Structure−Activity Relationship for Noncoplanar Polychlorinated Biphenyl Congeners toward the Ryanodine Receptor-Ca²⁺ Channel Complex Type 1 (RyR1)

Abstract

Ryanodine receptor isoforms are expressed in both excitable and nonexcitable tissues where they form microsomal Ca2+ release channels broadly involved in shaping cellular signaling. In this report, we provide a detailed structure-activity relationship (SAR) for polychlorinated biphenyl (PCB) congeners and metabolites necessary for enhancing ryanodine receptor type 1 (RyR1) activity using [3H]ryanodine ([3H]Ry) binding analysis. The 2,3,6-Cl PCB configuration is most important for optimal recognition by the RyR1 complex and/or critical for sensitizing its activation. Para substitution(s) diminishes the activity with para-chloro having a higher potency than the corresponding para-hydroxy derivative. The addition of a more bulky para-methyl-sulfonyl group eliminates the activity toward RyR1, supporting the importance of the para positions in binding RyR1. The requirement for an intact major T cell immunophilin FKBP12-RyR1 complex was observed with each of 12 active PCB congeners indicating a common mechanism requiring an immunophilin-regulated Ca2+ release channel. An excellent correlation between the relative potencies for doubling [3H]Ry binding and the corresponding initial rates of PCB-induced Ca2+ efflux indicates that [3H]Ry binding analysis provides a measure of dysregulation of microsomal Ca2+ transport. The SAR for activating RyR1 is consistent with those previously reported in several in vivo and in vitro studies, suggesting that a common mechanism may contribute to the toxicity of noncoplanar PCBs. A practical application of the receptor-based screen developed here with RyR1 is that it provides a quantitative SAR that may be useful in predicting biological activity and risk of mixtures containing noncoplanar PCB congeners that have low or a lack of aryl hydrocarbon receptor activity.

Applicability of QSAR analysis to the evaluation of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment

“…For example, Crofton (1996) described a SAR study of 14 different triazole fungicides which cause hyperactivity in rats. 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).…”

“…Chan et al (2008c) rat hepatocyte toxicity α,β-unsaturated aldehydes 11 Chan et al (2007) human and rat hepatocyte toxicity halobenzenes 12 Pessah et al (2005) developmental neurotoxicity ( …”

Perinatal exposure to a noncoplanar polychlorinated biphenyl alters tonotopy, receptive fields, and plasticity in rat primary auditory cortex

“…Noncoplanar PCBs have two or more ortho-chlorine substitutions and very weak or no aryl hydrocarbon receptor-binding activity. Recent studies find that noncoplanar PCBs are potent sensitizers of ryanodine receptor (RyR) calcium channels (5)(6)(7)(8)(9) and, as such, affect Ca 2ϩ release from intracellular stores (7)(8)(9)(10) and influence the cellular response to both chemical and electrical signals (11,12). RyRs, previously thought to exist only in muscle tissue, now are documented in both pre-and postsynaptic terminals in neurons in many brain areas (13)(14)(15); RyRs were shown to affect neuronal excitability (13,(15)(16)(17)(18)(19)(20)(21)(22) and synaptic plasticity, modulating both long-term potentiation and long-term depression (13,(16)(17)(18)(19).…”

Immunologic and neurodevelopmental susceptibilities of autism

“…Prominent examples are the polyaromatic hydrocarbons that mediate their toxicity through the arylhydrocarbon receptor (AhR), such as dioxin, or through selective interactions with ryanodine receptors (RyR) in the brain (Zimanyi and Pessah, 1991), such as non-coplanar polychlorinated biphenyls (PCBs). Interactions of non-coplanar PCBs with RyR greatly sensitize the release of Ca 2+ from the microsomal intracellular stores (Wong et al,1997;Pessah et al,2006), and are likely to contribute to imbalances in excitatory and inhibitory neurotransmission and the abnormal development of brain circuitry (Kenet et al, 2007; and review below by Lein). Sensitization of RyRs by PCBs has been shown to be responsible for a host of toxicological outcomes in vitro including amplification of NMDA-mediated excitation and Ca 2+ /caspase mediated apoptosis (Gafni et al,2004;Wong et al, 2001;Howard et al, 2003).…”