Minding the calcium store: Ryanodine receptor activation as a convergent mechanism of PCB toxicity

Abstract

Chronic low level polychlorinated biphenyls (PCB) exposures remain a significant public health concern since results from epidemiological studies indicate PCB burden is associated with immune system dysfunction, cardiovascular disease, and impairment of the developing nervous system. Of these various adverse health effects, developmental neurotoxicity has emerged as a particularly vulnerable endpoint in PCB toxicity. Arguably the most pervasive biological effects of PCBs could be mediated by their ability to alter the spatial and temporal fidelity of Ca 2+ signals through one or more receptor mediated processes. This review will focus on our current knowledge of the structure and function of ryanodine receptors (RyRs) in muscle and nerve cells and how PCBs and related non-coplanar structures alter these functions. The molecular and cellular mechanisms by which noncoplanar PCBs and related structures alter local and global Ca 2+ signaling properties and the possible short and long-term consequences of these perturbations on neurodevelopment and neurodegeneration are reviewed. Dioxin-like and non-dioxin-like PCBs Occurrence and concerns to public healthPolychlorinated biphenyls (PCBs) are synthetic chlorinated aromatic hydrocarbons that are non-flammable, chemically stable and have high boiling points. In the United States, PCBs were synthesized and marketed primarily as Aroclor® mixtures whose degree of chlorination was identified by a four-digit designation (e.g., 1248, 1254, 1260, etc.), with the first two digits identifying the mixture as PCBs and the last two digits identifying the percent of chlorine used during synthesis. A higher degree of PCB chlorination increases melting point and lipophilicity, whereas lower chlorination increases vapor pressure and water solubility. Similar PCB mixtures were synthesized worldwide and identified under several trade names such as Clophen® and Kanechlor®. PCB mixtures, especially those of intermediate chlorination, such as Aroclor 1248 and Aroclor 1254, were widely used in several industries for their insulation and heat dissipating properties. PCBs were also broadly incorporated into a variety of common products such as pesticide extenders, plastics, varnishes, adhesives, carbonless copy paper, newsprint, fluorescent light ballasts and caulking compounds (Ross, 2004).By 1977, when PCBs were banned, more than 600,000 tons were manufactured in the United States, and global production is estimated at over 1.5 million tons (Breivik, Sweetman, Pacyna, & Jones, 2002). Because of their extensive industrial use and chemical stability, PCBs have Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the conten...

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“…The present compounds will nevertheless be useful to silence RyR1, and probably other RyR isoforms, in a number of pathological conditions in which abnormal RyR1 channel activity is involved. These include skeletal and cardiac myopathies (60), neurodegenerative disorders (61,62), and environmentally triggered disorders (12). Our results suggest that MCa P-Thr 26 is capable of normalizing two important dysfunctional properties of RyR1: by decreasing the sensitivity of RyR1 to cytoplasmic Ca 2+ , allowing a decrease of spontaneous CICR (Fig.…”

“…It was first identified in skeletal muscles (10) but is also broadly expressed in many other tissues such as pre-and postsynaptic sites within neurons of the brain (11). RyR calcium channels regulate Ca 2+ release from intracellular stores, and therefore represent crucial players of a number of physiological and toxicological processes, from muscle contraction to gene expression (12). As a consequence, silencing of the gene encoding RyR1 is lethal at birth (13).…”

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“…A QSAR for PCB neurotoxicity (Pessah et al, 2005), based on data for 28 ortho-substituted PCBs, and building on earlier work (Nevalainen et al, 1994), revealed a relationship between electronic descriptors (E LUMO , E HOMO , the E LUMO −E HOMO gap, and molecular polarizability) and the binding affinity of PCBs to the aryl hydrocarbon (Ah) receptor. In particular, impairment of the developing nervous system by PCBs has been linked to their ability to alter the spatial and temporal fidelity of Ca2+ signalling in muscle and nerve cells through one or more receptor-mediated processes (Pessah et al, 2009). …”

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