Ortho-substituted polychlorinated biphenyls Alter microsomal calcium transport by direct interaction with ryanodine receptors of mammalian brain*
Open accessAbstract
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…
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PCB-induced impairment of mitochondrial and endoplasmic reticulum calcium handling, together with ryanodine receptor activation, can lead to sustained intracellular calcium elevation, excitotoxic stress, and neuronal injury.
“More generally, PCB-induced impairment of mitochondrial and endoplasmic reticulum calcium handling, together with ryanodine receptor activation, can lead to sustained intracellular calcium elevation, excitotoxic stress, and neuronal injury (Howard et al., 2003; Wong et al., 1997).”
From Environmental endocrine disruptors at the synapse: mechanisms linking chemical exposure to cognitive and behavioral dysfunction (2026) · cites this paper as Wong et al., 1997
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Jocsak, G., Kiss, D. S., Alymbaeva, D., Diebald, A., Zsarnovszky, A., Heinzlmann, A., & Bartha, T. (2026) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2026.1821381 · Cited by 1 · see citing works
- Authors
- Wong, P. W., Brackney, W. R., & Pessah, I. N.
- Affiliations
- University of California, Davis (US)
- Corresponding author
- Pessah, Isaac N.
- ORCID
- Pessah, Isaac N.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1997-06
- Volume
- 272
- Issue
- 24
- Pages
- 15145-15153
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2015667498
- Cited by
- 124
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 5 · 2018: 2 · 2017: 5 · 2016: 5 · 2015: 2 · 2014: 1 · 2013: 4 · 2012: 4
- FWCI
- 4.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01es005002-08)
- National Institute of Environmental Health Sciences (ES07059, ES05707, 1RO1 ES05002, T32ES007059)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Keywords
- polychlorinated biphenyls, ryanodine receptor, calcium transport, neuronal calcium signaling, PCB 95, structure-activity relationship, ryanodine-sensitive calcium stores, inositol 1,4,5-trisphosphate, brain, hippocampus, cerebellum, cerebral cortex, brain development, neuroplasticity
- MeSH terms
- Animals, Brain, Calcium, Microsomes, Muscle Proteins, Polychlorinated Biphenyls, Calcium Channels, Ion Transport, Ryanodine Receptor Calcium Release Channel, Rats, In Vitro Techniques
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