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

Abstract

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.

Comparison of Chlorantraniliprole and Flubendiamide Activity Toward Wild-Type and Malignant Hyperthermia-Susceptible Ryanodine Receptors and Heat Stress Intolerance

“…Three sequential addition of CaCl 2 resulted in active Ca 2þ accumulation into the JSR lumen through sarco/endoplasmic Ca 2þ -ATPase (SERCA) pump activity ( Figure 2A). Once extravesicular [Ca 2þ ] returned to baseline, subsequent addition of DMSO control did not alter baseline leak rate, consistent with previous reports (Feng et al, 2017;Niknam et al, 2013). Addition of low (nM) concentrations of CP or FD also failed to elicit net Ca 2þ efflux from the JSR vesicles (not shown).…”

Interactions of Dichlorodiphenyltrichloroethane (DDT) and Dichlorodiphenyldichloroethylene (DDE) With Skeletal Muscle Ryanodine Receptor Type 1

“…Macroscopic Ca 21 flux measurements. Net Ca 2þ flux across JSR membrane vesicles were assessed in real time using metallochromic Ca 2þ indicator dye arsenazo III (AsIII) as previously described in Feng et al (2017) and Truong and Pessah (2018). JSR membrane vesicles at 100 mg/ml were added into 35 C cuvettes containing aqueous medium (pH 7.4) consisting of (in mM) 100 KCl, 6 sodium pyrophosphate, 0.25 AsIII, and 20 4-morpholinepropanesulfonic acid (MOPS), 2 Mg 2þ ATP, 10 phosphocreatine, and 20 mg/ml creatine phosphokinase.…”

Evidence Implicating Non-Dioxin-Like Congeners as the Key Mediators of Polychlorinated Biphenyl (PCB) Developmental Neurotoxicity

“…Picomolar to nanomolar concentrations of NDL PCBs interact directly with RyR channels to stabilize the channel in its open configuration [223,224]. This RYR-PCB interaction exhibits a stringent SAR, including stereoselectivity, as determined via biochemical, electrophysiological, cellular, and in vivo approaches [147,[224][225][226][227][228][229][230].…”