs) of the mammalian central nervous system, revealing an arylhydrocarbon receptor (AhR)-independent mechanism through which PCBs disrupt neuronal Ca2ϩ signaling
Summary
Aroclor 1254 and PCB congeners (Ͼ99% pure) were purchased from Ultra Scientific (North Kensington, RI). [3H]Ryanodine (60 –90 Ci/ mmol; Ͼ 99%) and [3H]inositol 1,4,5-trisphosphate (15–30 Ci/mmol; Ͼ 95%) were purchased from DuPont NEN. Aroclor 1254 and PCB congeners (Ͼ99% pure) were purchased from Ultra Scientific (North Kensington, RI). [3H]Ryanodine (60 –90 Ci/ mmol; Ͼ 99%) and [3H]inositol 1,4,5-trisphosphate (15–30 Ci/mmol; Ͼ 95%) were purchased from DuPont NEN. Fluo-3 (pentammonium salt, Ն90% pure) was purchased from Molecular Probes (Eugene, OR). All other reagents were of the highest purity commercially available
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