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

Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Pharmacology [?] Therapeutics (Impact Factor: 9.72). 11/2009; 125(2):260-85. DOI: 10.1016/j.pharmthera.2009.10.009
Source: PubMed


Chronic low-level polychlorinated biphenyl (PCB) exposures remain a significant public health concern since results from epidemiological studies indicate that 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 Ca2+ 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 non-coplanar PCBs and related structures alter local and global Ca2+ signaling properties and the possible short and long-term consequences of these perturbations on neurodevelopment and neurodegeneration are reviewed.

Download full-text


Available from: Isaac Pessah, Oct 10, 2015
43 Reads
  • Source
    • "This is supported by studies demonstrating that increased RyR number and function is linked to increased muscle contractility and swimming performance in fish and mammals (Anttila et al., 2006, 2008; James et al., 2011; Seebacher et al., 2012). Increased levels of FKBP12 may confer tighter regulation of channel gating because: (1) the number of FKBP12 proteins bound to the RyR homotetramer varies by physiological and pathophysiological state (Zalk et al., 2007), (2) pharmacologically inhibited binding or genetically induced deficiencies in FKBP12 increases RyR channel open probability and mean open time; and (3) RyR conformational control can be regained when recombinant FKBP12 is added to channels exposed to Bastidin 10, a marine sponge extract known to disrupt the FKBP12/RyR complex (Pessah et al., 2010). These current findings are in agreement with chronic RyR1 leak and SR Ca 2+ depletion as NDL PCB induced consequences 3.3.2. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Atlantic killifish (Fundulus heteroclitus) thrive in New Bedford Harbor (NBH), MA, highly contaminated with polychlorinated biphenyls (PCBs). Resident killifish have evolved tolerance to dioxin-like (DL) PCBs, whose toxic effects through the aryl hydrocarbon receptor (AhR) are well studied. In NBH, non-dioxin like PCBs (NDL PCBs), which lack activity toward the AhR, vastly exceed levels of DL congeners yet how killifish counter NDL toxic effects has not been explored. In mammals and fish, NDL PCBs are potent activators of ryanodine receptors (RyR), Ca2+ release channels necessary for a vast array of physiological processes. In the current study we compared the expression and function of RyR related pathways in NBH killifish with killifish from the reference site at Scorton Creek (SC, MA). Relative to the SC fish, adults from NBH displayed increased levels of skeletal muscle RyR1 protein, and increased levels of FK506-binding protein 12 kDa (FKBP12), an accessory protein essential for NDL PCB-triggered changes in RyR channel function. In accordance with increased RyR1 levels, NBH killifish displayed increased maximal ligand binding, increased maximal response to Ca2+ activation and increased maximal response to activation by the NDL PCB congener PCB 95. Compared to SC, NBH embryos and larvae had increased levels of mtor and ryr2 transcripts at multiple stages of development, and generations, while levels of serca2 were decreased at 9 days post-fertilization in the F1 and F2 generations. These findings suggest that there are compensatory and heritable changes in RyR mediated Ca2+ signaling proteins or potential signaling partners in NBH killifish.
    Aquatic Toxicology 12/2014; 159. DOI:10.1016/j.aquatox.2014.12.017 · 3.45 Impact Factor
  • Source
    • "These considerations suggest the presence of a different pathway in the neurotoxicity of these compounds . Indeed, in literature PCB neurotoxicity has been related to many different mechanisms: it has been proposed their ability to alter patterns of ryanodine receptors (RyRs) expression in brain, altering calcium flux in excitable cells (Pessah et al., 2010; Kim et al., 2011); it has been suggested pollutants ability to induce an inflammatory phenomena in neurons, altering their function and inducing neurotoxicity (Banks and Lein, 2012); lastly, PCB are able to disrupt some epigenetic markers related to chromatin remodeling favoring or silencing the translation of genes important for neuronal development and function (Casati et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Perinatal polychlorinated biphenyl (PCB) exposures still remain a serious health concern because offspring receive PCB burden from mother during vulnerable processes of development. Since cytochrome P450 (CYP) represents a toxicological endpoint, in the present study, representing an extended investigation of a previous multitasked one, we explored the long-term responsiveness of CYP1A and CYP2B isoforms by Western blot analysis in liver and whole brain of lactating (PN12), weaning (PN21), and adult offspring (PN60) rats prenatally and lactationally exposed to a reconstituted PCB mixture (RM) of noncoplanar PCB138, 153, 180, and coplanar PCB126 congeners. We chose highly chlorinated PCBs instead of lower chlorinated one, because their recalcitrance to biotransformation makes easy their accumulation/persistence in tissues and breast milk. Dioxin-like congener PCB126 binding aryl hydrocarbon receptor (AHR) is responsible of many toxic effects. Pregnant Sprague-Dawley dams with high affinity AHR received subcutaneous injection of RM (10 mg/kg body weight) daily during gestation (days 15-19) and twice a week during breast-feeding. The results evidenced a transfer of PCBs to neonates through milk and a significant responsiveness of hepatic CYP in both mothers and offspring. In liver of exposed progeny, CYP isoforms exhibited a significant increment at PN12 (70% over control) and at PN21 (270% over control). Contrary to dams, in adult PCB offspring CYP levels showed a decline up to values similar to those of control. This transient developmental responsiveness of CYP isoforms in offspring liver reflects roughly the time course of hepatic PCB levels previously reported. Even if congeners were detected in brain, we failed in evidencing a responsiveness of CYP isoforms probably because of region-specific CYP expression in this organ. In conclusion, induction of offspring hepatic CYP is index of liver PCB burden, and despite the insensitivity of whole brain CYP we cannot exclude brain vulnerability toward PCB. © 2012 Wiley Periodicals, Inc. Environ Toxicol, 2012.
    Environmental Toxicology 08/2014; 29(8). DOI:10.1002/tox.21812 · 3.20 Impact Factor
  • Source
    • "In addition, rat myogenic cultures exposed to PCB mixture Aroclor 1254 in vitro inhibited myoblast differentiation (Guo et al., 1994). These results indicate that in addition to developmental neurotoxicity mediated by interactions of NDL-PCB with RyRs expressed in the CNS (Pessah et al., 2010), direct actions with RyR1 expressed in skeletal muscle could contribute to motor dysfunction, especially during critical perinatal periods of muscle development. There is increasing interest in whether metabolites of NDL- PCBs maintain biological activity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) are legacy environmental contaminants with contemporary unintentional sources. NDL-PCBs interact with ryanodine receptors (RyRs), Ca2+ channels of sarcoplasmic/endoplasmic reticulum (SR/ER) that regulate excitationcontraction coupling (ECC) and Ca2+-dependent cell signaling in muscle. Activities of four chiral congeners PCB91, 95, 132, 149 and their respective 4- and 5-hydroxy (-OH) derivatives toward rabbit skeletal muscle ryanodine receptor (RyR1) are investigated using [3H]ryanodine binding and SR Ca2+ flux analyses. Although 5-OH metabolites have comparable activity to their respective parent in both assays, 4-OH derivatives are unable to trigger Ca2+ release from SR microsomes in the presence of Ca2+-ATPase activity. PCB95 and derivatives are investigated using single channel voltage-clamp and primary murine embryonic muscle cells (myotubes). Like PCB95, 5-OH-PCB95 quickly and persistently increases channel open probability (Po>0.9) by stabilizing the full-open channel state, whereas 4-OH-PCB95 transiently enhances Po. Ca2+ imaging of myotubes loaded with Fluo-4 show acute exposure to PCB95 (5HM) potentiates ECC and caffeine responses, and partially depletes SR Ca2+ stores. Exposure to 5-OH-PCB95 (5HM) increases cytoplasmic Ca2+ leading to rapid ECC failure in 50% of myotubes with the remainder retaining negligible responses. 4-OH-PCB95 neither increases baseline Ca2+ nor causes ECC failure, but depresses ECC and caffeine responses by 50%. With longer (3h) exposure to 300nM PCB95, 5-OH-PCB95 or 4-OH-PCB95 decreases the number of ECC responsive myotubes by 22%, 81%, and 51% compared to control by depleting SR Ca2+ and/or uncoupling ECC. NDL-PCBs and their 5-OH and 4-OH metabolites differentially influence RyR1 channel activity and ECC in embryonic skeletal muscle.
    Toxicological Sciences 09/2013; · 3.85 Impact Factor
Show more