Pharmacology & Therapeutics 125 (2010) 260–285

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Pharmacology & Therapeutics

journal homepage: www.elsevier.com/locate/pharmthera

Associate Editor: Carey Pope Minding the store: activation as a convergent mechanism of PCB toxicity

Isaac N. Pessah ⁎, Gennady Cherednichenko, Pamela J. Lein

Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA article info abstract

Keywords: Chronic low-level polychlorinated biphenyl (PCB) exposures remain a significant public health concern since (RyR) results from epidemiological studies indicate that PCB burden is associated with immune system Calcium-induced calcium release dysfunction, cardiovascular , and impairment of the developing nervous system. Of these various Calcium regulation adverse health effects, developmental neurotoxicity has emerged as a particularly vulnerable endpoint in Polychlorinated biphenyls PCB toxicity. Arguably the most pervasive biological effects of PCBs could be mediated by their ability to alter Triclosan fi 2+ Bastadins the spatial and temporal delity of Ca signals through one or more receptor-mediated processes. This Polybrominated diphenylethers review will focus on our current knowledge of the structure and function of ryanodine receptors (RyRs) in Developmental neurotoxicity muscle and nerve cells and how PCBs and related non-coplanar structures alter these functions. The Activity dependent plasticity 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 are reviewed. © 2009 Elsevier Inc. All rights reserved.

Contents

1. Introduction ...... 260 2. Ryanodine receptor macromolecular complexes: significance to polychlorinated biphenyl-mediated Ca2+ dysregulation ...... 263 Acknowledgments ...... 278 References ...... 278

1. Introduction synthesized worldwide and identified under several trade names such as Clophen® and Kanechlor®. PCB mixtures, especially those of inter- 1.1. Polychlorinated biphenyls: Occurrence and concerns to public health mediate chlorination, such as Aroclor 1248 and Aroclor 1254, were widely used in several industries for their insulation and heat dis- Polychlorinated biphenyls (PCBs) are synthetic chlorinated aro- sipating properties. PCBs were also broadly incorporated into a variety matic hydrocarbons that are non-flammable, chemically stable and of common products such as pesticide extenders, plastics, varnishes, have high boiling points. In the United States, PCBs were synthesized adhesives, carbonless copy paper, newsprint, fluorescent light ballasts and marketed primarily as Aroclor® mixtures whose degree of and caulking compounds (Ross, 2004). chlorination was identified by a four-digit designation (e.g., 1248, By 1977, when PCBs were banned, more than 600,000 tons were 1254, 1260, etc.), with the first two digits identifying the mixture as manufactured in the United States, and global production is estimated PCBs and the last two digits identifying the percent of chlorine used at over 1.5 million tons (Breivik et al., 2002). Because of their exten- during synthesis. A higher degree of PCB chlorination increases sive industrial use and chemical stability, PCBs have accumulated in melting point and lipophilicity, whereas lower chlorination increases the environment and biota. PCBs have been identified in approxi- vapor pressure and water solubility. Similar PCB mixtures were mately one third of the sites listed on the National Priorities List (NPL) and Superfund Sites (Anonymous, 2007). The average PCB levels in the environment and human blood have steadily declined since 1977. ⁎ Corresponding author. Tel.: 530 752 6696. However, geographic “hotspots” of relatively high PCB contamination E-mail address: [email protected] (I.N. Pessah). persist due to improper disposal, and mobilization of PCBs from

0163-7258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.pharmthera.2009.10.009 I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285 261 historical end uses in and around urban environments (legacy PCBs). arguably the two most important physicochemical parameters for Specific examples of PCB hotspots in the United States that contribute optimizing tight binding to AhR, although the position of para and meta to higher human exposures include the San Francisco Bay watershed substituents influences apparent binding affinity. A growing number of (Davis et al., 2007), the Hudson River watershed (Schneider et al., environmental chemicals are known to activate or inhibit AhR, thereby 2007; Asher et al., 2007), Chicago air (Sun et al., 2006; Hu et al., 2008; regulating its translocation to the nucleus where it dimerizes with AhR Zhao et al., 2009), and regions of Lake Erie near urban centers (Sun nuclear translocator (ARNT) (Denison & Nagy, 2003). The AhR–ARNT et al., 2007; Robinson et al., 2008). Thus, chronic low-level PCB complex binds to the DNA core sequence 5′-GCGTG-3′ in the promoter exposures remain a significant public health concern since results region of dioxin-responsive to regulate their expression. Pro- from epidemiological studies indicate that PCB burden is associated longed activation of AhR and its responsive genes has been implicated in with immune system dysfunction (Heilmann et al., 2006; Selgrade, diverse toxicological sequelae associated with chronic, low-level expo- 2007; Park et al., 2008a,b), cardiovascular disease (Hennig et al., 2005; sures to TCDD, polycyclic aromatic hydrocarbons (PAHs), and coplanar Humblet et al., 2008; Dziennis et al., 2008; Everett et al., 2008; Helyar PCBs (Carpenter, 2006; Mitchell & Elferink, 2009). Thus, the risk to et al., 2009), and impairment of the developing nervous system human, fish and wildlife associated with PCB exposures is assessed by (Jacobson et al., 1992; Chen et al., 1992; Koopman-Esseboom et al., assigning an equivalence factor (TEF) that reflects the AhR activity of 1996; Schantz et al., 2003; Grandjean & Landrigan, 2006; Roegge & any individual PCB congener relative to TCDD, which is arbitrarily Schantz, 2006; Rogan & Ragan, 2007; Stewart et al., 2008). Of these assigned a TEF of 1.0. various adverse health effects, developmental neurotoxicity has Several limitations of the TEF concept have been identified (Van emerged as a particularly vulnerable endpoint in PCB toxicity. den Berg et al., 2006). Arguably the most important limitation for Whether neurological, immunological and cardiovascular impair- predicting PCB toxicity based solely on an AhR-based TEF is the fact ments are interrelated by one or more convergent mechanisms, or that PCBs having one or more chlorines in the ortho-positions are arise independently from biologically distinct mechanisms continues non-coplanar structures with very low or no activity towards the AhR to be debated. Furthermore, which PCB structures confer specific yet they exhibit significant toxicological activity. In vitro studies have health risks to the general public or to a susceptible population, identified PCB 95 (Fig. 1) among the most biologically active non- remains unclear. coplanar structures and its occurrence in human and environmental samples has been recently scrutinized using improved analytical 1.2. Non-dioxin-like polychlorinated biphenyl methods. PCB 95 has been detected in human tissues (Covaci et al., structures—convergent mechanisms mediated by ryanodine receptors 2002; Chu et al., 2003a; DeCaprio et al., 2005; Jursa et al., 2006), and in environmental samples including indoor and outdoor air, top soil, Of the 209 possible PCB congeners that were synthesized as tidal marsh sediments, grass, diets, and human feces (Robson & commercial mixtures, most of the scientific and regulatory attention Harrad, 2004; Harrad et al., 2006; Hwang et al., 2006; Zhao et al., has been directed toward the so-called dioxin-like PCBs that lack at least 2009; Wong et al., 2009). Recent studies indicate that non-coplanar two chlorines in the ortho-positions. The phenyl rings of dioxin-like PCBs currently predominate in biological and environmental samples. PCBs, for example PCB 77 (3,3′,4,4′-tetrachlorobiphenyl) and PCB 126 For example, PCB 153 (Fig. 1) has been identified as a major con- (3,3′,4,4′,5-pentachlorobiphenyl), assume a coplanar orientation that tributor to total PCB burden in humans (Longnecker et al., 2003; Moon mimics the planar structure of dioxin (2,3,7,8-tetrachlorodibenzo-p- et al., 2009; Agudo et al., 2009; Axelrad et al., 2009). dioxin; TCDD), the archetypical agonist for the arylhydrocarbon The ortho-rich PCBs and metabolites of both ortho-rich and ortho- hydroxylase receptor (AhR) (Fig. 1). Coplanarity and lipophilicity are poor PCBs have a number of actions independent of the AhR that have

Fig. 1. Coplanar structure of dioxin and two examples of dioxin-like PCBs. Non-dioxin-like PCBs have N2 chlorine substitutions in the ortho-position that introduce steric hindrance thereby promoting non-coplanar geometry, as typified by PCB 95 and PCB 153. 3-D projections were calculated using the Molecular Dynamics Tool of ChemIDplus Advanced (Nat. Lib. Med.). 262 I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285 been termed “non-dioxin-like”. Mono-ortho-substituted PCBs may tions ≤1µM(Wong & Pessah, 1996; Pessah et al., 2006). Fig. 2 have dioxin-like and non-dioxin-like activities. However mono-ortho demonstrates the relative activity of 28 non-coplanar PCBs toward RyR1 congeners commonly detected in tissues, such as PCB 118 (2,3,4,4′,5- and their relative contribution to total PCB burden reported in Fox River pentachlorobiphenyl) and PCB 156 (2,3,3′,4,4′,5-hexachlorobiphenyl), fish (52%) (Kostyniak et al., 2005), San Francisco Bay tidal marsh have extremely low TEF values (≪0.0001), and their apparent AhR sediments (∼50%) (Hwang et al., 2006), and human serum (∼45%) activity could be largely attributed to coplanar contaminants (Peters, (DeCaprio et al., 2005). Because not all the PCBs detected in these studies et al. 2006). Several biological activities have been experimentally have been tested for RyR activity, these estimates of the occurrence of demonstrated with non-dioxin-like PCBs, and these were recently RyR-active PCBs are conservative. Therefore, the PCB congeners found in reviewed (Mariussen & Fonnum, 2006; Fonnum et al., 2006). highest abundance in environmental samples and tissues collected from Endocrine effects include weak estrogenicity (Safe, 2004), enhanced humans and animals are capable of directly and potently interacting insulin (Fischer et al., 1999) and arachidonic acid secretion (Bae with a major family of intracellular Ca2+ channels. RyRs are broadly et al., 1999a), and disruption of the hypothalamo–pituitary–thyroid expressed in most types where they participate in shaping axis. Two possibly convergent mechanisms actively being investi- temporally and spatially defined Ca2+ signals that are essential for gated include (1) disruption of thyroid metabolism and regulating several aspects of cellular signaling that regulate growth, signaling (Zoeller et al., 2000; Zoeller, 2005; Knerr & Schrenk, movement, metabolism, secretion and plasticity. 2006), and (2) perturbations in cellular Ca2+ signaling (Tilson and Significant to the neurotoxic potential of PCBs, RyR channel Kodavanti, 1998; Pessah, 2001). Arguably the most pervasive activity regulates a variety of physiological and pathophysiological biological effects of PCBs could be mediated by their ability to processes in the central (Berridge, 2006; Dai et al., 2009), and periph- alter the spatial and temporal fidelity of Ca2+ signals through one or eral nervous systems (Jackson & Thayer, 2006; Buchholz et al., 2007; more receptor-mediated processes. The pivotal roles of Ca2+ signals Behringer et al., 2009). Decrements in neonatal reflexes, cognitive in regulating movement, metabolism, growth, proliferation, function, motor activity, tremors, changes in autonomic functioning, transcription and in virtually all cell types is well and hearing impairments are consistent findings with developmental established. Kodavanti et al. first reported that exposure to non- PCB exposures in studies of humans and animals, and are primarily coplanar PCBs elevate cytoplasmic Ca2+ in cultured cerebellar attributed to adverse effects on the developing CNS (Stewart et al., granule (Kodavanti et al., 1993), and several mechanisms 2000; Mariussen & Fonnum, 2006; Roegge & Schantz, 2006; Kenet were proposed including disruption of membrane properties et al., 2007; Darras, 2008; Fitzgerald et al., 2008). The possibility that (Kodavanti et al., 1996). A selective receptor-targeted mechanism PCBs might directly influence peripheral neurons and their effectors was also proposed based on the stringent structure–activity including skeletal, cardiac, and smooth muscle, and cochlear hair cells, relationship of PCBs for enhancing the activity of ryanodine all of which express functionally essential RyRs, has not received receptors (RyRs), a family of intracellular Ca2+ channels (Wong & nearly as much investigation as their influence on the developing Pessah, 1996). For example, PCB 95 and PCB 153 at concentrations endocrine and central nervous systems. ≤10 µM lack detectable AhR activity, yet significantly enhance the In addition to TH, studies on the endocrine disrupting effects of activity of type 1 (RyR1) and type 2 (RyR2) isoforms at concentra- PCBs and related organohalogens have also focused on estrogen,

Fig. 2. Relative concentration of 28 non-coplanar PCBs needed to double [3H]ryanodine binding to ryanodine receptor type 1 (RyR1; black bars) and their corresponding occurrence in Fox River fish, marsh sediments, and human serum (red bars). PCBs in parentheses are co-eluting congeners. I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285 263 insulin, and their respective signaling pathways (Fonnum et al., 2006; muscle disorders. Similar functional and/or physical coupling of RyRs Zoeller, 2007; Carpenter, 2008). Considering that RyRs have been to context-specific have been identified in smooth muscle, shown to regulate several aspects of these same endocrine functions neurons and other cell types. (Islam, 2002; Dillmann, 2002; Muchekehu & Harvey, 2008), a The composition of RyR macromolecular complexes is therefore an common convergent mechanism may contribute to pathological important consideration when interpreting the seemingly diverse in endocrine signaling and abnormal responses in target organs that vitro and in vivo actions attributed to non-coplanar PCB congeners depend on RyR activity for mediating appropriate Ca2+ signals. and Aroclor mixtures in a wide variety of tissues and cell types. PCBs This review will focus on our current knowledge of the structure have been shown to enhance Ca2+ release from sarcoplasmic and function of RyRs in muscle and nerve cells and how PCBs and reticulum/ (SR/ER) and mitochondrial stores, related non-coplanar structures alter these functions. Our current and to promote Ca2+ entry, but whether these effects stem from knowledge of how RyRs assemble into arrays and clusters, how they convergent receptor-mediated mechanisms or multiple “nonspecific” generate local releases of Ca2+ termed sparks, and trigger global Ca2+ influences on membrane integrity has been debated (Pessah, & Wong, waves is most advanced in studies of skeletal, cardiac and smooth 2001; Inglefield et al., 2001). PCBs also alter the activities of RyR muscle. The topic is reviewed here first to provide context to the “accessory” proteins including the multifunctional protein , molecular mechanisms by which PCBs and related structures PKA (Inglefield et al., 2002; Llansola et al., 2009) and PKC (Kodavanti influence RyR structure and function. The molecular and cellular et al., 1994), (Olivero & Ganey, 2001; Benninghoff & mechanisms by which non-coplanar PCBs and related structures alter Thomas, 2005), and FKBP12 (FK506 binding protein 12 kDa), the local and global Ca2+ signaling properties and the possible short and major T-cell immunophilin (Wong & Pessah, 1997; Wong et al., long-term consequences of these perturbations on neurodevelopment 2001b; Gafni et al., 2004). Additionally, PCB toxicity in excitable and and neurodegeneration will then be discussed. non excitable cells appears to be mediated at least in part by oxidative stress and involves biotransformation via quinone and hydroxylated 2. Ryanodine receptor macromolecular complexes: metabolites, and altered activities of key antioxidant defense enzymes significance to polychlorinated biphenyl-mediated Ca2+ dysregulation such as glutathione transferases, NADH/NAD(P)H oxidoreductases, and possibly selenoproteins (Howard et al., 2003; Murugesan et al., As might be predicted by their size and critical contribution to 2007; Duntas, 2008; Wei et al., 2009; Liu et al., 2009a). Many of muscle function, multiple factors contribute to the precise regulation these proteins have been directly implicated in redox regulation of of RyR channel activity. In skeletal and at least 20 RyRs. protein–protein interactions have been described for the two major isoforms RyR1 (type 1 RyR) and RyR2 (type 2 RyR), respectively 2.1. Organization, function and dysfunction of ryanodine receptor complexes (Fig. 3), and these interactions influence important aspects of Ca2+ channel function that are either essential for excitation–contraction Ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate 2+ (EC) coupling or fine-tune the spatial and temporal properties of local receptors (IP3Rs) are a family of Ca channels that are broadly and global Ca2+ signals in the myocyte. Many of these interactions, expressed throughout the central and peripheral nervous systems. when disrupted, have been shown to contribute to RyR-mediated The distribution, structure, and function of RyRs are best understood susceptibility to muscle damage and to the progression of several in striated muscle where expression of RyR1 and RyR2 isoforms are

Fig. 3. Several proteins interact with RyRs to regulate their function as high conductance Ca2+ channels in striated muscle. The large cytoplasmic assembly (“junctional foot”) interacts with ion channels in the plasma membrane, cytoplasmic signaling proteins, and cytoplasmic enzymes that regulate phosphorylation and redox sensing. The transmembrane assembly that anchors RyRs to the ER/SR interacts with proteins that fine-tune communication with the Ca2+ stores within the SR/ER lumen. For clarity, interactions have been left out of the schematic. 264 I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285 essential for engaging the process of EC coupling in skeletal and Gao et al., 2005). Highly reactive (hyper-reactive) cysteine residues cardiac muscle, respectively. In mice, targeted deletion of RyR1 results within the RyR sequence and possibly accessory proteins have been in a birth-lethal (Takeshima et al., 1994; Buck et al., 1997), identified, and these confer redox sensing properties to the Ca2+ whereas RyR2 null mice do not survive past embryonic day 9 channel complex (Liu & Pessah, 1994; Liu et al., 1994; Voss et al., (Takeshima et al., 1998). These are consistent with the 2004; Phimister et al., 2007; Jurynec et al., 2008). Shifts in RyR activity failure to engage EC coupling in these tissues at times critical for the in response to localized changes of glutathione (GSH/GSSG), nitric animal's survival. A third isoform, RyR3, is not essential for EC oxide, oxygen, and ROS appear to constitute a fundamental physio- coupling although it is transiently expressed in during logical and pathophysiological mechanism that adjusts local and embryonic development and is down regulated in most, but not all, global cellular Ca2+ signals to the changing local redox environment. fibers postnatally (Tarroni et al., 1997; Conti et al., 2005; Legrand The mechanisms appear to involve glutathionylation, nitrosylation, et al., 2008). Targeted deletion of RyR3 does not impair muscle electron delocalization, and oxidation of hyper-reactive cysteines function or survival, but does seem to impact neurobehavioral func- within RyR complexes (Zable et al., 1997; Xia et al., 2000; Feng & tion (Section 2.5.2). Pessah, 2002; Aracena et al., 2003; Aracena-Parks et al., 2006; Sun et al., 2008; Terentyev et al., 2008). PCBs appear to mediate toxicity, at 2.2. Ryanodine receptors in striated muscle least in part, by mechanisms involving oxidative stress (Howard et al., 2003; Lyng & Seegal, 2008; Glauert et al., 2008; Liu et al., 2009a). Thus, In striated muscle, RyR channels are anchored to specialized in addition to direct binding of PCBs to RyRs, PCB metabolites that regions of the SR of the developing myotube and adult fiber, termed possess redox active moieties, such as quinones and semiquinones junctional regions, where the SR and transverse tubule membranes (Machala et al., 2004; Spencer et al., 2009), would be expected to approach within 10–15 nm of each other (Fig. 4). In the context of confer additional activities toward modifying RyRs and their signaling these junctions, RyRs organize into tetrameric arrays or clusters that events. In this regard, site-selective oxidation of RyRs was already span the junctional SR-T tubule space (Franzini-Armstrong et al., demonstrated for naphthoquinones, benzoquinones, and benzo[a] 2005; Di Biase & Franzini-Armstrong, 2005). Each tetramer has four- pyrene 7,8-dione (Feng et al., 1999; Pessah et al., 2001; Gao et al., fold symmetry and constitutes a functional channel of ∼2.2 MDa that 2005). regulates releases of Ca2+ stored within the lumen of the SR into the As spark frequency and spatial spread of Ca2+ increases with . physiological (e.g. plasma membrane depolarization) or pharmaco- Coordinated gating (activation and inactivation) of multiple RyR logical (e.g., ) stimuli, Ca2+ waves are initiated that are capable channels generates spatially limited and temporally defined release of of propagating throughout the cell in which they occur (Cheng & Ca2+ sparks (Gonzalez et al., 2000; Chun et al., 2003; Gyorke et al., Lederer, 2008). Thus activation of RyRs is a means of eliciting con- 2007; Cheng & Lederer, 2008). Thus sparks represent quantal releases trolled release of SR Ca2+ stores and is a major source of both local and of Ca2+ from the lumen of junctional SR to a restricted area of the global Ca2+ signals that are essential for regulating contractility of cytoplasm. Although spontaneous and evoked Ca2+ sparks are striated and smooth muscle. commonly observed in cardiomyocytes, smooth muscle myocytes, and invertebrate skeletal muscle, they are rarely detected in intact 2.2.1. Could non-coplanar polychlorinated adult mammalian skeletal muscle under physiological conditions. The biphenyls alter ryanodine receptor function in striated muscle? lack of sparks in mammalian skeletal muscle is likely because the L- Skeletal and cardiac muscle represent major organs for the initial 2+ type Ca channel CaV1.1 confers direct negative regulation of RyR1 disposition of PCBs following exposure (Matthews & Anderson, 1975; (Lee et al., 2004; Zhou et al., 2006). However, Ca2+ sparks can be Matthews & Tuey, 1980; Brandt et al., 1981; Birnbaum, 1983). Muscle readily detected in mammalian skeletal muscle under pathophysio- tissues are therefore considered critical compartments when formu- logical conditions that generate reactive oxygen species (ROS) lating physiologically based pharmacokinetic models that faithfully (Martins et al., 2008). This is not unexpected since both RyR1 and reproduce :blood partitioning (Parham et al., 1997). A recent RyR2 are exquisitely sensitive to sulfhydryl modification by com- study of Galapogos sea lions identified the congener profile of PCBs pounds that generate ROS (Abramson et al., 1988; Favero et al., 1995), found in muscle biopsies (Alava et al., 2009). Results from this study redox cyclers, and cysteine arylators (Abramson et al., 1988; Pessah indicate that the 10 most active congeners identified based on [3H] et al., 1990; Feng et al., 1999; Pessah et al., 2001; Pessah et al., 2002; ryanodine-binding analysis (Fig. 2) represented nearly 25% of the total

Fig. 4. (A) Electron micrograph of the T-tubule/SR junction of negatively stained skeletal myotubes. Arrows indicate the position of densely staining “junctional feet” that are the large cytoplasmic domain of a row of RyR1s that span the junctional space between the two membranes (adapted from (Protasi et al., 1998)). (B) 3-D model of the relative orientation of four CaV1.1 (i.e., α1s) L-type Ca2+ channel subunits (brown) and RyR1 (green) based on cyroEM reconstruction studies (adapted from (Wolf et al., 2003). I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285 265

PCB burden found in muscle (Alava et al., 2009). In rodents exposed to with a small C-terminal transmembrane assembly anchored within the PCB 136, the low-dose group displayed significantly higher PCB levels membrane and a massive cytoplasmic (“junctional foot”)assembly in cardiac and skeletal muscles compared to other tissues, such as spanning the T-tubule SR junction (Franzini-Armstrong et al., 2005; Di adipose tissue and the liver (Kania-Korwel et al., 2008a,b). Biase & Franzini-Armstrong, 2005)(Fig. 4). Although the composition of Surprisingly, if and how non-coplanar PCBs modify the properties key proteins comprising the CRUs of skeletal and cardiac muscles are of striated muscle EC coupling has only recently been examined. The strikingly similar (Fig. 3), skeletal muscle does not require Ca2+ entry 2+ physical interactions between CaV1.1 and RyR1 that trigger skeletal through the L-type voltage-gated Ca channel (CaV1.1) to trigger 2+ muscle EC coupling provide a relevant experimental model for testing activation of RyR1 and SR Ca release. Rather, CaV1.1 and RyR1 whether non-coplanar PCBs can impair the fidelity of this otherwise physically interact such that four CaV1.1 subunits in the T-tubule tight form of conformational coupling between two Ca2+ channels. membrane orient over every second RyR1 anchored to the junctional SR. The amplitude of Ca2+ transients in mouse embryonic myotubes This structural arrangement engages a form of bidirectional signaling in elicited by low frequency (0.1 Hz) electrical pulses was significantly which T-tubule depolarization is sensed by the S4 segment of CaV1.1 and enhanced within 2.5 min after initiating perfusion of 5 µM PCB 95 in transmitted to RyR1 through conformational shifts of the “critical the external medium compared to the solvent control, and PCB 95 domain” (residues 720–765 of CaV1.1) residing within the cytoplasmic prevented recovery of the Ca2+ signal to its original baseline (Fig. 5A loop between repeats II and III (Grabner et al., 1999). RyR1 transmits a and B) (Cherednichenko & Pessah, in preparation). When higher retrograde signal to not only enhance L-type Ca2+ entry current (Nakai frequency electrical pulse trains were evoked (2.5 and 5 Hz), PCB 95 et al., 1996; Fleig et al., 1996; Sheridan et al., 2006), but also affect 2+ not only amplified Ca transient amplitudes but also caused ectopic precise alignment of CaV1.1 and associated subunits into tetradic arrays Ca2+ transients immediately after electrical stimuli were suspended within the T-tubule membrane (Protasi et al., 1998). In myotubes and (arrows, Fig. 5C), and these were not observed in the absence of PCB. some adult fibers, retrograde signaling from RyR1 to CaV1.1 appears to How non-coplanar PCBs and related structures influence the coupling be essential for preventing decrement and ultimate failure of EC between RyRs and plasmalemmal Ca2+ channels (Fig. 4), and their coupling during prolonged high frequency (tetanic) electrical pulse direct impacts on skeletal and cardiac muscle function clearly needs trains, through a process termed excitation-coupled Ca2+ entry (ECCE) more attention. (Cherednichenko et al., 2004a).

Initial results using pharmacological tools indicated that CaV1.1 2.2.2. Ryanodine receptor associations with plasma membrane proteins was the voltage sensor that triggers ECCE, and that the L-type Ca2+ Over the last 15 years major advances have been made in channel was unlikely to constitute the Ca2+ conduction pathway for understanding how RyR structure relates to function and identifying ECCE. More recent evidence indicates that the L-type channel is a key accessory proteins that regulate activation and inhibition of Ca2+ major contributor to ECCE (Bannister et al., 2009). Pharmacological release from ER/SR stores. Most of our understanding comes from agents that influence conformational states of RyR1 influence studies of RyR1 in skeletal muscle and RyR2 in cardiac muscle where electrophysiological properties of the L-type Ca2+ current and ECCE they assemble in macromolecular complexes termed Ca2+ release units in similar ways. For example, experimental conditions that permit the (CRUs). The central component of the CRU is the RyR homotetramer, alkaloid ryanodine to lock RyR1 channels in a persistently closed (non- conducting) conformation (Zimanyi et al., 1992) also causes signifi-

cant reduction in the inter-tetrad distances of the CaV1.1 complex (Paolini et al., 2004)andinfluences the activation–deactivation kinetics of ECCE (Cherednichenko et al., 2004a; Bannister et al., 2009). Importantly, missense that affect RyR1 function can dramatically alter the properties of both orthograde and retrograde signaling, modifying channel functions on both side of the junction (Hurne et al., 2005; Yang et al., 2007a; Cherednichenko et al., 2008; Andronache et al., 2009; Bannister et al., 2009). In contrast to skeletal muscle, conformational coupling between L- 2+ type Ca channels (CaV1.2) and RyR2 is not sufficient to trigger EC coupling in the absence of Ca2+ entry across the T-tubular membrane in cardiomyocytes. Rather tight functional coupling between L-type 2+ Ca entry mediated by CaV1.2 channels within the T-tubule membrane and RyR2s occurs across narrow 12 nm junctions through the process of Ca2+-induced Ca2+ release (CICR) (Bers, 2008).

Depolarization of the T-tubule membrane triggers CaV1.2-mediated localized Ca2+ influx (termed sparklets) that in turn triggers RyR2- mediated sparks immediately across the junctional space. Depending on the intensity of stimuli arriving at the T-tubule membrane and other local “environmental” factors that influence RyR2 activity (e.g., phosphorylation state), summation of sparks can produce local and propagated Ca2+waves through the process of CICR (Cheng & Lederer, 2008).

In addition to interactions with voltage-gated channels (CaV1.1 and fi CaV1.2) as described above, RyRs have been shown to directly or Fig. 5. Skeletal myotubes acutely exposed to 5 µM PCB 95 exhibited signi cantly higher 2+ Ca2+ transient amplitudes evoked by low frequency (0.1 Hz) electrical pulse trains indirectly interact with and regulate the function of store-operated Ca (A&B;pb0.05) and a failure to recover their original baseline (i.e., resting Ca2+ level) channels (SOCCs) in some, but not all muscle tissues examined. For compared to the corresponding control period when solvent (DMSO) alone was example, the transient receptor protein channels TrpC3 (Kiselyov et al., perfused (Ctrl). (C) Responses to 10 s electrical pulse trains of 2.5 or 5 Hz resulted in 2000; Lee et al., 2006a; Woo et al., 2009), TrpM4 (Morita et al., 2007), significantly higher transient amplitudes compared to the corresponding control (Ctrl) and TrpV4 (Earley et al., 2005) were shown to interact with RyR period. Ectopic Ca2+ transients (red arrows) are frequently observed soon after – electrical stimuli ceased in the PCB-exposed myotubes and were not observed in complexes. However, Trp RyR interactions may not be the major 2+ control. Adapted from (Cherednichenko, in preparation). mechanism responsible for store-operated Ca entry (SOCE) in skeletal 266 I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285 muscle. Knockdown of STIM and Orai, the essential components of the et al., 2003). Since the first report that FKBP12 stabilizes the functional 2+ 2+ Ca -release activated Ca current (ICRAC), greatly suppresses SOCE in behavior of RyR1 (Brillantes et al., 1994), disruption of FKBP12/12.6 RyR skeletal muscle cells without impairing ECCE (Lyfenko & Dirksen, 2008), complexes has been associated with heritable and acquired disorders of and SOCE is not dependent on RyR1 expression (Cherednichenko et al., cardiac (Zalk et al., 2007; Gyorke & Carnes, 2008)andskeletal(Bellinger 2004a; Lyfenko & Dirksen, 2008). However, STIM was recently shown to et al., 2008; Bellinger et al., 2009)muscle. gate TrpC channels by electrostatic interaction (Zeng et al., 2008). PCB-triggered Ca2+ release from junctional SR membrane vesicles Homer is a family of proteins shown to regulate signal transduc- isolated from skeletal muscle can be selectively negated by pretreat- tion, synaptogenesis, and receptor trafficking in neurons (Xiao et al., ment with either the immunosuppressive drug FK506 or rapamycin 2000; Szumlinski et al., 2006). Both short and long forms of Homer (Fig. 6B) without inhibiting responses to other RyR1 channel activators interact with RyR1 and RyR2 and regulate channel function in an such as caffeine (Wong & Pessah, 1997). FK506 and rapamycin tightly additive biphasic manner that is highly dependent on their relative bind to the greasy binding pocket of FKBP12 promoting dissociation of concentration, but is independent of multimerization via the coiled- the FKBP12/RyR1 complex and possibly preventing rebinding. Rapa- coil domains found in Homer long forms (Feng et al., 2002; Ward mycin and FK506 interfere with the actions of PCB 95 (and other active et al., 2004; Feng et al., 2008; Pouliquin et al., 2009). As demonstrated PCBs) in the same concentration range that promotes the dissociation earlier in neurons where Homer links IP3R responses to mGluR1 of the FKBP12/RyR1 complex, suggesting that PCBs interact with a signaling, Homer may also play a scaffolding function in striated binding site formed at the FKBP12/RyR1 complex interface to enhance muscle linking RyR1 and RyR2 to CaV1.1 or CaV1.2, respectively, to channel open probability (Fig. 6A). However, an allosteric mechanism regulate the gain of EC coupling (Huang et al., 2007; Pouliquin et al., has not been ruled out. 2009). In skeletal muscle, Homer appears to also link TrpC channels to Nevertheless, the molecular mechanism by which PCB 95 affects the the cytoskeletal matrix and function to regulate mechanotransduction RyR1/FKBP12 is mediated by direct stabilization of the channel in the full (Stiber et al., 2008). open state (Fig. 7). Samso and coworkers (2009) recently utilized PCB 95 Three important consequences of co-localization and functional to better understand the basis for RyR1 conformational transitions coupling of RyRs with Ca2+ channels residing in the surface between closed and open states. Single-channel biophysical character- membrane include: (1) it permits local signaling microdomains; (2) ization of the two states in bilayer lipid membranes (Fig. 7,leftand it confers a mechanism for reciprocal regulation between channels in middle panels) and cryoelectron microscopy of frozen single-particles the plasma membrane and RyRs anchored within the SR/ER in their hydrated state (Fig. 7 right panel) were performed on identical membrane; and (3) it provides direct feedback about the state of samples and conditions to permit direct correspondence between Ca2+ filling within the SR/ER lumen. Thus chemical agents that biophysical state and structural conformation of the channel. PCB 95 interact with RyR and alter its conformation and function are likely to appears to invert the thermodynamic stability of the RyR1/FKBP12 influence not only the properties of Ca2+ release from stores, but also channel complex producing extremely long-lived openings inter- Ca2+ entry through SOCE and ECCE mechanisms. spersed with extremely short-lived transitions to the closed state, although the unitary current is indistinguishable from the native open 2.2.3. Ryanodine receptor associations with cytoplasmic proteins state. By contrast, the presence of very low Ca2+ on the cytoplasmic side Two T-cell immunophilins, FK506 binding protein 12 kDa (FKBP12) (pCa2+b108 set in the presence of the Ca2+ chelator EGTA) after fusion and its isoform FKBP12.6 (also referred to as calstabins 1 and 2) can of an actively gating channel completely stabilized the fully closed state tightly bind to RyR1 (Jayaraman et al., 1992) and RyR2 (Timerman et al., of the channel. The corresponding three-dimensional structures at 1996). Although up to four FKBPs can bind per functional RyR channel ∼10 Å resolution provided information about the structure surrounding (one per subunit), the ratio of FKBP isoform/RyR is likely to vary the ion pathway indicating the presence of two right-handed bundles according to tissue and with changing physiological or pathophysio- emerging from the putative ion gate (the cytoplasmic “inner branches” logical states (Zalk et al., 2007; Lehnart, 2007). Cryo-electron micros- and the transmembrane “inner helices”)(Samso et al., 2009). The PCB copy (EM) reconstruction of frozen hydrated RyR1 tetramers revealed 95 modified state causes a precise relocation of the inner helices and that FKBP12 binds adjacent to cytoplasmic domain 9 of the clamp region inner branches resulting in an ∼4 Å increase in diameter of the ion gate complex (Wagenknecht et al., 1997; Samso et al., 2006; Serysheva et al., (Fig. 7, right panel). Six of the identifiable transmembrane segments of 2008)(Fig. 6A, top view of cytoplasmic “foot” domain). Mutagenesis RyR1 have similar organization to those of the mammalian Kv1.2 studies with RyR1 suggest essential contributions of Val-2461-Pro-2462 . Upon gating to the PCB 95-induced open state, the (corresponding RyR2 residues Ile-2427-Pro-2428) in the binding distal cytoplasmic domains move towards the transmembrane domain interaction (Gaburjakova et al., 2001), but the N-terminal residues while the central cytoplasmic domains move away from it, and also 305-1937 of RyR2 may also contribute to binding FKBP12.6 (Masumiya away from the four-fold axis (Samso et al., 2009).

Fig. 6. (A) 3-D structure of RyR1 in the closed state at 10 Å resolution showing the location of the FKBP12 docking site near domain 9 (adapted from (Samso et al., 2009). (B) PCB 95 triggered Ca2+ release from skeletal junctional SR is inhibited by pre-incubating with rapamycin that disrupts the FKBP12/RyR1 complex (adapted from (Wong & Pessah, 1997). I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285 267

Fig. 7. PCB 95 directly stabilizes the fully open (conducting) conformation of the RyR1/FKBP12 channel complex reconstituted in the bilayer lipid membrane preparation, whereas EGTA fully closes the channel (left and middle panels). Right panels show the corresponding structural shifts calculated from cryoEM reconstruction of single hydrated particles showing the main constrictions along the ion pathway in the closed and open states. The cytosolic constriction (cc) relaxes and the inner branches (ib) become more separated in the open state. Adapted from (Samso et al., 2009).

Similar FKBP12/RyR1-dependent Ca2+ release and direct activation dependent manner. Both proteins appear to compete with a common of RyR1 channels have been demonstrated with bastadin-5 (Fig. 8) and conserved site within the clamp domains corresponding to residues bastadin-10, two members of a family of over 20 bromotyrosine- 3614-3643 (Wright et al., 2008). Although ApoCaM can enhance RyR derived macrolactams that have been isolated from the Verongid activity, it is thought that Ca2+-CaM provides the major physiological marine sponges Ianthella sp. (Mack et al., 1994; Chen et al., 1999). Like regulatory role, inhibiting RyR channel activity as local Ca2+ concen- PCB 95, bastadin-10 (B10) dramatically stabilizes the open conforma- tration rises (Meissner, 2002). By contrast, Ca2+-S100A1 stimulates RyR tion of the RyR1 channel, possibly by reducing the free energy channel activity. Competition between Ca2+-CaM and Ca2+-S100A1 on associated with closed to open channel transitions. The stability of the RyRs has been proposed to confer tight but dynamic regulation of EC channel open state induced by B10 sensitized the channel to activation coupling gain with temporal changes in local Ca2+ concentration in by Ca2+ to such an extent that it essentially obviated regulation by skeletal and cardiac muscle (Wright et al., 2008). PCB 95 and bastadin-5 physiological concentrations of Ca2+ and relieved inhibition by and 10 were shown to dramatically shift the Ca2+ dependence of RyR1 physiological Mg2+. These actions of B10 were produced only on the channel activation and inhibition independently of exogenously added cytoplasmic face of the channel, were selectively eliminated by CaM or SA1001A (Wong & Pessah, 1996; Chen et al., 1999). Whether pretreatment of channels with FK506 or rapamycin, and were these compounds shift the dynamic regulation mediated through CaM reconstituted by exogenous addition of human recombinant FKBP12. and S100A1 remains to be investigated. Bastadin-10 dramatically enhances spark frequency and duration in The Ca2+ binding protein sorcin and presenilin 2 (PS2) are adult frog skeletal muscle fibers (Gonzalez et al., 2000), whereas ubiquitously expressed in various tissues including neurons and bastadin-5 was shown to influence both resting Ca2+ and caffeine- cardiomyocytes and each has been demonstrated to influence RyR evoked transients in cultured myotubes (Pessah et al., 1997; Yang function. Sorcin interacts with the C-terminal endoproteolytic fragment et al., 2007b). The reduced pharmacophore that confers RyR activity of PS2 in a Ca2+ dependent manner, but not with full-length PS2 (Pack- resides within the ‘eastern’ and ‘western’ non-coplanar bromocatechol Chung et al., 2000), but the interaction may not be essential for ether moieties that resemble hydroxylated brominated dipheny- modulation of RyR. In tissues, PS2 was shown to physically interact lethers defined by the dashed boxes in Fig. 8 (Masuno et al., 2006). with RyR2. Papillary muscle PS2 knockout mice display enhanced peak The widely used antibacterial triclosan, a non-coplanar chloroca- amplitudes of Ca2+ transients and peak tension compared to wild type techol ether (Fig. 8), was shown to activate RyR1 and mobilize Ca2+ (Takeda et al., 2005). Sorcin inhibits Ca2+ channel activity and atten- from SR stores of intact primary skeletal myotubes (Ahn et al., 2008). uates spark activity and was proposed to contribute a physiological Both non-coplanar PCBs and bastadins also enhance RyR2 activity means for terminating Ca2+ induced Ca2+ release in cardiac muscle although the requirement for FKBP12.6 has not been reported. (Farrell et al., 2003; Stern & Cheng, 2004; Farrell et al., 2004). Calmodulin (CaM) and S100A1 are two widely expressed Ca2+ At least three Ser residues within the junctional foot assembly of binding proteins that interact with RyR1 and RyR2 isoforms in a Ca2+- RyR1 (Ser 2844) and RyR2 (Ser 2808, Ser 2814, Ser 2030), can be 268 I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285

Fig. 8. Bastadin 5 showing “eastern” and “western” dibromocatechol ethers (red boxes) that are the putative pharmacophores for RyR1. The structure of the antibacterial triclosan is shown in the lower right. phosphorylated by PKA (Wehrens et al., 2006; Aydin et al., 2008), Ca2+- with functional impairments in cardiac RyR2 channels in the CaM II (Currie et al., 2004; Huke & Bers, 2008) and possibly PKC streptozotocin-induced model of type 1 diabetes (Shao et al., 2009). (Takasago et al., 1991). Evidence that the scaffolding protein mAKAP Several enzymes and proteins involved in regulating cellular redox tethers PKA in close proximity to protein phosphatase A1 and A2 (PPA1 status have been also demonstrated to directly regulate RyR channel and PPA2) within the RyR2 complex, possibly through a leucine/ activity. The mu isoform of glutathione-s-transferase (GST mu) was isoleucine zipper (LIZ) motif, suggests tight regulation of RyR2 shown to promote inactivation of RyR1 and RyR2, whereas its distant phosphorylation in response to changes in cellular cAMP, such as relative CLIC-2 that functions as a appears to those that normally occur with β-adrenergic stimulation (Marx et al., selectively attenuate the activity of RyR2 in the presence of a GSH: 2001; Marks et al., 2002). However, RyR phosphorylation is complex in GSSG redox buffer (Abdellatif et al., 2007; Jalilian et al., 2008; Meng both striated muscle and neurons, and appears to be dynamically et al., 2009). Selenoprotein N (SepN) is physically associated with regulated with shifting physiological and pathophysiological states RyR1 of skeletal muscle and it appears to be essential for conferring (Zalk et al., 2007; Dai et al., 2009). regulation of RyR1 channels by GSH:GSSG redox potential (Jurynec Altered patterns of RyR phosphorylation are associated with et al., 2008). Importantly the absence of SepN in skeletal muscle changes in RyR nitrosylation, glutathionylation, and depletion of appears to contribute to a subset of congenital myopathies and altered FKBP12/12.6 from its binding site located within the clamp region. redox regulation of RyR1 has been implicated in their etiology. Importantly these changes have been strongly implicated in the NAD(P)H oxidases are major sources of superoxide generation in etiology of several heritable and acquired disorders of striated muscle, myocytes, especially during and after acute myocardial including susceptibility (MHS) and central infarction. For example tachycardia augments the association of the core disease (CCD) (Durham et al., 2008), Duchenne muscular NAD(P)H oxidase cytosolic subunit p47phox to the SR fraction, dystrophy (Bellinger et al., 2009), catecholaminergic polymorphic without modifying the content of the membrane integral subunit (CPVT), arrhythmogenic right ventricular gp91phox (Sanchez et al., 2005). The enzymatic oxidation of NADH is dysplasia type 2 (ARVD2), and ischemic heart failure (Blayney & Lai, tightly linked with negative regulation of RyR2 channel activity in 2009). Over 120 missense or deletion mutations within RyR1 have cardiac myocytes. Inhibition of NADH oxidase activity with nanomolar been associated with MHS, (CCD) and/or rotenone or pyribaben relieves this negative regulation and increases multiminicore disease (MmD) in skeletal muscle (Robinson et al., RyR2 channel activity, spark frequency, and Ca2+ oscillations in 2006). Nearly 25 mutations have been identified within RyR2 that cardiomyocytes (Cherednichenko et al., 2004b). contribute to CPVT (Gyorke, 2009; Liu et al., 2009b). Significant RyRs are emerging as a central integrator of not only physiological increases in RyR Ser phosphorylation and Cys nitrosylation have been signals, but also of pathophysiological responses to oxidative stress that associated with an increased Ca2+ leak through RyR channels carrying may arise from mutations in the RyR proteins themselves, their a few of these mutations and these can markedly reduce the Ca2+ accessory proteins, metabolic imbalances, or insults from xenobiotic content of the ER/SR lumen. RyR mutations also alter the fidelity of chemicals such as PCBs. Whether RyR-active PCBs and related non- ECCE (Yang et al., 2007a; Cherednichenko et al., 2008) perhaps further coplanar structures influence the phosphorylation, nitrosylation, and/or compounding SR Ca2+ depletion. Whether hyper-phosphorylation, glutathionylation state of the receptor complex has not been explored. nitrosylation, and/or glutathionylation of RyRs with mutations are common convergence points of CRU dysfunction and progression of 2.2.4. Ryanodine receptor associations with these diverse disorders is currently being intensely investigated. Of integral and luminal proteins relevance to the toxicity of PCBs and related chemicals that alter the Within the junctional SR sacks of cardiac and skeletal muscle, RyRs function of RyRs, it should be noted that RyR mutations may remain form a protein complex with and junctin (which are anchored phenotypically silent or subclinical until triggered by one or more within the membrane), and that resides within the SR environmental exposures or stressors. Recently, changes in the lumen (Liu & Pessah, 1994; Guo et al., 1996). Ultrastructural and phosphorylation state (at Ser 2808 and Ser 2814) were associated biochemical evidence supports a model in which triadin and junctin I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285 269 interact directly with RyRs and may act to scaffold calsequestrin (a low through RyRs, and is triggered by NMDA receptor-mediated Ca2+ affinity SR Ca2+ binding protein) near the RyR lumen to control the influx. Junctophilins stabilize close apposition of “junctional” postsyn- availability of Ca2+ near RyRs thereby providing luminal control aptic membranes that permit crosstalk between RyRs and their (feedback) to the CRU about the local filling state of the Ca2+ store signaling partners in the plasma membrane. These observations reveal (Beard et al., 2009). Ablation of either triadin or calsequestrin the essential role of RyRs in mediating changes in synaptic plasticity expression in the heart results in ventricular (Chopra (Kakizawa et al., 2008). These newly discovered mechanisms might be et al., 2007, 2009). Both PCBs and bastadins were shown to influence directly relevant to how PCBs mediate neurotoxicity. the balance of regulated RyR1 channels (i.e., those sensitive to ryanodine) and their ryanodine-insensitive “leak” states in isolated 2.3. Structure–activity of polychlorinated biphenyls toward RyR1 and RyR2 SR and BC3H1 cells, possibly by converting low conductance leak states into high conductance channel states (Wong & Pessah, 1997; Non-coplanar PCBs were shown to potently and selectively Pessah et al., 1997). More recently, bastadin 5's ability to convert sensitize both RyR1 and RyR2 channel activities in studies with SR ryanodine-insensitive Ca2+ leak to ryanodine-sensitive channels was membranes isolated from mammalian skeletal and cardiac muscle, shown to lower resting free Ca2+ in intact myotubes expressing wild respectively, using radioligand binding studies with [3H]ryanodine type RyR1 and those expressing MH susceptibility mutations, but only ([3H]Ry) and macroscopic Ca2+ flux measurements across isolated SR in the presence of RyR1 channel blockers (ryanodine or FLA 365) (Yang membrane vesicles (Wong & Pessah, 1996). [3H]Ry binds to RyR1 with et al., 2007b). In this regard, myotubes with MH mutations have high selectivity and specificity only to an activated conformation of significantly higher resting intracellular Ca2+ levels than those RyRs, thereby providing a rapid and quantitative method for screening expressing wild type RyR1, and the reductions afforded by bastadin chemicals that enhance or inhibit channel activity (Pessah et al., 1985; 5 in the presence of ryanodine are significantly greater (Fig. 9). Pessah et al., 1987). Fig. 10 (left panel) highlights two important Junctophilins are integral ER/SR proteins that form non-covalent aspects of the PCB structure–activity relationship towards RyR1: (1) interactions with membrane lipids through their MORN (membrane chlorine substitutions at the ortho-positions which restrict the occupation recognition nexus) motifs, and are primarily responsible for biphenyl rings to non-coplanarity; and (2) the contribution of para- stabilizing close apposition of the junctional regions SR/ER and the substituents which can reduce or eliminate activity. For example PCB plasmalemma in both muscle cells and neurons (Takeshima et al., 2000; 126, one of the most potent PCB congeners toward the arylhydro- Kakizawa et al., 2008). Junctophilins are therefore essential for creating carbon hydroxylase (Ah) receptor, lacks activity toward RyR1 at its a specialized milieu that permits the large junctional foot assembly of solubility limits. In general, PCBs lacking at least one ortho-substitution RyRs to physically and functionally interact with proteins in the plasma are inactive toward RyR1 and RyR2, regardless of the degree of membrane. The importance of proper assembly of junctional assembly chlorination. A similar structure–activity profile applies for activation has been recently underscored in mice with targeted deletions or of RyR2 channels isolated from cardiac muscle (Wong & Pessah, 1996), mutations in junctophilins. Deletion of junctophilin isoform 1 (JP1), the ER preparations isolated from adult cerebellum, hippocampus or major form expressed in skeletal muscle, results in weak EC coupling cortex contain all three RyR isoforms, although RyR1 and RyR2 and contractile failure that is lethal shortly after birth (Ito et al., 2001). predominate (Wong et al., 1997a). Of the congeners assayed on ER The lack of JP1 may also negate critical aspects of channel regulation preparations from , non-coplanar PCB 95 exhibited the highest because JP1 and RyR1 interact in a conformationally sensitive manner potency toward activating high-affinity [3H]Ry binding, whereas that involves hyper-reactive Cys residues (Phimister et al., 2007). mono-ortho PCB 66 (2,3,4,4′-tetrachlorobiphenyl) and PCB 126 were Deletion of junctophilin isoform 2 (JP2), the major form in cardiac inactive. Ca2+ transport measurements made with cortical ER vesicles muscle functionally uncouples CaV1.2 and RyR2 and is embryonic lethal revealed that PCB 95 discriminates between inositol 1,4,5-trispho- due to contractile failure, whereas 5 missense mutations are associated sphate- and ryanodine-sensitive stores, and PCB 95 induced Ca2+ was with hypertrophic cardiomyopathy in humans (Matsushita et al., 2007; dose-dependent and completely inhibited by ryanodine receptor Landstrom et al., 2007). blockers (Wong et al., 1997a). Mice lacking neural junctophilins (JP3 and JP4) exhibit impaired A more detailed structure–activity analysis was completed with exploratory behavior in the open-field task, and impaired performance RyR1. Fig. 2 shows a ranking of the 28 most active congeners of 35 in the Y-maze and multiple-trial passive avoidance tests indicating tested based on the concentration required to double [3H]Ry binding impaired short- and long-term memory (Moriguchi et al., 2006). activity to RyR1 (Pessah et al., 2006). Many of these are found in Ablation of JP3 and JP4 uncouples functional interactions among environmental and human samples and collectively they can NMDA receptors, ryanodine receptors, and small-conductance Ca2+- comprise up to 50% of the total PCB burden. PCB 95 and PCB 136 activated K+ channels activation. These results reveal that activation of (2,2′,3,3′,6,6′-hexachlorobiphenyl) share asymmetric chlorine sub- small-conductance Ca2+-activated K+ channels, which is necessary for stitutions on the phenyl rings (2,3,6 and 2′,3′,6′ for PCB 136 vs. 2, 5 afterhyperpolarization in hippocampal neurons, requires Ca2+ release and 2′,5′ for PCB95) and both are racemic mixtures of two atropisomers (see below). The 2′,5′-Cl configuration of PCB 95 is equivalent to a 3′6′-Cl configuration of PCB 136 (i.e. 2,3,6,2′,5′ vs. 2,3,6,3′,6′) assuming a calculated dihedral angle of ∼90° based on the crystal solution of PCB 84 (Lehmler et al., 2005b). The 2,3,6-Cl configuration on one ring with ortho, meta on the other is optimal for recognizing a binding site within the RyR1 complex and for sensitizing channel activation. Para-chloro substitution lowers the maximum efficacy towards RyR1 regardless of the presence of one or more ortho-substitutions. Comparing the relative activities of PCB 30 and PCB 75 (2,4,6,4′-tetrachlorobiphenyl), the additional para-Cl-substi- tution completely eliminates activity towards RyR1. Thus complete lack of activity observed here with PCB 75 is likely due to the di-para- chloro substitution. In general, PCB structures possessing 4,4′-Cl Fig. 9. Bastadin 5 in the presence of a ryanodine concentration that blocks RyR1 exhibit lower activity towards RyR1, regardless of the presence of one channels reduces resting Ca2+ to a greater extent in cells expressing missense mutations that confer MH susceptibility to humans than in cell expressing wild type or more ortho-substitutions (Pessah et al., 2006). Hydroxylated PCBs RyR1 (Wt). ⁎pb0.05 adapted from (Yang et al., 2007a, b). are appearing in human tissues and there is currently great interest in 270 I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285

Fig. 10. Dose–response relationship of selected PCBs towards enhancing the binding of [3H]Ry to RyR1 showing the importance of ortho-substitutions (non-coplanarity (left panel) and substitutions at the para position. determining whether these metabolites are more biologically active Ca2+ stores by activating RyR1 in the presence of low (resting) levels of than the corresponding parent structures (Fernandez et al., 2008; Park cytoplasmic Ca2+, and (+) PCB 136 failed to competitively inhibit the et al., 2008a,b; Park et al., 2009; Liu et al., 2009a). The 4-OH derivative actions of (-) PCB 136. The mechanism by which (−) PCB 136 promotes of PCB 30 (4′OH-PCB 30) was found to be significantly more active RyR activity is to coordinately stabilize the open, while destabilizing the toward RyR1 than the parent PCB 30 (2,4,6-Cl) (Fig. 10, right panel). closed states of the RyR1 channel. Thus a para-OH group on the phenyl ring that carries no other The enantiospecificity of (−) PCB 136 indicates that the spatial deactivating substitution confers potency and efficacy towards configuration of the chlorine substitutions about the biphenyl is signifi- activating RyR1. Two possible mechanisms could be responsible. cantly more important than the overall physicochemical properties of First, the acidic property of the lone phenyl-OH substituent is likely to the PCB for optimizing interactions with RyRs and implies a highly contribute hydrogen-bonding potential to stabilize interactions with ordered binding interaction between active PCBs and their site(s) of the receptor site. Alternatively, if the hydroxyl group is partially or interaction within RyR complexes. It is interesting to note that the four wholly ionized, then electrostatic interactions would be expected to most active PCBs toward RyR thus far tested are chiral (Figs. 2 and 11) stabilize the PCB-RyR1 complex. In support of this interpretation, the although the degree of enantiospecificity toward sensitizing RyR activity di-OH derivative of PCB30, 3′,4′-di-OH,2,4,6-PCB, was found to possess may vary (Lehmler et al., 2005a; Pessah et al., 2009). lower potency but similar efficacy to PCB 30. The presence of two adjacent –OH moieties would be expected to promote intramolecular 2.4. Ryanodine receptors in smooth muscle hydrogen bonding and could preclude stabilizing interactions with RyR1 that impact the apparent affinity and efficacy for channel All three RyR isoforms are expressed in smooth muscle myocytes activation (Pessah et al., 2006). There is an excellent correlation (McGeown, 2004). The patterns of RyR isoform expression and their (r2 =0.87) between the initial rate of PCB-induced Ca2+ efflux and the contribution to smooth muscle contractility differ among specificorgans concentration needed to increase [3H]Ry binding by two fold, a mea- in which they are found including vascular, urinary bladder, ureter, sure of potency (Fig. 11), and PCB-induced Ca2+ release from ER/SR airway and the gastrointestinal track (McGeown, 2004; Cheng & Lederer, membrane without inhibiting the SR/ER Ca2+-ATPase (SERCA pump). Moreover, the release can be completely inhibited by prior block of RyR channels with ryanodine or , suggesting that a selective receptor-mediated mechanism is responsible.

2.3.1. Enatioselectivity of chiral polychlorinated biphenyls toward ryanodine receptors Nineteen of the possible 209 polychlorinated biphenyl (PCB) structures exist as pairs of atropisomers (also referred to as enantio- mers) that are sufficiently stable to permit separation by gas or liquid chromatography using chiral column matrices (Haglund, 1996). Stable enantiomeric PCB structures have unsymmetrical chlorine substitutions in their respective phenyl rings and possess ≥3 chlorine atoms in the ortho-positions that restrict the degree of rotation about the biphenyl bond. Evidence of enantioselective enrichment of PCB atropisomers in environmental samples (Pessah, 2001; Wong et al., 2001a, 2004; Robson & Harrad, 2004; Asher et al., 2007; Jamshidi et al., 2007; Wong et al., 2007), food (Bordajandi et al., 2005; Bordajandi et al., 2008; Bordajandi & Gonzalez, 2008), as well as biological tissues from animals (Chu et al., 2003b; Kania-Korwel et al., 2007, 2008a,b) and humans (Chu et al., 2003a; Harrad et al., 2006) are being widely reported. Fig. 11. Correlation between the PCB concentration needed to double [3H]Ry binding to Recently (−) PCB 136 was shown to directly sensitize activation of RyR1 RyR1 and the initial rate of PCB-induced Ca2+ efflux from SR vesicles (data for each and RyR2, whereas (+) PCB 136 did not when assayed at either 25 or congener were normalized to respective parameters obtained with PCB 95). BZ 37 °C (Pessah et al., 2009)(Fig. 12). (−) PCB 136 rapidly mobilized SR numbers are given, Adapted from (Pessah et al., 2006). I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285 271

Fig. 12. (A) PCB 136 is chiral because the asymmetric distribution of chlorines prevents interconversion of its (+) and (-) atropisomers. Upon separation, (-) PCB 136 was found to be active towards enhancing the activity of RyR1 (B) and RyR2 (C), whereas (+) PCB 136 was not active. Adapted from (Pessah et al., 2009).

2008). RyRs also localize to regions of SR that are in close proximity to MAPK-mediated phosphorylation of 43 that resulted in (≤100 nm) to the plasma membrane of a variety of smooth muscle inhibition of myometrial gap junctions. However, additional studies myocytes where they are responsible for generating spontaneous and revealed that antioxidants could reverse the inhibitory influence of depolarization evoked CICR (Lesh et al., 1998; Gollasch et al., 1998). The PCB on contraction and synchronicity without restoring patterns of expression of RyR isoforms are highly dependent on the type function (Chung & Caruso, 2006), suggesting other mechanisms are of smooth muscle and multiple isoforms can be expressed within a involved. Paradoxically, complex PCB mixtures significantly stimulat- smooth (Chalmers et al., 2007). For example, recent RT-PCR ed uterine contraction frequency with the least chlorinated mixture, results have indicated that RyR2 and RyR3 are expressed in cultured Aroclor 1242, being most potent. The actions of micromolar Aroclor myocytes from rat mesenteric artery (Berra-Romani et al., 2008)orvas 1242 on uterine smooth muscle contractility seem at least in part deferens (Ohno et al., 2009), although the ratio of the two isoforms can mediated by enhanced Ca2+ entry through a nifedipine-sensitive change with proliferation. In contrast, uterine smooth muscle expresses pathway (Bae et al., 1999b; Wrobel et al., 2005). Aroclor 1260 did not two splice variants of RyR3 that are differentially expressed in exhibit significant effects on rat uterine strips in vitro (Bae et al., 2001; nonpregnant and pregnant myometrium, although their functional Tsuneta et al., 2008). However subsequent to microbial metabolism, a significance has been recently questioned (Noble et al., 2009). It appears partially dechlorinated mixture dominated by ortho-substituted PCBs that expression of a functional long form of RyR3 is responsive to caffeine with ≤4 chlorines substituents increased uterine contraction fre- and cADP ribose, whereas expression of a non-functional short form can quency over 7-fold. Exposure of bovine myometrial cells to A1248 inhibit the function of the long form when they are concomitantly initially increased the spontaneous force of contractions but with expressed (Dabertrand et al., 2007). At the end of pregnancy, the relative longer exposures (≥24 h) was inhibitory (Wrobel et al., 2005). Non- expression of RyR3 long form appears to increase suggesting physiolog- coplanar PCB-153 (2,2′,4,4′,5,5′-hexachlorobiphenyl) increased the ical regulation of RyR3 alternative splicing may be important in spontaneous and oxytocin-evoked frequency of myometrial contrac- regulating uterine contractility at the end of pregnancy. tions, and these effects were greater in cells isolated before than after In smooth muscle that undergoes driven phasic ovulation. On the other hand, PCB 153 delayed or inhibited oxytocin- contraction (e.g., smooth muscle of the uterer), the periodicity of Ca2+ stimulated rise in intracellular Ca2+ concentration without altering sparks appear to be functionally coupled to pacemaker ionic currents cell viability (Wrobel et al., 2005; Wrobel & Kotwica, 2005). Ortho- that, collectively, set the rhythm of the firing of action potentials (Wang substituted PCBs and their metabolites were found to reduce et al., 2002; Burdyga & Wray, 2005; Wray et al., 2005). By contrast, RyRs proliferation of myometrial cells originating from pregnant women expressed in arterial and urinary bladder smooth muscles are co- exposed in vitro (Bredhult et al., 2007). localized with and tightly coupled to large conductance Ca2+-activated The mechanisms responsible for the seemingly paradoxical effects potassium channels (BKCa) that mediate spontaneous outward currents of PCBs on uterine smooth muscle contractility (decreased contractil- (STOCs) (Nelson et al., 1995; Jaggar et al., 1998; Perez et al., 1999; ity produced by PCB 4 vs. enhanced contractility induced by an ortho- Herrera & Nelson, 2002). Voltage-activated Ca2+ entry into arterial rich mixtures and PCB153) are currently not understood. Collectively smooth muscle is primarily responsible for enhancing tone. However, an these results suggest that non-coplanar PCBs, especially lightly important consequence of the co-localization and tight functional chlorinated congeners, are most active toward altering myometrial 2+ coupling between RyRs and BKCa is that activation of sub-plasmalemmal contractility through a mechanism involving altered Ca signaling. RyR-mediated Ca2+-induced Ca2+ release efficiently enhances STOCs thereby hyperpolarizing the surface membrane and shutting off 2.5. Polychlorinated biphenyl developmental neurotoxicity voltage-dependent Ca2+ entry (Nelson et al., 1995). Therefore, activation of RyRs plays a pivotal physiological role in arterial smooth 2.5.1. Ryanodine receptors in the nervous system muscle relaxation and the abnormal RyR-BKCa coupling has been shown Neurons have an extensive ER membrane system that extends to cause hypertension and left ventricular hypertrophy (Pluger et al., deep into the soma to envelope the nucleus and out into proximal 2000; Brenner et al., 2000; Amberg et al., 2003). regions of the dendrites and axon. Specialized regions of the ER closely appose the plasma membrane and are present in more distal aspects 2.4.1. Cellular toxicity of polychlorinated biphenyls to smooth muscle of the such as growth cones, axon terminals and dendritic Exposure of uterine smooth muscle cells isolated from gestation spines. As in non-neuronal cells, Ca2+ release from neuronal ER stores day 10–pregnant rats to non-coplanar PCB 4 (2,2′-dichlorobiphenyl) can be evoked by stimulation of RyRs or IP3Rs, and both receptor types was shown to inhibit contractility and synchronization (Chung & Loch can couple to the activation of neurotransmitter-gated receptors Caruso, 2005). These effects on contractility were initially attributed and voltage-gated Ca2+ channels on the plasma membrane. This 272 I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285 organization enables the ER to function not only as a buffer and source immunoreactivity was detected in all hippocampal subfields but was of Ca2+ in axonal and somatodendritic compartments but to also stronger in CA1 than CA3. Intense RyR3 immunoreactivity was detected discriminate between different types of neuronal activity and inte- along the dentate gyrus/hilus border and within the hilus. grate Ca2+-dependent signaling between the plasma membrane, RyR expression has also been documented in non-neuronal cells of cytosol and nucleus (Berridge, 2006; Bardo et al., 2006). Ca2+ spark- the CNS. Diffuse staining of the hippocampal neuropil indicates that like events arising from both RyRs and IP3Rs in nerve growth factor- RyR3 is expressed in astrocytic processes (Matyash et al., 2002), and differentiated PC12 cells and cultured hippocampal neurons exhibit separate studies of cultured glial cells derived from rodent brain different kinetic properties than their counterparts found in cardiac confirmed RyR expression in not only astrocytes (Matyash et al., 2002; muscle, with greater spatial width and significantly longer duration Straub & Nelson, 2007) but also oligodendrocytes (Haak et al., 2001; (Koizumi et al., 1999a,b). Long lasting local Ca2+ signals spreading Weerth et al., 2007). These studies further indicated that astrocytes several microns, called “syntillas” have been measured within (Matyash et al., 2002) and oligodendrocyte progenitors (Haak et al., presynaptic terminals of basket cells of the cerebellum (Collin et al., 2001) express RyR3 but not RyR1 or RyR2. In oligodendrocyte 2005), and in peptidergic terminals of murine hypothalamic neurons progenitor, RyR3 and IP3R type 2 were shown to have a differential and neuroendocrine (chromaffin) cells (De Crescenzo et al., 2004; distribution within their processes that might explain differences in ZhuGe et al., 2006; De Crescenzo et al., 2006). Syntillas observed in local and global Ca2+ signals mediated by these two channel types, hypothalamic neuronal terminals are triggered by membrane depo- and their functional interactions appear to determine the spatial and larization and are restricted near the inner leaflet of the plasma temporal characteristics of Ca2+ signaling in these cells. In contrast, membrane. RyR1s anchored to the ER in very close proximity to human microglia cultured from both fetal and adult brain samples plasmalemmal L-type voltage-dependent Ca2+ channels engage in a express mRNA for RyR1 and RyR2, whereas RyR3 mRNA can be form of voltage-induced Ca2+ release (VICaR) that is similar to muscle detected only in fetal microglial cells. RyR expression has also been EC coupling (De Crescenzo et al., 2006). examined in peripheral nervous system (PNS) neurons. Transcripts High-affinity [3H]ryanodine-binding sites are expressed in rat encoding RyR2 and RyR3 but not RyR1 have been detected in brain microsomal fractions from cerebral cortex, cerebellum, hippo- sympathetic ganglia isolated from adult rats and ganglionic levels of campus and brainstem (Zimanyi & Pessah, 1991) and form caffeine RyR3 but not RyR2 mRNA decline with advanced age (Vanterpool sensitive Ca2+ channels (McPherson et al., 1991). All three RyR et al., 2006). Immunohistochemical studies of dorsal root ganglia isoforms are expressed in the central nervous system (CNS) but are (DRG) revealed immunoreactivity for RyR3 but not RyR1 or RyR2 differentially distributed between specific brain regions, cell types and (Lokuta et al., 2002; Ouyang et al., 2005) in these sensory neurons. subcellular localizations, reflecting their participation in specialized functions. In situ hybridization studies of mouse brain (Mori et al., 2.5.2. Ryanodine receptor-mediated mechanisms in neurodevelopment 2000) indicate that during embryogenesis, RyR1 is predominantly Given that RyRs are expressed in both presynaptic and postsyn- expressed in the rostral cortical plate whereas RyR3 is prominent in aptic sites in virtually all brain areas (Ogawa & Murayama, 1995; the caudal cortical plate and hippocampus. However, from postnatal Nozaki et al., 1999; Hidalgo, 2005) as well as in CNS glial cells and PNS day 7 into adulthood, RyR2 expression is upregulated and RyR3 ex- neurons, it is perhaps not unexpected that experimental evidence pression downregulated so that RyR1 and RyR2 are more highly and indicates that RyRs contribute to fundamentally important aspects of broadly expressed than RyR3. In the postnatal brain, RyR1 expression neuronal excitability and use-dependent synaptic plasticity (Berridge, is most prominent in the dentate gyrus and Purkinje cell layer but this 1998; Korkotian & Segal, 1999; Matus, 2000; Kennedy, 2000; Segal, isoform has also been detected in the caudate/putamen nuclei, olfac- 2001). In axon terminals, RyRs mediate spontaneous, evoked and tory tubercle, olfactory bulb, and cortex. RyR2 is the major isoform facilitated neurotransmission (Liu et al., 2005; Collin et al., 2005; expressed in many brain regions and RyR2 transcripts have been Dunn & Syed, 2006; De Crescenzo et al., 2006; Shimizu et al., 2008) observed in the hippocampus, cerebellum, medial habitual nuclei, and regulate the mobilization and recycling of synaptic vesicles amygdala, cortex and more anterior brain regions including the (Shakiryanova et al., 2007; Levitan, 2008). RyRs localized to the granular cell layer of the olfactory bulb. In the cerebellum, RyR2 mRNA somatodendritic domain influence the intracellular encoding of specifically localized to the granular cell layer. RyR3, which accounts neural activity and are implicated in modulating both neurochemical for about 2% of the total RyR protein in the brain (Murayama & Ogawa, (Berridge, 2006; Bardo et al., 2006) and structural (Segal et al., 2000) 1996), shows distinctive patterns of expression in several structures of aspects of synaptic plasticity. Diverse neurochemical changes associ- mouse brain. RyR3-specific appeared to preferentially stain ated with dendritic synaptic plasticity have been shown to rely on RyR the granular layer in the cerebellum even though the signal intensity function, including: 1) activity-dependent postsynaptic translation was less than RyR2. Immunocytochemical studies have also detected (Jourdi et al., 2009)andsecretion(Kolarow et al., 2007)of RyR3 in the hippocampus and sporadic patterns of RyR3 staining have neurotrophins, 2) modulation of Gq-coupled receptor function by been reported in the thalamus and the caudate/putamen nuclei. stress peptides and (Riegel & Williams, 2008); 3) activity- Detailed in situ hybridization (Furuichi et al., 1994; Giannini et al., dependent enhancement of glutamate responses and the associated 1995; Mori et al., 2000) and immunocytochemical (Hertle & Yeckel, increase of GluR1 within spines mediated by synaptopodin, an actin- 2007) studies of the distribution of RyR isoforms in the hippocampus of binding protein that co-localizes with RyRs within the rodent indicate that RyR1 is enriched in the stratum oriens, of hippocampal neurons (Vlachos et al., 2009); and 4) sequential stratum pyramidale and stratum radiatum of CA1 and CA3 subfields of activation of CaM kinases, CREB and transcription of genes encoding hippocampus. The densest RyR1 immunolabeling localized to the Ca2+-regulated proteins triggered by repetitive or prolonged depo- somata of pyramidal cells within the stratum pyramidale and portions larization of hippocampal neurons (Deisseroth et al., 1998). RyRs of their apical dendrites in the stratum radiatum (Hertle & Yeckel, 2007). similarly function in peripheral neurons to regulate the release of By contrast, RyR1 has relatively lower expression in dentate gyrus. RyR2 (Cong et al., 2004; Ouyang et al., 2005; Huang et al., 2008) and is primarily expressed in the cells of the dentate gyrus and in the stratum response to (Brain et al., 2001; Locknar et al., 2004) neurotransmitters lucidum of CA3 with weaker staining in pyramidal cells in stratum and neuropeptides, and their function underlies the exocytotic release pyramidale and within stratum radiatum of CA1 (Lai et al., 1992; Hertle of glutamate from astrocytes (reviewed in Reyes & Parpura, 2009). & Yeckel, 2007). RyR2 is localized in axons to a greater degree than in Changes in postsynaptic efficacy are also associated with morpholog- dendrites, and is most densely distributed in the hippocampal mossy ical changes in dendritic spines. Pulse application of caffeine, a RyR fiber pathway and in axon bundles traversing the cortical laminae agonist, has been reported to cause a rapid and significant increase in (Seymour-Laurent & Barish, 1995; Hertle & Yeckel, 2007). RyR3 the size of existing dendritic spines in mature cultures of hippocampal I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285 273 neurons and this effect is blocked by antagonizing concentrations the fetal and postnatal brain (White & Barone, 2001). The spatiotem- of ryanodine (Korkotian & Segal, 1999), supporting the involvement poral pattern of apoptosis in the developing CNS is tightly regulated and of RyR in mediating activity-dependent changes in dendritic spine disruption of either the timing or the magnitude of apoptosis in a given morphology. brain region can alter cell number and thus connectivity, causing deficits Consistent with the demonstrated role of RyRs in neurotransmis- in higher order function even in the absence of obvious pathology sion and synaptic plasticity at the cellular level, ligands that directly (Sastry & Rao, 2000; Barone et al., 2000; Martin, 2001). Increased Ca2+ modulate RyR, such as ryanodine, alter functional aspects of neuro- and ROS are significant triggers of apoptosis, and RyR activation a critical plasticity including long-term potentiation (LTP) (Wang et al., 1996) component of apoptotic signaling pathways (Berridge et al., 2000; and long-term depression (LTD) (Wang et al., 1997) in the hippo- Robertson et al., 2001; Carmody & Cotter, 2001; Ermak & Davies, 2002; campus. FK506 and rapamycin, which deregulate RyR2 by dissociating Ravagnan et al., 2002). the RyR2/FKBP12/12.6 complexes also inhibit LTD (Li et al., 1998). RyRs have also been implicated in regulating morphogenetic Thus, RyRs appear to play a critical role in use-dependent plasticity processes in the developing nervous system. Specifically, RyR3 has that underlies the early stages of associative memory. Earlier evidence been shown to be necessary for astrocyte migration (Matyash et al., suggested that RyR2 through its interaction with might also 2002), and for axonal growth cone responses to nitric oxide (Welshhans alter Ca2+ signaling over a longer time frame, implying a critical role & Rehder, 2007) or activation of cell adhesion molecules (Ooashi et al., for RyRs in the consolidation phase of associative memory (Alkon 2005). With respect to the latter, in the presence of RyR3-mediated et al., 1998). Most intriguing is a work showing a tight correlation CICR, growth cones exhibited attractive turning, but in the absence of between acquisition of spatial learning and selective upregulation of RyR3-mediated CICR, Ca2+ signaling elicited growth cone repulsion. RyR2 in the dentate gyrus and CA3 (Cavallaro et al., 1997), implicating The authors suggest on the basis of these observations that the source of RyR2 in storage phases of associative memory (Alkon et al., 1998). Ca2+ influx, rather than its amplitude or the baseline Ca2+ level, is the Additional studies demonstrate that mice with targeted deletion of primary determinant of the direction of axonal growth cone turning. RyR3 have deficits in contextual fear conditioning but improved Based on pharmacological inhibition studies, RyRs have also been spatial learning in the Morris water maze task (Futatsugi et al., 1999; implicated in regulating Ca2+-dependent neurite outgrowth (Arie et al., Kouzu et al., 2000). Interestingly, comprehensive behavioral pheno- 2009) in DRG neurons, a cell type that extends only axons, as well as typing of RyR3 knockout mice revealed decreased social interaction, activity-dependent dendritic growth and retraction in retinal ganglia hyperactivity and mildly impaired prepulse inhibition, whereas no neurons (Lohmann et al., 2002; Lohmann et al., 2005). A generalization measurable impairments in motor function and working and emerging from studies of activity-dependent dendritic growth is that reference memory tests were detected (Matsuo et al., 2009). Ca2+ exerts bimodal effects on dendritic structure. Thus, increased A recent discovery is that RyRs also function as a key element of intracellular Ca2+ has been linked to both dendritic growth and to the output pathway from the molecular circadian clock in neurons of dendritic retraction (reviewed in Redmond et al., 2002; Segal et al., the suprachiasmatic nucleus (SCN). Electrophysiological and calcium 2000; Lohmann & Wong, 2005). Two possibilities have been proposed to mobilization experiments indicate that RyR activation by administra- explain why Ca2+ signaling stimulates dendritic growth in some cases tion of caffeine or 100 nM ryanodine increased the firing frequency of while inhibiting dendritic plasticity in others. First, Segal et al. (2000) SCN neurons, whereas inhibition of RyRs by or 80 μM suggest that moderate and/or transient increases in intracellular Ca2+ ryanodine decreased firing rate, suggesting that RyRs are involved in the cause growth of dendritic branches and spines, whereas large Ca2+ circadian rhythmicity of SCN neurons (Aguilar-Roblero et al., 2007). increases cause destabilization and retraction of these dendritic Subsequent behavioral studies demonstrated that RyR activation structures (Fig. 13). Consistent with this possibility, relatively sustained induced a significant shortening of the endogenous period, whereas increases in intracellular Ca2+ vs. transient changes in Ca2+ influx RyR inhibition disrupted circadian rhythmicity. In both experiments, the activate different Ca2+-dependent signaling pathways with distinct period of rhythmicity returned to basal levels upon cessation of effects on dendrites (Wilson et al., 2000; Redmond et al., 2002). The pharmacological treatment (Mercado et al., 2009). In light of these second possibility is that dendritic responses to Ca2+ differ with studies, it is interesting to note that it had been reported some 25 years neuronal maturation such that early in development, increased Ca2+ earlier that PCBs interfered with rhythmic pituitary–adrenal function in promotes dendritic growth, while later in development, increased Ca2+ rats (Dunn et al., 1983). functions to stabilize dendritic structure (Lohmann & Wong, 2005). Dynamic changes in intracellular Ca2+ concentrations play a crucial While pharmacological manipulation of RyRs has been shown to role in not only neuronal excitability and synaptic plasticity but also in influence activity-dependent dendritic morphogenesis, the specific and differentiation, cell movement, and isoforms associated with any specific effect have yet to be determined. (Cline, 2001; Spitzer et al., 2004; Moody & Bosma, 2005; Zheng & Poo, In addition to regulating neurodevelopment and physiological 2007). Thus, it might be predicted that RyRs function to regulate processes in the central and peripheral nervous system, RyRs are also diverse aspects of neurodevelopment, and emerging evidence sup- implicated in Ca2+ dysregulation associated with cell toxicity, aging ports that prediction. Early reports that RyRs are upregulated during and neurodegeneration (reviewed in Thibault et al., 2007). The model NGF-induced differentiation of adrenal chromaffin cells (Jimenez & that has been proposed is that aging and/or pathological changes Hernandez-Cruz, 2001) suggested the possibility that RyRs mediate occur in both L-type Ca2+ channels and RyRs and these interact to the CICR necessary for neurogenesis and neuronal differentiation. abnormally amplify Ca2+ transients. In turn, the increased transients In support of this hypothesis, it was recently shown that activation of result in dysregulation of multiple Ca2+-dependent processes 2+ L-type Ca channels, GABAA receptors or RyRs promoted neuronal ultimately accelerating functional decline. Diverse pathogenic stimuli, differentiation, while inhibition of these channels/receptors had the including HIV-1 Tat (Norman et al., 2008), amyloid-beta and prion opposite effect on mouse embryonic stem (ES) cells (Yu et al., 2008). peptides (Ferreiro et al., 2008) as well as mutations associated with Moreover, the activity of intracellular Ca2+ signaling, expression of the neurodegeneration such as the presenilin (PS2) (Lee et al., neuronal NeuroD and the rate of neurogenesis were 2006a,b) activate apoptotic or excitotoxic pathways via RyR-depen- significantly inhibited in neuronal cells derived from embryonic stem dent mechanisms that increase intracellular Ca2+ levels in neurons. cells obtained from RyR2 deficient mice relative to wild type controls Consistent with this model, two recent reports confirm a role for 2+ even in the presence of L-type Ca channel and GABAA receptor interactions between presenilins and RyRs in regulating release of activation. Apoptosis is another neurodevelopmental process that is calcium from both presynaptic and postsynaptic ER (Zhang et al., essential to normal brain development (Martin, 2001; Dikranian et al., 2009; Chakroborty et al., 2009). This interaction is perturbed in 3xTg- 2001), occurring in proliferative zones and in postmitotic cells in both AD mice such that RyR-evoked Ca2+ release in CA1 pyramidal neurons 274 I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285

psychological effects from prior exposures. Whether early-life expo- sures to PCBs increase susceptibility to neurodegenerative processes that contribute to dementia and motor deficits is difficult to determine from these studies because the critical exposure period could not be identified. However, several recent studies using experimental animal models support this possibility. The first set of studies utilized a well- established model of focal cerebral ischemia, middle cerebral artery occlusion (MCAO) in rats, to demonstrate that exposure to Aroclor 1254 in the maternal diet throughout gestation and lactation confers neuro- protection against focal ischemic stress in the adult brain (Dziennis et al., 2008). Congener-specific analyses of tissues harvested from adult animals immediately following MCAO indicated no difference in PCB levels between control and PCB-exposed brains, suggesting that PCB effects on stroke outcome may reflect PCB interactions with develop- mental processes. In the second set of studies, developmental PCB exposure was shown to infl uence seizure susceptibility in the weanling Fig. 13. Proposed relationship between intracellular Ca2+ concentration and dendritic and young adult rat. Seizure susceptibility was assessed by quantifying growth. Adapted from (Segal et al., 2000). the threshold for seizures induced by flurothyl (bis-2,2,2-triflurothyl ether), a convulsive drug used to investigate seizure susceptibility in is markedly increased resulting in altered synaptic of rodents (Ferland & Applegate, 1998; Szot et al., 2001) and the response these neurons relative to wild type mice (Chakroborty et al., 2009). to pentylenetetrazole (PTZ), which kindles seizures within 15–20 Interestingly, the RyR2 isoform was found to be selectively increased injections of initially subconvulsive doses in rats (Corda et al., 1991). more than fivefold in the hippocampus of 3xTg-AD mice relative to Exposure to PCB 95 in the maternal diet from gestational day 5 through controls and the authors propose this as the mechanism to explain the weaning on postnatal day 21 significantly decreased seizure thresholds deviant, yet functional evident in presymptomatic in animals challenged with flurothyl on postnatal day 35 and caused 3xTg-AD mice long before the onset of AD histopathology. RyR- faster kindling with PTZ on postnatal days 60–83 (Lein et al., in press). dependent Ca2+ release from presynaptic internal stores is also re- Considered collectively, these studies support the possibility that quired for ethanol to increase spontaneous γ-aminobutyric acid exposure of the developing brain to PCBs may elicit persistent changes release onto cerebellum Purkinje neurons (Kelm et al., 2007), and the in the brain that influence the susceptibility of the adult brain to sub- imbalance between excitatory and inhibitory circuits that underlies sequent stressors. NMDA receptor-mediated epileptiform persistent activity is blocked How developmental PCB exposure causes persistent neuropsycho- by inhibition of the ryanodine receptor (Gao & Goldman-Rakic, 2006). logical impairment in either children or adults has yet to be resolved. These observations support the hypothesis that factors that alter RyR Several lines of evidence suggest mechanisms independent of the AhR. expression and/or function have the potential to interfere with First, congener-specific analyses of brain tissues from human subjects normal neurodevelopment and neuronal function. (Corrigan et al., 1998) and experimental animals (Dziennis et al., 2008; Yang et al., 2009) exhibiting neuropsychological impairment associ- 2.5.3. Experimental evidence of ryanodine ated with exposure to complex PCB mixtures indicate enrichment of receptor-mediated mechanisms of polychlorinated biphenyl neurotoxicity non-coplanar ortho-rich congeners. Second, studies utilizing purified Of the various adverse effects associated with PCBs, developmental congeners have consistently demonstrated developmental neurotox- neurotoxicity has emerged as a particularly vulnerable endpoint icity associated with non-coplanar ortho-rich congeners (Tilson & (NIEHS, 1999; Schantz et al., 2003; Carpenter, 2006). Population- Kodavanti, 1998; Schantz et al., 2003; Kodavanti, 2005; Fonnum et al., based studies have consistently demonstrated that PCBs negatively 2006; Mariussen & Fonnum, 2006). For example, perinatal exposure to impact neuropsychological function in exposed children (Schantz et al., PCB 95 has been shown to persistently alter cognitive and psychomo- 2003; Carpenter, 2006; Korrick & Sagiv, 2008). PCB exposure has been tor activity in rodent models (Schantz et al., 1997) as well as LTP in positively correlated with decreased IQ scores, impaired learning and hippocampal slice cultures (Wong et al., 1997b),and to alter the ratio memory, lower reading comprehension, attentional deficits and of excitatory to inhibitory neurotransmission in the developing psychomotor dysfunction (Chen et al., 1992; Jacobson et al., 1992; auditory cortex (Kenet et al., 2007) and hippocampal slice cultures Koopman-Esseboom et al., 1996; Schantz et al., 2003; Roegge & Schantz, (Kim et al., 2009a). 2006; Grandjean & Landrigan, 2006; Rogan & Ragan, 2007; Stewart et al., The mechanisms underlying the neurotoxic effects of non-coplanar 2008). Comparable cognitive and psychomotor behavioral deficits are PCBs are only partially understood. Biological activities associated with observed in primate and rodent models following developmental PCB ortho-rich and hydroxyl metabolites of ortho-poor PCBs include: 1) exposures (Schantz et al., 1989; Tilson et al., 1990; Schantz et al., 1995; endocrine disruption, specifically weak estrogenicity (Safe, 2004), Schantz, 1996; Rice, 1998; Tilson & Kodavanti, 1998). More recently, it enhanced insulin (Fischer et al., 1999) and arachidonic acid secretion has been postulated that exposure of the developing brain to PCBs may (Bae et al., 1999a), and disruption of the hypothalamic–pituitary– also influence the susceptibility of the adult brain to acute stressors and thyroid axis (Zoeller et al., 2000; Zoeller, 2005; Knerr & Schrenk, neurodegeneration (Lein et al., in press). This hypothesis is derived in 2006); 2) reduced levels of dopamine and other biogenic amines in the part from a mortality study of 17,000 workers occupationally exposed to brain and in cultured neurons (Seegal, 1996; Mariussen & Fonnum, PCBs that revealed an increased incidence of PD in female subjects 2006); and 3) increased levels of reactive oxygen species (ROS) and (Steenland et al., 2006)andfindings of a positive correlation between intracellular Ca2+ in neurons (Kodavanti, 2005; Mariussen & Fonnum, PCB exposure and depression and impaired memory and learning 2006). There is evidence that non-coplanar PCBs may induce increases among adults 49-86 years of age living in Michigan and exposed to PCBs in intracellular Ca2+ by several mechanisms, including influx of extra- via consumption of Great Lakes fish (Schantz et al., 2001) and adults 55– cellular Ca2+ through L-type voltage-sensitive Ca2+ channels or the 74 years of age living along regions of the Hudson River in New York that NMDA receptor (Mundy et al., 1999; Inglefield & Shafer, 2000) or via 2+ have been heavily contaminated with PCBs (Fitzgerald et al., 2008). In release of intracellular Ca stores subsequent to activation of IP3Rs the latter study, the PCB body burdens of affected individuals were (Inglefield et al., 2001) or RyR (Wong et al., 1997a); however, RyR similar to those of the general population, suggesting persistent neuro- activation is the most sensitive of these mechanisms (Wong & Pessah, I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285 275

1996; Wong et al., 1997a,b). It is interesting to note that these mechanisms may not be mutually exclusive since RyR activation is known to interact with IP3R and with both L-type voltage-sensitive Ca2+ channels and the NMDA receptor (see Section 2.5.4.), and low µM concentrations of non-coplanar PCBs have been shown to enhance significantly the sensitivity of primary cultured neurons to NMDA- and AMPA-elicited Ca2+ signals (Gafni et al., 2004), revealing a functional link between PCB amplification of RyR signaling and sensitivity to excitatory amino acids. The causal relationship between these biological activities of non- coplanar PCBs and the neuropsychological deficits associated with PCB developmental neurotoxicity remains a pressing question in the field. It has been postulated that these biological activities contribute to the developmental neurotoxicity associated with non-coplanar PCBs by interfering with the patterning of neuronal connectivity in the developing brain (Seegal, 1996; Gilbert, 2000). Critical determinants of neuronal connectivity include neuronal apoptosis (Sastry & Rao, 2000; Barone et al., 2000; Martin, 2001) and dendritic morphogenesis Fig. 14. Developmental A1254 exposure interferes with normal dendritic growth and (Matus, 2000; Kennedy, 2000). Altered patterns of neuronal apoptosis experience-dependent dendritic plasticity. Dendritic morphology was analyzed among not only impact neuronal connectivity in the developing brain, but P31 rats trained in the Morris water maze (Maze) and among littermates identically also influence the susceptibility of the adult brain to subsequent housed and exposed but not trained (Non-Maze). As seen in representative camera environmental insults or aging (Langston et al., 1999; Barlow et al., lucida drawings of the basilar dendritic arbor of cortical neurons, developmental exposure to A1254 at 1 or 6 mg/kg/d in the dam's diet throughout gestation and 2007). The shape of the dendritic arbor determines the total synaptic lactation significantly increased dendritic arborization relative to vehicle controls input a neuron can receive (Purpura, 1967; Purves, 1975, 1988), and (0 mg/kg/d A1254). Maze training significantly increased dendritic complexity among influences the types and distribution of these inputs (Miller & Jacobs, animals in the control group but this experience-dependent plasticity was blocked 1984; Sejnowski, 1997; Schuman, 1997). Altered patterns of dendritic among animals in the A1254 treatment groups with a more pronounced effect observed in the lower treatment group. Data are presented as the mean±SEM (N=17-21 growth and plasticity are associated with impaired neuropsycholog- neurons per group). The percent changes in dendritic length were calculated using data ical function in experimental models (Berger-Sweeney & Hohmann, obtained from 17-21 neurons per treatment group. The percent change in dendritic 1997) and are thought to contribute to diverse disorders of length as a function of maze training was calculated as the difference in dendritic length neurodevelopmental origin (Zoghbi, 2003; Pardo & Eberhart, 2007; of neurons in maze-trained animals vs. non-maze-trained animals divided by the ⁎ b Connors et al., 2008) as well as neurodegenerative (de Ruiter dendritic length of neurons in maze-trained animals multiplied by 100. p 0.05; ⁎⁎pb0.01; ⁎⁎⁎pb0.001. From (D. Yang et al., 2009). & Uylings, 1987; Jagadha & Becker, 1989; Flood & Coleman, 1990). Each of the biological activities associated with non-coplanar PCBs have been shown to influence neuronal apoptosis and to contribute to and inhibition of training-induced RyR upregulation. Moreover, the the dynamic control of dendritic growth; however, to date, experi- dose–response relationship for PCB effects on dendritic growth and mental evidence linking these activities to PCB-induced alterations plasticity was similar to that of PCB effects on RyR expression but in neuronal connectivity has been reported only for RyR-dependent not to that of PCB effects on thyroid hormone levels or sex-steroid- mechanisms. dependent developmental endpoints (Yang et al., 2009). Increased PCBs have been shown to induce caspase-dependent apoptosis in RyR expression in brain tissues has also been associated with PCB- primary cultures of hippocampal neurons (Howard et al., 2003). induced changes in (Royland et al., 2008; Royland & Neuronal apoptosis was induced by A1254 and non-coplanar PCB 47 Kodavanti, 2008) and locomotor activity (Roegge et al., 2006). In vitro but not by coplanar PCB 77. Aroclor 1254 contains predominantly studies confirmed a link between PCB sensitization of RyR and effects ortho-rich PCBs with significant activity at the RyR (Wong & Pessah, on dendritic arborization. PCB 95, a congener with potent RyR activity, 1996; Wong et al., 1997a), and SAR studies identified PCB 47 as a RyR- but not PCB 66, a congener with negligible RyR activity, promoted active congener and the coplanar PCB 77 as a congener with negligible dendritic growth in primary cortical neuron cultures and this effect activity at the RyR (Pessah et al., 2006). Further evidence that RyR was blocked by pharmacological antagonism of RyR activity (D. Yang activation mediated the pro-apoptotic activity of PCBs includes the et al., 2009). The downstream mechanisms by which PCB sensitization inhibition of PCB-induced apoptosis by FLA 365, a selective RyR of the RyR influences dendritic arborization have yet to be established, antagonist (Chiesi et al., 1988; Mack et al., 1992) but not by antagonists but it is postulated these involve modulation of Ca2+-dependent previously shown to block PCB-mediated Ca2+ flux through L-type signaling pathways linked to activity-dependent dendritic growth and voltage-sensitive channels, NMDA receptors, and IP3Rs in cultured plasticity. Activation of a CaMK-CREB-Wnt signaling pathway has neurons. recently been demonstrated to link neuronal activity to transcription Recent evidence suggests that PCBs may also interfere with of gene products that regulate dendritic growth (Wayman et al., 2006) neuronal connectivity in vivo. Developmental exposure to A1254 (Fig. 15); and activity-dependent translation is mediated by the was observed to enhance basal levels of dendritic growth but block serine-threonine protein kinase mammalian target of rapamycin experience-dependent dendritic growth in the cortex and cerebellum (mTOR) (Takei et al., 2004; Kumar et al., 2005; Jaworski et al., 2005; of weanling rats (Lein et al., 2007; Yang et al., 2009)(Fig. 14), and Gong et al., 2006). RyR activation has been shown to cause sequential developmental exposure to PCB 95 was reported to disrupt the balance activation of CaM kinases, CREB and transcription of genes encoding of neuronal inhibition to excitation in the developing rat auditory Ca2+-regulated proteins (Deisseroth et al., 1998); translation mechan- cortex (Kenet et al., 2007). Several lines of evidence suggest that PCB isms of activity-dependent growth are Ca2+-dependent; and PCB sensitization of RyRs contributes to the effects of these compounds on effects on RyR-mediated Ca2+ signaling require interactions with neuronal connectivity. First, these changes in neuronal connectivity FKBP12 (Wong & Pessah, 1997; Wong et al., 2001a,b; Gafni et al., are associated with exposure to non-coplanar PCB congeners with 2004), which regulates mTOR activity (reviewed in Chen & Fang high affinity for the RyR. Second, PCB-induced changes in dendritic (2002)). growth and plasticity are coincident with increased [3H]ryanodine- These data linking a direct molecular effect of PCBs (RyR activation) binding sites and RyR expression in the brains of untrained animals to disruption of specific neurodevelopmental events (neuronal 276 I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285

Fig. 15. Activity increases intracellular Ca2+ via NMDA receptor activation and calcium-induced calcium release, which alters dendritic growth via transcriptional or translational mechanisms. The former involves CaMK I activation and enhanced CREB-dependent Wnt transcription; Wnt binds the Frizzled receptor to activate downstream effector molecules β-catenin, JNK and Rac. The latter involves Ca2+-dependent activation of mTOR, which relieves repression of initiation factor-4E by 4EBP1. mTOR is regulated by FKBP12, which is targeted by non-coplanar PCBs. apoptosis and dendritic growth and plasticity) provide the first evidence developmental exposure to PCBs are associated with low frequency of a receptor-based mechanism for PCB developmental neurotoxicity. hearing loss and damage to cochlear hair cells, especially outer hair This not only provides a powerful means for predicting which of the 209 cells (Goldey et al., 1995; Lasky et al., 2002). Since TH is necessary for possible congeners within the PCB family present the greatest risks to normal cochlear development (Uziel, 1986), the loss of hair cells has neurodevelopment, but also supports the development of mechanism- been considered the indirect consequence of TH deficiency during based tools for screening other chemical classes of environmental health critical periods of development. However, the profile of cochlear concern, such as PBDEs. Human polymorphisms in RYR genes are linked damage following PCB exposure is not entirely consistent with models to environmentally triggered disorders including malignant hyperther- of hypothyroidism, and TH replacement in PCB-exposed rats only mia (MH) (Gronert et al., 2004), cardiac arrhythmias (Wehrens et al., partially reversed hearing deficits (Goldey & Crofton, 1998; Crofton 2005), and sudden death (Laitinen et al., 2004), suggesting the testable et al., 2000; Crofton & Zoeller, 2005; Sharlin et al., 2006). Additional hypothesis that individuals with mutation(s) in one or more CRU evidence that an alternative, TH independent, mechanism contributes proteins exhibit increased susceptibility to developmental neurotoxicity to PCB ototoxicity was recently presented (Powers et al., 2009). resulting from low-level environmental exposures to non-coplanar Interestingly, these effects on cochlear development are produced PCBs. In support of this hypothesis, we recently showed that non- primarily by non-coplanar PCBs (Kostyniak et al., 2005; Powers et al., coplanar PCB 95 is significantly more potent and efficacious in dis- 2006), and all three RyR isoforms are differentially expressed rupting cation regulation of MH mutation R615C-RyR1 compared to throughout the organ of Corti, including inner and outer hair cells, wild type RyR1 (Ta & Pessah, 2007). Considered together, these and within spiral ganglion neurons (Morton-Jones et al., 2006; Grant observations identify non-coplanar PCBs with high RyR activity as et al., 2006). RyR1 is the major isoform expressed in the outer hair candidate environmental risk factors in neurodevelopmental disorders cells where it is co-localized with nicotinic cholinergic receptors at and provide insight regarding potential gene-environment interactions “synaptic cisterns” resembling triadic junctions that are essential for that influence susceptibility to environmentally triggered neurodeve- engaging excitation–contraction coupling in skeletal muscle (Liou- lopmental deficits. dyno et al., 2004). RyR1 channels tightly couple Ca2+ release from ER stores in response to cholinergic input to the outer hair cell thereby 2.5.4. Ryanodine receptors as a point of regulating Ca2+-activated potassium currents that are necessary for convergence in polychlorinated biphenyl neurotoxicity long-term survival of olivocochlear fibers and synapses (Murthy et al., While emerging evidence clearly identifies RyRs as critical 2009). RyRs expressed in inner hair cells functionally couple to Ca2+- molecular targets in PCB developmental neurotoxicity, other biolog- activated potassium channels (Beurg et al., 2005), whereas in spiral ical activities have been ascribed to non-coplanar PCBs, including ganglion neurons, RyRs are functionally coupled to somatic AMPA-type increased intracellular levels of ROS (Mariussen & Fonnum, 2006; glutamate receptors (Morton-Jones et al., 2008). These observations Fonnum et al., 2006), disruption of thyroid hormone signaling suggest the possibility that the cochlea represents a direct target of RyR- (Zoeller, 2007; Crofton, 2008) and decreased levels of dopamine active PCBs, and that RyR-dependent mechanisms work in parallel or in (Mariussen & Fonnum, 2006). Are these biological activities causally series with TH-dependent mechanisms to cause ototoxicity. related to PCB developmental neurotoxicity, and if so, do they Emerging evidence from diverse areas of research raises the in- represent divergent or convergent mechanisms of PCB developmental triguing possibility that RyR sensitization contributes to other known neurotoxicity? biological activities of PCBs. For example, it has been demonstrated that In the case of PCB disruption of thyroid hormone signaling, animal PCBs activate the RyR causing release of Ca2+ from the ER (Wong & studies have shown that reductions in circulating TH levels with Pessah, 1997),whichinturncanincreaseproductionofROS(Ravagnan I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285 277

seen following PCB exposure, including inhibition of tyrosine hydroxylase and L-aromatic acid decarboxylase (Angus & Contreras, 1996; Angus et al., 1997), two of the enzymes involved in the synthesis of dopamine, decreased striatal levels of the dopamine transport (DAT) (Caudle et al., 2006) and selective activation of oxidative stress- related pathways in dopaminergic neurons (Lee & Opanashuk, 2004). Ryanodine induces dopamine release from striatal dopaminergic neurons and this effect is significantly attenuated in striatal slices isolated from RyR3 null mice (Wan et al., 1999). More recently, it has been demonstrated that pharmacological manipulations of RyR activity alter somatodendritic dopamine release (Patel et al., 2009) as well as action potential- and NMDA receptor-evoked Ca2+ signaling (Cui et al., 2007; Harnett et al., 2009) in midbrain dopaminergic neurons, and that internal Ca2+stores are necessary for the abnormal release of dopamine via reverse transport through the dopamine transporter caused by amphetamine and methamphetamine (Goodwin et al., 2009). Collectively these observations provide biological plausi- bility to the intriguing speculation that RyR sensitization may be a convergent mechanism of PCB developmental neurotoxicity.

2.6. Convergent mechanism for Fig. 16. Mechanisms by which non-coplanar PCBs might induce apoptotic DNA non-coplanar POPs: toward an alternative equivalence factor fragmentation. Specific non-coplanar PCBs may directly activate the ryanodine receptor (RyR) causing release of Ca2+ from endoplasmic reticular (ER) stores. Increased cytoplasmic Ca2+ activates caspases resulting in apoptosis. Increased cytoplasmic Ca2+ The observation that RyRs play a critical role in diverse tissue types may also cause increased mitochondrial Ca2+ influx, which increases generation of and in numerous cellular processes raises an interesting challenge in reactive oxygen species (ROS) thereby promoting caspase-dependent apoptosis. Alterna- light of emerging data identifying RyRs as a direct molecular target in tively, or in addition, PCBs may generate ROS directly, which then increase cytoplasmic PCB neurodevelopmental toxicity. What factor(s) determine the levels of Ca2+ via activation of RyRs. Blocking the L-type voltage-sensitive Ca2+ channel specificity of PCB toxicity? Why do PCBs seem to preferentially target with verapamil or the NMDA receptor with APV does not have any effect on PCB-induced DNA fragmentation, suggesting that, in this model system, extracellular calcium is not the developing nervous system? Certainly the timing of exposure will involved in the apoptotic signaling pathway. influence the biological outcomes of PCB exposures, as will pharma- cokinetic parameters such as dosage, the metabolites produced, and distribution of PCBs within the body. But other factors that could be et al., 2002; Ermak & Davies, 2002)(Fig. 16). This might be a reciprocal equally important include expression patterns of RyRs and the com- interaction in that ROS can directly modulate the channel activity of the plement of accessory proteins that comprise the calcium release unit RyR (Feng et al., 2000; Pessah, 2001). An interesting speculation is that as well as the antioxidant capacity of the cell. Alternatively, perhaps RyR-dependent mechanisms also contribute to the decreased levels of the developing nervous system is not the only preferential target, and circulating thyroid hormone associated with PCB exposure. The thyroid we have simply missed toxic effects of PCBs on peripheral target gland is a major target organ of the sympathetic nervous system, and organs (muscle, cochlea, pancreatic beta cells, etc) because little sympathetic neurons express RyRs (Vanterpool et al., 2006) and neuro- attention has been paid to these endpoints. Given the role of the RyR transmitter release from sympathetic neurons is regulated by RyR in a number of peripheral tissues where PCBs have been shown to activity (Cong et al., 2004). Conversely, since thyroid hormone regulates have effects, at least in vitro, understanding how PCBs impact these RyR expression in at least the heart (Jiang et al., 2000; Dillmann, 2002; peripheral targets and their implications for human and animal health Hudecova et al., 2004), perhaps PCB effects on RYR expression are and risk assessment seem warranted. mediated in part by changes in thyroid hormone signaling. Another interesting hypothesis that emerges from consideration of Emerging evidence regarding a role for RyRs in regulating the structure–activity relationship of PCB interactions with the RyR is dopamine homeostasis suggests the possibility that PCB sensitization whether the RyR functions as a target for other toxicants that possess of RyRs contributes to the effects of PCBs on dopamine. Several mech- non-coplanar structures. Obvious candidates are the polybrominated anisms are currently postulated to contribute to dopamine reductions diphenyl ethers (PBDEs) (Fig. 17). Recently Dingemans and coworkers

Fig. 17. 3-D projections of Bisphenol A, triclosan, and 2,2,′,4,4′-tetrabromodiphenylether (BDE-47). 3-D projections were calculated with the Molecular Dynamics Tool of ChemIDplus Advanced (Nat. Lib. Med.). 278 I.N. Pessah et al. / Pharmacology & Therapeutics 125 (2010) 260–285 reported that the 6-hydroxyl metabolite of BDE-47 (20-120 µM) rapidly Anonymous (2007). Final National Priorities List (NPL) Sites as of Sep. 27, 2007 http:// fl 2+ www.epa.gov/superfund/sites/query/queryhtm/nplprop.htm. in uences intracellular Ca homeostasis in PC12 cells, which can be at Aracena, P., Sanchez, G., Donoso, P., Hamilton, S. L., & Hidalgo, C. (2003). S- least partially accounted for by release from the ER store (Dingemans glutathionylation decreases Mg2+ inhibition and S-nitrosylation enhances Ca2+ et al., 2008). Preliminary evidence that certain PBDE congeners and their activation of RyR1 channels. J Biol Chem 278(44), 42927−42935. Aracena-Parks, P., Goonasekera, S. A., Gilman, C. P., Dirksen, R. T., Hidalgo, C., & metabolites directly alter RyR function has emerged (Kim et al., 2009b). Hamilton, S. L. (2006). Identification of cysteines involved in S-nitrosylation, S- Careful consideration of the 3-dimensional structure of these and glutathionylation, and oxidation to disulfides in ryanodine receptor type 1. JBiolChem related environmental contaminants of concern to human health may 281(52), 40354−40368. reveal other RyR ligands. One such candidate, triclosan (Fig. 17), has Arie, Y., Iketani, M., Takamatsu, K., Mikoshiba, K., Goshima, Y., & Takei, K. (2009). Developmental changes in the regulation of calcium-dependent neurite outgrowth. 2+ been shown in pilot studies to alter Ca signals in a RyR-dependent Biochem Biophys Res Commun 379(1), 11−15. manner (Ahn et al., 2008). Another candidate, bisphenol A (Fig. 17), Asher, B. J., Wong, C. S., & Rodenburg, L. A. (2007). Chiral source apportionment of remains untested. 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The SAR data available for PCB interactions with RyRs, and the Nonshivering thermogenesis protects against defective calcium handling in muscle. identification of a RyR-based mechanism of neurodevelopmental FASEB J 22(11), 3919−3924. toxicity, suggest the utility of developing an alternative TEF strategy Bae, J., Peters-Golden, M., & Loch-Caruso, R. (1999a). Stimulation of pregnant rat uterine contraction by the polychlorinated biphenyl (PCB) mixture aroclor 1242 for non-dioxin-like PCBs based on their relative RyR activity. This may be mediated by arachidonic acid release through activation of strategy has great appeal for assessing the risk of neurodevelopmental A2 enzymes. J Pharmacol Exp Ther 289(2), 1112−1120. toxicity associated with exposure to mixtures of PCBs and has the Bae, J., Stuenkel, E. L., & Loch-Caruso, R. (1999b). 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