Interplay of calcium and cadmium in mediating cadmium toxicity.

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Contents lists available at ScienceDirect

Chemico-Biological Interactions journal homepage: www.elsevier.com/locate/chembioint

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Mini-review

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Interplay of calcium and cadmium in mediating cadmium toxicity

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Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto M5S 1A8, Canada

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a r t i c l e

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Grace Choong, Ying Liu, Douglas M. Templeton ⇑

i n f o

Article history: Received 7 November 2013 Received in revised form 31 December 2013 Accepted 13 January 2014 Available online xxxx

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Keywords: Cadmium Calcium Calmodulin CaMK-II Cytoskeleton Apoptosis

a b s t r a c t The environmentally important toxic metal, cadmium, exists as the Cd2+ ion in biological systems, and in this state structurally resembles Ca2+. Thus, although cadmium exerts a broad range of adverse actions on cells by virtue of its propensity to bind to protein thiol groups, it is now well appreciated that Cd2+ participates in a number of Ca2+-dependent pathways, attributable to its actions as a Ca2+ mimetic, with a central role for calmodulin, and the Ca2+/calmodlin-dependent protein kinase II (CaMK-II) that mediates effects on cytoskeletal dynamics and apoptotic cell death. Cadmium interacts with receptors and ion channels on the cell surface, and with the intracellular estrogen receptor where it binds competitively to residues shared by Ca2+. It increases cytosolic [Ca2+] through several mechanisms, but also decreases transcript levels of some Ca2+-transporter genes. It initiates mitochondrial apoptotic pathways, and activates calpains, contributing to mitochondria-independent apoptosis. However, the recent discovery of the role CaMK-II plays in Cd2+-induced cell death, and subsequent implication of CaMK-II in Cd2+-dependent alterations of cytoskeletal dynamics, has opened a new area of mechanistic cadmium toxicology that is a focus of this review. Calmodulin is necessary for induction of apoptosis by several agents, yet induction of apoptosis by Cd2+ is prevented by CaMK-II block, and Ca2+-dependent phosphorylation of CaMK-II has been linked to increased Cd2+-dependent apoptosis. Calmodulin antagonism suppresses Cd2+-induced phosphorylation of Erk1/2 and the Akt survival pathway. The involvement of CaMK-II in the effects of Cd2+ on cell morphology, and particularly the actin cytoskeleton, is profound, favouring actin depolymerization, disrupting focal adhesions, and directing phosphorylated FAK into a cellular membrane. CaMK-II is also implicated in effects of Cd2+ on microtubules and cadherin junctions. A key question for future cadmium research is whether cytoskeletal disruption leads to apoptosis, or rather if apoptosis initiates cytoskeletal disruption in the context of Cd2+. Ó 2014 Published by Elsevier Ireland Ltd.

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Contents 1. 2. 3.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physicochemical properties of cadmium and calcium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Channels and receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Role of calcium channels in cadmium uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Binding of cadmium to receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Effects of Cd2+ on intracellular Ca2+ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Calmodulin and CaMK-II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Effects of Cd2+ on the calcium-effector protein calmodulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Effect of cadmium on CaMK-II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: AIF, apoptosis-inducing factor; CaM, calmodulin; CaMK-II, Ca2+/calmodulin-dependent protein kinase II; CaMP, Ca2+/CaM-dependent protein kinases phosphatase; ERa, estrogen receptor a; Erk, extracellular signal-regulated kinase; FA, focal adhesion; FAK, focal adhesion kinase; IP3, inositol trisphosphate; JNK, cJun N-terminal kinase; MAP, microtubule associated protein; MAPK, mitogen activated protein kinase; MT, microtuble; MTPT, mitochondrial permeability transition pore; NOS, nitric oxide synthetase; PDE, phosphodiesterase; PLC, phospholipase C; PMCA, plasma membrane Ca2+-ATPase; SERCA, sarcoplasmic/endoplasmic reticulum Ca2+-ATPase; SOC, store-operated Ca2+ channel; SR, sarcoplasmic reticulum; TFP, trifluoperzaine; TPEN, tetrakis-(2-pyridylmethyl)ethylenediamine; TRP, transient receptor protein; VDDC, voltage-dependent calcium channel. ⇑ Corresponding author. Address: Department of Laboratory Medicine and Pathobiology, Medical Sciences Building Rm. 6302, University of Toronto, 1 King’s College Circle, Toronto M5S 1A8, Canada. Tel.: +1 416 978 3972; fax: +1 416 978 5959. E-mail address: [email protected] (D.M. Templeton). 0009-2797/$ - see front matter Ó 2014 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.cbi.2014.01.007

Please cite this article in press as: G. Choong et al., Interplay of calcium and cadmium in mediating cadmium toxicity, Chemico-Biological Interactions (2014), http://dx.doi.org/10.1016/j.cbi.2014.01.007

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Cell death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Cadmium and apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Effects of cadmium on mitochondrial-dependent apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Effect of cadmium on calpains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Role of calmodulin in apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. Role of CaMK-II in apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cadmium and cellular morphology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Actin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Microtubules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Cadherins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Focal adhesions and intermediate filaments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

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Cadmium (Cd) is a toxic metal occurring in the environment that has been shown to cause adverse health effects in the general population [1–4], and is listed as a class I carcinogen by the International Agency for Research on Cancer [5]. Major sources of Cd exposure in an occupational setting occur in industries involved with Cd and Zn mining and refining, electroplating, and battery, plastics, pigment, electronics production [6,7]. Such occupational exposures are now generally minimized by careful practices of industrial hygiene, as well as by regulation of usage. Historically, Germany and the Scandinavian countries were among the first jurisdictions to attempt to control environmental exposure by selectively banning use of Cd in some forms. Now, severe restrictions are being implemented throughout the European Union under the Registration, Evaluation, Authorization and Restrictions of chemicals (REACH) program, and a decline in use of Cd in coatings, pigments and stabilizers has meant that currently the major consumption of Cd is in the production of Ni–Cd batteries. Because Cd is not degraded, its continual release into the environment from industrial activity results in an ever-increasing environmental burden and entry into the food chain [6]. In recent years, then, attention has shifted from the obvious effects of Cd in occupational health to recognition of Cd as an important environmental problem. Non-occupational exposure is mainly from the diet [3], with an estimated individual daily consumption of 30 lg in the USA, and considerably higher in China and Japan [8]. Because of the Cd content of tobacco, smokers have several times the blood levels and kidney concentrations of Cd found in nonsmokers. Epidemiological studies such as Cadmibel [9,10] have drawn attention to exposure in the general population, and widespread toxicity among wildlife is recognized [11]. Evidence is mounting that environmental exposures are associated with cancers of the kidney, bladder, prostate, and endometrium [1]. Studies from the Karolinska Institute have identified a benchmark dose for Cd that produces a definite renal response in Swedish and Japanese populations with low environmental exposure [12], and have concluded that there is no margin of safety between the onset of adverse effects on the kidney and Cd exposures in the general population [1]. A recent review of Cd exposure from different food sources notes that speciation (i.e., Cd2+ vs. protein-bound Cd) does not play a significant role in Cd bioavailability [13]. Nordberg [14] has provided a historical review on the development of Cd toxicology. Newer sources of Cd exposure are worth mentioning as these raise a cautionary note for future risk and global health impact. Unregulated recycling of e-waste as a cottage industry is exposing children and adults to extreme levels of Cd in Asia and Africa [15,16]. Phosphate-based fertilizers containing natural amounts

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of Cd have recently been termed the ‘‘Trojan Horse of the green revolution’’ as outbreaks of endemic chronic renal failure appeared in Sri Lanka following increased Cd contamination of soil and water from increased fertilization [17]; such cases should be anticipated elsewhere in developing countries. Quantum dots based on CdSe and CdTe are being developed for possible medical applications, and their toxicity is largely unknown [18,19]. And, a growing use of Cd in the manufacture of CdTe solar panels is exempt from some regulations. Of major concern is that Cd has a long biological half-life (10–30 years in humans) in part due to its low excretion rate and ability to accumulate in various tissues [1,20]. Depending on the dose, route, and duration of exposure, the major organ systems affected by Cd include the lungs, liver, kidney, and muscoskeletal system [1,14]. In particular, the liver and the kidney generally contain a third of the total Cd load in the body. Prolonged exposure to Cd can lead to renal dysfunction and osteomalacia in humans. Nephrotoxic damage is considered to be an underlying factor for establishing important biomarkers of Cd toxicity, resulting as it does in proteinuria, polyuria, and general dysfunction of the kidney. Cadmium is not a physiologically necessary metal, and it can disrupt signaling cascades that lead to a variety of toxic effects. In particular, because of the physicochemical similarities between Cd2+ and calcium ion (Ca2+), many studies have sought to determine how Cd can effect changes in calcium signaling pathways and their resultant toxic effects. This review will focus on changes in intracellular cytosolic Ca2+ concentrations ([Ca2+]i), and the role of calcium effectors, calmodulin (CaM) and Ca2+/calmodulindependent protein kinase II (CaMK-II) in mediating cadmium toxicity.

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2. Physicochemical properties of cadmium and calcium

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Cadmium is a group 12 element in the periodic table with a complete 4d electron shell, resulting in a very stable divalent cation (Cd2+). Calcium ion (Ca2+) is found in the group 2 elements, and also occurs as a divalent cation in aqueous solution. Divalent Cd2+ and Ca2+ have very similar physicochemical properties, with ionic radii of Ca2+ (0.97 Å) and Cd2+ (0.99 Å) giving similar charge/radius ratios (Ca2+ = 2.02 e/Å, Cd2+ = 2.06 e/Å), determining that these ions are able to exert strong electrostatic forces on biological macromolecules [21]. This favours the exchange of the two metals in Ca2+-binding proteins, and it has been shown that Cd2+ can displace Ca2+ from its binding sites in calmodulin (CaM) [22], sarcolemma [23], and troponin C [24] in vitro, with the potential to affect other Ca2+-binding proteins. There are several properties in which Cd2+ is distinct from Ca2+. Cadmium ion is considered a ‘‘soft ion’’ compared to Ca2+, which is

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a ‘‘hard ion’’. Soft ions do not have noble-gas configuration and prefer soft donors forming more stable complexes with the softer, more polarizable N and S donor ligands. In contrast, hard ions are considered to have more noble gas-like electronic configurations, with low or intermediate polarizability and a high affinity for halogens. Ultimately, these differences result in different coordination abilities among these ions, where stronger covalent bonds form between soft ligands and stronger ionic bonds between hard ligands. Thermodynamically, these ions are distinct. Soft ions are more weakly hydrated than hard ions, though covalent soft–soft bond formation is favourable because the reaction is highly exothermic. In contrast, an increase in entropy upon loss of hydration in hard-hard bond formation is a thermodynamically favourable reaction [21]. Despite these differences between Ca2+ and Cd2+, toxicity can result when Cd2+ interacts with Ca2+ at binding sites in proteins [21].

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3. Channels and receptors

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3.1. Role of calcium channels in cadmium uptake

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Several pathways have been proposed to be involved in transport of Cd2+ into cells. Cadmium can be taken up through facilitated diffusion or active transport. Transporters and receptors for free and complexed forms of essential metals such as Ca2+, Fe2+, Zn2+ or Cu2+ may mediate uptake of Cd2+ [25,26]. Because the ionic radii of Ca2+ and Cd2+ are similar, Cd2+ can possibly be taken up by voltage- or receptor-operated Ca2+ channels, and inhibition of Ca2+ channels can sometimes protect against Cd2+ toxicity. The calcium channel blocker nimodipine produced a shift of the LD50 of Cd2+ from 15 to 45 lM in the GH4C1 pituitary cell line. However, nimodipine did not protect LLC-PK1 (kidney proximal tubule) or a neuroblastoma cell line from Cd2+ [27], and only provided partial protection in Chinese hamster ovary cells [28]. In the hepatic human cell line WRL-68, the calcium channel blockers nifedipine and verapamil inhibited uptake of Cd2+ by 35%, suggesting that in these cells only one third of the Cd2+ entering the cell does so through Ca2+ channels [29]. In primary rat hepatocytes, diltiazem, verapamil, nifedipine and nitrendipine inhibited uptake of Cd2+, but not Hg2+, with maximal inhibition resulting in an approximately 30% decrease of Cd2+ uptake [30]. There is some evidence directly supporting increased Cd2+ uptake through L- or N-type voltage-dependent calcium channels (VDCCs). While Cd2+ inhibits VDCCs with an IC50 of 0.3 lM in some cells [31], in HeLa cells lacking VDCCs, Cd2+ was unable to induce apoptosis or cellular toxicity [32]. T-type VDCCs may play a role in Cd uptake, as inhibition of these channels by mibefradil reduced Cd2+ uptake, and decreased expression of T-type channels was observed in a Cd-resistant cell line [33]. It appears that Cd2+ uptake through Ca2+ channels is dependent on cell type and context, suggesting that VDCCs may not be a general mechanism of Cd2+ transport. In electrically non-excitable cells, Ca2+ uptake can occur through several distinct processes with the major pathway involving store-operated Ca2+ channels (SOCs). SOCs are activated in response to depletion of non-mitochondrial sources of Ca2+ [34]. Inhibition of SOCs did not affect Cd2+ uptake in Madin–Darby kidney cells [34] or human glomerular mesangial cells [35]. However, TRPV6, a part of the family of transient receptor proteins (TRPs) involved in Ca2+ uptake, increased Cd2+ uptake when the human protein was heterologously expressed in HEK293 cells [36]. There is some evidence that TRPs regulate SOCs activity [36,37], though the exact role requires further clarification. As CaM binds to the cytosolic domain of TRPs [37], TRPs may have an important, yet undetermined role, in Cd toxicity.

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3.2. Binding of cadmium to receptors

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Extracellular Cd2+ may alter signaling cascades by binding to receptors on the cell surface and activate or inhibit them. Though such binding has been shown to involve thiol groups on receptors [38,39], it is also possible that Cd2+ can bind to Ca2+-binding sites on receptors and alter their function. It is believed that Cd2+ can associate with a xenobiotic receptor [40]. However, the identity of this receptor is unknown. This receptor responds to decreases in external pH or Na concentration, whereas the presence of external Ca2+ and Mg2+ potentiates release of stored Ca2+ by Cd2+ [40]. Determining the identity of this xenobiotic receptor may shed further light into the possible mechanisms of Ca2+ release and signaling. One well characterized intracellular receptor affected by Cd2+ is the estrogen receptor a (ERa). Cadmium has been described as a metalloestrogen because of its ability to bind to and activate the ERa in the absence of estrogen, leading to increased breast cancer cell proliferation [41,42]. It binds to ERa with an equilibrium dissociation constant of 4–5 10 10 M and blocks the binding of 17b-estradiol in a noncompetitive manner [43]. Fechner et al. (2011) have shown that Cd binds to the ligand-binding domain of ERa, leading to conformational changes, possibly through interactions with the thiol groups. Interestingly, extracellular Ca2+ can also bind to and activate ERa and requires Glu-523, Asp-538, and Cys-381 in the ligand-binding domain for activation. Cadmium competes with Ca2+ for binding to ERa and blocks its binding with a Ki of 1 lM, and also requires those same residues to stimulate receptor function [44,45]. An added level of complexity is the role of the transmembrane estrogen receptor, G-protein coupled receptor 30 (GPR30), which may be involved in Cd-induced breast cancer cell proliferation [42]. In a human breast cancer cell line, SKBR3 (GPR30-inactive, ERa / , ERb / ), Cd2+ was unable to induce proliferation compared to the pairwise control expressing endogenous GPR30. This indicates that Cd activation of estrogen receptor signaling may occur through activation of a cell surface bound GPCR in addition to its effects on activation on the nuclear ERa. Therefore, it is possible that Cd2+ activates ERa by mimicking Ca2+, or by binding to thiol groups, to stimulate a physiological response.

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3.3. Effects of Cd2+ on intracellular Ca2+

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Calcium is a major second messenger involved in multiple signaling cascades. Intracellular levels of cytosolic Ca2+ are tightly regulated, and basal levels of Ca2+ are usually kept below 100 nM through cooperation of ion channels, ion exchangers, and ATPase pumps. Among the latter are the plasma membrane Ca2+-ATPase (PMCA) and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) that actively pump Ca2+ out of the cytoplasm. Low-affinity/high-capacity intracellular buffering proteins such as calreticulin and calsequestrin are also involved in Ca2+ homeostasis. Transient elevations in cytosolic Ca2+ concentration ([Ca2+]i) of several hundred nM to >1 lM occur either by influx through ligand- or voltage-gated ion channels, or by release from intracellular stores [46]. Upon receptor stimulation, inositol trisphosphate (IP3) is produced and releases Ca2+ from the ER through IP3 receptor-gated channels or ryanodine receptors on the sarcoplasmic reticulum (SR). Differences in the signal duration and amplitude, and subcellular location of the stimulus, determine outcomes such as cell division, cell motility, muscle contraction, metabolic activity, and apoptosis [47,48]. Cadmium causes a transient increase in [Ca2+]i through several mechanisms. This can occur by production of IP3 and release of sequestered Ca2+ from intracellular stores. Cadmium has been shown to stimulate IP3 production in skin fibroblasts [49]. Cadmium at concentrations >10 lM significantly increases [Ca2+]i

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levels in both HL-7702 and Raji cells at 6 h [50]. However, rat aortic smooth muscle, rat embryo fibroblasts, and human epidermoid carcinoma cells did not respond to Cd2+ in this manner [49], indicating that release of intracellular cytosolic Ca2+ in response to Cd2+ is cell-specific. Calcium-dependent phospholipase C (PLC) is the major enzyme generating IP3 and diacylglycerol, and a PLC inhibitor was observed to diminish Cd2+-evoked increase in [Ca2+]i in Xenopus oocytes [51], indicating that Cd activation of PLC may mediate this rise of [Ca2+]i. It is unlikely that Cd2+ directly causes Ca2+ release from intracellular stores, as there is very little Cd2+ uptake at these short times. Cadmium likely acts at an extracellular receptor, as use of TPEN – a cell-permeable Cd2+ chelator – prior to Cd treatment only caused a slight inhibition of Ca2+ release from intracellular stores [49]. The identity of this receptor has yet to be determined, but it is reversibly blocked by the presence Zn2+ [40], binds to lectin [52], and is believed to be a G-protein coupled receptor [53]. Cadmium can also inhibit Ca2+-ATPase preventing Ca2+ efflux. It has been shown that Cd2+ is a non-competitive inhibitor of erythrocyte Ca2+-ATPase [54,55]. Inhibition of Ca2+-ATPase by thapsigargin also reduces changes in Ca2+ concentrations induced by Cd2+. This may occur through binding to thiol groups of proteins involved in Ca2+ sequestration resulting in release of Ca2+ from microscomes with an increase in [Ca2+]i. Cadmium-mediated elevations of intracellular Ca2+ can also occur through SERCA pump inhibition, but prolonged exposure to Cd2+ leads to depletion of the ER Ca2+ pool and results in decreases in [Ca2+]i [56] (Fig. 1). Although numerous studies have shown that Cd increases [Ca2+]i, it has also been implicated in Ca2+ depletion [57]. However, in the presence of high Ca2+ concentrations, the expression of these exchangers was increased starting at 48 h, indicating that the extracellular environment has a role in Ca2+-related gene expression. Cadmium decreases intracellular Ca2+ stores through binding to thiol groups on a specific cell surface receptor of the Xenopus oocyte [51], and also of HEK293 cells [53], although the identity of the receptor has yet to be determined. Cadmium has also been shown to deplete Ca2+ stores over longer periods of time (>24 h) [57]. Therefore, Cd2+ is able to initiate rapid rises in [Ca2+]i, possibly through stimulation of IP3 production; however, Cd eventually leads to decreases of [Ca2+]i as Ca2+ is lost from the cell.

4. Calmodulin and CaMK-II

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4.1. Effects of Cd2+ on the calcium-effector protein calmodulin

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Calmodulin (CaM), a major Ca2+ sensor in non-muscle cells, is a ubiquitous Ca2+-binding protein that responds to and regulates intracellular Ca2+ levels. It consists of four EF-hand Ca2+-binding motifs, two in its N-terminal domain and two in its C-terminal domain. It requires at least two Ca2+ sites to be occupied to form a complex, and an additional site to activate its downstream target enzymes. When CaM binds to Ca2+, it alters its conformation, exposing a hydrophobic patch that interacts with receptor enzymes to form a quaternary complex. It does not have any intrinsic kinase activity and lacks tissue and species specificity [47,58]. It has several substrates, including adenylate cyclase, Ca2+-ATPase, myosin light chain kinase and Ca2+/CaM-dependent protein kinases (CaMK) and phosphatases (CaMP) [46]. Calmodulin activation can result in activation of biogenic amine-synthesizing enzymes, tyrosine hydroylase and tryptophan hydroxylase [47]. The antagonist of CaM, trifluoperzaine (TFP), binds with high affinity to the hydrophobic region of CaM and prevents interaction with its target enzymes [47]. It has been reported that Cd2+ can displace Ca2+ from CaM leading to its activation, and thus induce intracellular Ca2+ mobilization [22]. Ca2+-ATPase inhibition and activation of CaM by several ions are directly correlated with the similarity of ionic radii to Ca2+ [22,30]. Calmodulin has 2 high-affinity binding sites, each with a Kd of 4.5 lM for Cd2+, and Cd2+ induces a similar conformational change in the protein as does Ca2+, while fostering interaction between CaM and phosphodiesterase (PDE) similar to that caused by Ca2+ [59,60]. However, binding of Cd2+ is more complicated than binding of Ca2+; Cd2+ alone does not activate PDE activity to the maximal level, but the addition of 5 lM Ca2+ does, indicating that the similarity of the ionic radii of Cd2+ and Ca2+ alone does not determine this effect [60]. As all of these experiments were conducted in vitro using purified CaM, the effects in vivo still remain to be determined. Increased phosphorylation of proteins upon Cd2+ treatment was dependent upon CaM in a rainbow trout gonadal cell line [61]. This increase was concentration-dependent up to 200 lM Cd2+, after

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Fig. 1. Cadmium alters intracellular Ca2+ levels. Some of the major interactions described in the text are shown: Diacylglycerol (DAG), G-protein-coupled receptor (GPCR), inositol trisphosphate (IP3), phosphatidylinositol-4,5-bisphosphate (PIP2), plasma membrane Ca2+-ATPase (PMCA), phospholipase C-gamma (PLCc), sarcoplasmic/ endoplasmic reticulum Ca2+-ATPase (SERCA). ‘ + ’ Indicates activation, ‘ ’ indicates inhibition.


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which higher concentrations of Cd2+ resulted in decreased protein phosphorylation. In erythrocyte ghosts, Cd2+ only inhibited Ca2+/ Mg2+-ATPase in a non-competitive manner [54]. However, when Cd2+ associates with CaM, the inhibitory effect on Ca2+/Mg2+-ATPase activity is via a competitive interaction between the Cd2+-CaM and Ca2+-CaM bound forms. The competitive nature of inhibition of ATPase activity in the presence of Ca2+ and Cd2+ indicates that Cd2+ binding to thiol groups on Ca2+/Mg2+-ATPase is not a likely mechanism of inhibition, as binding to thiol groups is a non-competitive interaction. Alterations in CaM activation can affect downstream signaling factors, the major ones of which are the family of Ca2+/CaM-dependent protein kinases. The effects on the specific kinase CaMK-II is explored in more detail in the next section.

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4.2. Effect of cadmium on CaMK-II

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Calcium requires a variety of effectors to sustain signaling events. One such family of effectors is CaMK’s. These include CaMKK (a, b), CaMK-I (a, b, c, d) and CaMK-IV [46]. These homomultimeric kinases show different modes of regulation by phosphorylation than heteromultimeric CaMK-II. CaMK-I and CaMK-IV have an activation loop phosphorylation site that is absent in CaMK-II [46,62]. This loop becomes phosphorylated and increases Ca2+/CaM-dependent activities. Activation of CaMKs can be investigated by increasing [Ca2+]i levels, though interpretation of those results is difficult, as they were obtained under non-physiological conditions [46]. Loss of substrate specificity and mislocalized activated kinases may promote non-physiological responses and aberrant cellular signaling. Activation of kinases such as myosin light chain kinase, phosphorylase kinase, and CaMK-III occurs downstream of CaMK-II. Excessive activation of CaMK-II has been linked to various pathologies, including cardiac hypertrophy [63] and ischemia–reperfusion injury [64]. CaMK-II is a ubiquitous enzyme present in all cell types examined and consists of a family of multifunctional serine/threonine protein kinases. Each isoform (a, b, c, d) is encoded by a separate gene. The a and b forms are found in nervous tissues whereas the c and d forms are found in all tissues [65]. The occurrence of several isoforms can result in formation of homomultimers and heteromultimers. CaMK-II forms a heteromeric dodecamer of a, b, c, d subunits with two hexameric rings stacked on top of one another in neural tissues [58]. Each isoform can be subdivided into an N-terminal catalytic domain, a C-terminal association domain, and a central autoregulatory domain. Regulated by changes in intracellular Ca2+, CaM binds to CaMK-II, resulting in release of the catalytic domain from the autoregulatory loop [66]. Subsequently it can become autophosphorylated at Thr286/287 (the numbering depending on the isoform), resulting in dissociation from CaM and sustained activation (autonomous activity) even when Ca2+ levels fall [58,65]. CaMK-II is expressed abundantly in neurons and regulates a variety of neural functions. Non-neuronal functions include osteogenic differentiation and maintenance of vascular tone [67]. Activation of CaMK-II by Cd2+ can occur through two possible processes; oxidative modification of a methionine residue on CaMK-II [68], or inhibition of phosphatases [69]. Recent work by Erickson et al. [68] has shown that Met-281/282 found in the autoregulatory domain is oxidized, preventing association with the kinase domain in a manner similar to that of Thr-286/287 autophosphorylation. Because CaMK-II is a downstream signal of both reactive oxygen species (ROS) and intracellular increases in Ca2+, both of which are induced by Cd2+, it is possible that Cd2+ can activate and mediate its downstream effects through these parallel cascades. Cadmium increases autophosphorylation and activation of CaMK-II in mesangial cells [70] and neuronal cells

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[50]. We have shown that CaMK-II activation is biphasic with increased cellular autonomous activity at 10 lM CdCl2 treatment, increasing from 10% to 37% of maximal CaM-dependent activity between 4 and 6 h [70]. CaMK-II affects downstream signaling cascades that involve the mitogen activated protein kinases (MAPKs), including p38 kinase, Erk1/2 and c-Jun N-terminal kinase (JNK). It is possible that extracellular Cd2+ elicits Erk1/2-dependent processes by binding to a Ca2+-sensing receptor. In mesangial cells, Erk, JNK and p38 MAPKs, all activated by Cd2+ [71,72]. Previous work has shown that activation of CaMK-II contributes to the observed effects of Cd on MAPKs. CaMK-II is also implicated in the indirect activation of epidermal growth factor receptor (EGFR) [72] and Cd2+-induced caspase-independent apoptosis [70,73].

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5. Cell death

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5.1. Cadmium and apoptosis

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Apoptosis, or programmed cell death, is a highly regulated process that is dependent on several factors, including release of intracellular Ca2+ [74]. The intrinsic pathway primarily involves processes that converge on caspase-3 signaling and it can be further subdivided into mitochondrial-dependent or mitochondrialindependent mechanisms. Mitochondrial-dependent changes to the mitochondrial permeability transition pore (MPTP) by accumulation of the BCL-2 family members Bax and Bak, result in mitochondrial membrane depolarization and release of cytochrome c with apoptosome formation and activation of caspase 9, or release of apoptosis-inducing factor (AIF), which bypasses the caspases. The mitochondrial-independent pathway involves the cysteine protease calpain, which can directly activate or cleave capsases and members of the Bcl-2 family [75]. In contrast, extrinsic apoptosis involves activation of extracellular receptors (e.g., TNFa, Fas) leading to caspase-8 activation. Both mechanisms converge on cleavage of the pro-caspase-3 (Fig. 2), which initiates the apoptotic program [76]. The following sections focus on the effects of cadmium and calcium on the initiation of the apoptotic cascade.

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5.2. Effects of cadmium on mitochondrial-dependent apoptosis

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Cadmium has been shown to mediate apoptosis in several cell lines, although the exact mechanism depends on concentration, exposure time and cell type [77–81]. One possible mechanism is through alterations in Ca2+ homeostasis. Apoptosis was detected in cells treated with Cd2+ correlated with significant elevations of [Ca2+]i; this likely occurs through release of intracellular Ca2+ stores rather than influx of extracellular Ca2+, because BAPTA-AM (an intracellular Ca2+ chelator), but not extracellular EGTA, was able to inhibit Cd-dependent apoptosis [50]. A rise in [Ca2+]i can activate enzymes and lead to mitochondrial dysfunction resulting in apoptosis. Cadmium neurotoxicity has been shown to be linked to an increase in intracellular [Ca2+]i, cleavage of caspase-9 and caspase-3, and decreased mitochondrial membrane potential [82]. In particular, Cd2+ is known to accumulate in the mitochondria, resulting in mitochondrial swelling and mitochondrial-dependent apoptosis [83]. Cadmium inhibits function of electron transport chain complexes, resulting in mitochondrial uncoupling [84]. In rainbow trout fish liver, Cd2+ and Ca2+ accumulation in mitochondria changed the mitochondrial permeability transition and increased oxidative stress [83]. It is believed that Cd2+ enters mitochondria through Ca2+-transport pathways, and the formation of the MPTP may further favour Cd2+ uptake. Dithiothreitrol had a potent effect in preventing Cd2+ accumulation in the mitochondria, possibly through reduction of thiol groups oxidized by Cd2+, or Cd2+

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Fig. 2. Cadmium and cell death. Cadmium initiates apoptosis and pro-survival cascades through changes to intracellular Ca2+, CaM, and CaMK-II. Cadmium can initiate apoptosis through the extrinsic pathway, through activation of CaM and its association with Fas and FADD, and through mitochondrial-dependent (cytochrome c and AIF release) and mitochondrial-independent (calpain activation) pathways. Pro-survival signals can be mediated by activation of ERK by CaMK-II. ‘ + ’ indicates activation, ‘ ’ indicates inhibition, and ‘?’ denotes an unknown interaction. Abbreviations are: apoptotic protease activating factor 1 (APAF-1), apoptosis inducing factor (AIF), fas-associated protein with death domain (FADD), mitogen-activated protein kinase family members (MAPKs), reactive oxygen species (ROS). See text for more details.

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bound to mitochondrial sites [83]. MPTP inhibitors and electron transport chain inhibitors are known to play a role in Cd toxicity [85]. A link has been established between Cd-induced ROS production and changes to the mitochondrion [86]. In human hepatocarinoma cells 1 lM Cd2+ resulted in chromatin condensation and DNA fragmentation, an effect that was independent of caspase activation [80]. Loss of mitochondrial membrane potential was detected at 12 h preceding apoptosis, indicating that the mitochondria probably had a role. Intracellular Ca2+ levels and ROS production were elevated in these cells, causing mitochondrial membrane lipid peroxidation and disruption of mitochondrial membrane potential with release of AIF. ROS alters expression of mitochondrial antiapoptotic proteins [87], further indicating a link between Cd2+, Ca2+, oxidative stress, and apoptosis.

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5.3. Effect of cadmium on calpains

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Calpains are Ca -activated cysteine proteases that cleave many substrates, including some components of the apoptotic pathways. They have been implicated in both cleavage and inhibition of caspases [77]. Their targets also include the pro-apoptotic factors Bax and Bid. Calpains also function in mediating degradation of DNA and cellular proteins and have been linked to increased ceramide production [79]. Ceramide, a component of the structural backbone of sphingolipids/spingomyelin, plays a role in intracellular signaling as a second messenger, and has been shown in turn to be an inducer of calpains [79]. Cadmium activates calpains, thus contributing to a mitochondrial-independent pathway of apoptosis. In HEK293 cells Cddependent calpain activation results in N-terminal cleavage of Bax protein and its insertion into the mitochondrial membrane leading further to caspase-3 activation [53]. This effect was dependent on PLC activation accompanied by a rise in [Ca2+]i after 24 h

exposure to Cd2+. Activation of calpains has also been implicated in the apoptotic mechanism initiated in lung epithelial fibroblasts by Cd2+ [88].

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5.4. Role of calmodulin in apoptosis

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Calmodulin has been linked to apoptotic pathways. Brnjic et al. [74] showed that several apoptosis-inducing agents in a chemical library required Ca2+, CaM and CaMK-II to initiate apoptotic signaling when human colon carcinoma cells were used as a screening target. They found, using several probes, that calpain activation was insufficient to induce apoptosis in the tumor cells, but that CaMK-II and CaM play a major role in the induction, likely though sustained Ca2+ levels and activation of JNK. Overexpression of CaM also causes Ca-dependent apoptosis of pancreatic b-cells, possibly through Ca-dependent activation of neuronal nitric oxide synthetase (nNOS), as inhibition of nNOS activity decreased hyperglycemia [89]. And, in alveolar macrophages exposed to Pneumocystis pneumonia, CaM antagonism resulted in increased ROS and apoptosis [90]. The majority of studies have linked CaM to the extrinsic apoptotic pathway. Antagonism of CaM leads to induction of apoptosis in cholangiocarcinoma cells through a Fas-mediated pathway [91]. A similar result was found in osteoclasts [92], and a comparable observation was made with CD4+ cells, where CaM had a role in binding to the gp160 of HIV, resulting in Fas-dependent apoptosis [93,94]. Whether CaM has a role in mediating Cd-dependent apoptosis through an extrinsic apoptotic pathway has not been investigated.

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5.5. Role of CaMK-II in apoptosis

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Downstream of CaM, CaMK-II can activate several signaling cascades involved in cell survival or apoptosis. CaMK-II has been

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implicated in the development of apoptosis and necrosis of cardiomyocytes in irreversible ischemia–reperfusion injury [64], and is believed to be a central regulator of signaling cascades involved in the sacroplasmic reticulum and mitochondria that promote cellular apoptosis and necrosis [95]. However, CaMK-II has a beneficial role in mediating reversible ischemia–reperfusion injury, although if the ischemic period is extended, CaMK-II increases apoptosis and necrosis, eventually leading to alterations in contractile function [96]. Inhibition of CaMK-II resulted in decreased TUNEL-positive staining, decreased ratio of Bax/Bcl-2, and reduced activation of caspase-3 in an ischemia–reperfusion injury model [64]. It has also been shown to decrease the release of cytochrome c by preventing MPTP formation and preserving the integrity of the mitochondria. Overall, CaMK-II and CaMK-II-dependent phosphorylation of the SR, overload of mitochondrial Ca2+, cytochrome c release and caspase-3 activation lead to apoptosis, indicating that cardiac ischemia–reperfusion injury involves a CaMK-II-dependent mitochondrial pathway [97]. Erickson et al. [66] showed that NADPH oxidase-derived ROS directly activated CaMK-II through methionine oxidation and p38-MAPK activation, and that cardiac apoptosis was dependent on this pathway. Factors downstream of CaMK-II that have a role in mediating pro-survival or cell death pathways include the MAPKs. In contrast to the work on neuronal [98–100] and cardiac models, very few studies have examined the role of CaMK-II in apoptosis in Cd2+-treated cells. We have shown that activation of CaMK-II mediates Cd2+-dependent apoptosis in mesangial cells [81], an effect similarly shown in neurons [101]. This results in activation of MAPK and mTOR in neuronal cells [102]. Cadmium may induce ER release of Ca2+ by IP3 receptors and extracellular Ca2+ influx through CRAC channels on the plasma membrane, resulting in [Ca2+]i elevation and CaMK-II phosphorylation. Cadmium may activate MAPK through ROS generation, which can activate Erk1/2 and JNK as well as inhibit the negative regulators, protein phosphatase 2A and protein phosphatase 5, initiating neuronal cell death [91]. Use of EGTA to deplete extracellular Ca2+ abolished the elevation in [Ca2+]i induced by 10 and 20 lM Cd2+ in neuronal cells, partly through decreased Ca2+ influx [102]. Use of the CaM antagonist TFP partially blocked Cd-induced phosphorylation of Erk1/2, JNK and p38 and decreased phosphorylation of Akt and mTOR [103]. Erk5, a new member of the MAPK family, has increased phosphorylation on threonine and tyrosine residues after exposure to Cd2+ and that this rise was rapid and transient in a manner similar to Erk1/2 phosphorylation [104]. Like Erk1/2 [105], Erk5 may have an anti-apoptotic effect after Cd2+ treatment; at 50 lM CdCl2 for 2 h, there was a transient increase of phosphorylation of Erk5 and Erk1/2, and phosphorylation of the anti-apoptotic transcription factors CREB, c-fos and ATF-1 was also increased and was sustained over a period of time [104]. Although apoptosis has been closely linked to the formation of ROS, the evidence suggesting the role of Ca2+, CaM and CaMK-II in ROS-induced apoptosis following Cd2+ exposure is ambiguous. Inhibition of CaM by TFP resulted in a diminution of the Cd-dependent increases in ROS observed in neuronal cells [102]. In contrast, CaMK-II increased phosphorylation and activation of NOX5 in bovine aortic endothelial cells [106], although inhibition of CaMK-II did not prevent ROS production in smooth muscle cells [107]. Because Cd can activate CaMK-II, increases in ROS in cell types that express NOX may have a role to play in ROS production. Elevated ROS have been shown to up-regulate the expression of endothelial NO synthase (eNOS) in endothelial cells in a CaMK-II-dependent manner [108]. Further work needs to be performed to elucidate the mechanisms linking CaM, CaMK-II, and ROS.

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6. Cadmium and cellular morphology

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6.1. Actin

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Actin is a major cellular structural protein that is highly conserved across eukaryotic cells, with important roles in maintaining cellular morphology, motility, proliferation, tissue repair and protein trafficking [109–111]. There are six isoforms of actin each encoded by a different gene, with the b and c isoforms being the major ones in non-muscle cells [109]. Actin exists in a dynamic equilibrium between globular (G-) actin and filamentous (F-) actin. Polymerization of G-actin into F-actin occurs through several regulated processes dependent upon actin nucleation events and several proteins - including profilin and actin-related protein 2/3 (Arp2/3) – that help initiate nucleation events needed to induce polymerization/depolymerization in the presence of Mg2+ and Ca2+ [112]. Actin treadmilling involves the addition of actin monomers at the barbed (or +) end in an adenosine triphosphate (ATP)bound state, and dissociation from the pointed (or ) end that is primarily in the adenosine disphosphate (ADP)-bound state [110,111]. Several Ca-binding protein families have a major role in maintaining actin dynamics. These include proteins important for actin filament severing (e.g. gelsolin) [113], nucleation (e.g. Rho GTPases), and filament cross-linking (e.g. a-actinin) [114]. Actin also associates with CaM [115]. In mast cells, CaM association with the actin cytoskeleton induces cortical F-actin disassembly [116]. A specific CaM mutant (cmd1A) in Saccharomyces cerevisiae has defective actin organization. Calmodulin can also activate and associate with other proteins that have a role in modulating actin dynamics. CaMK-II has been shown to positively regulate actin polymerization. The a and b isoforms of CaMK-II have been shown to have an actin binding domain involved in actin bundling in dendritic spines [117,118]. Recently, Hoffman et al. [119] showed that the CaMK-IId isoform also has F-actin bundling properties, whereas the c-isoform initiates a layered structure in filaments. Liu and Templeton [120] showed that in rat mesangial cells, CaMK-IId associates with actin filaments upon Cd2+ treatment, and that this association is abrogated by inhibition of CaMK-II. Therefore, it is possible that actin association with CaMK-II in non-neural cells has an important role in modulating cytoskeletal dynamics. It has been shown that Cd2+ contributes to depolymerization of the actin cytoskeleton in several cell lines, including rat mesangial cells [121]. In mesangial cells, Cd2+ selectively disrupts the F-actin cytoskeleton without a subsequent increase in G-actin monomers, unlike other divalent cations tested at similar concentrations [121,122]. This was not due to changes in [Ca2+]i, as inhibition of Ca2+ release from intracellular stores did not abrogate this effect. Interestingly, Cd2+ at concentrations >100 lM increased the rate of polymerization of G-actin monomers in vitro, whereas lower concentrations stabilized filaments [122,123]. However, when actin was polymerized in the presence of lysates from Cd-exposed cells, there was a decrease in the rate of G-actin polymerization, indicating that other cellular factors are involved [122]. In mesangial cells, the cellular factors that have been implicated in mediating cytoskeletal disruption by Cd2+ are gelsolin [124] and CaMK-II [120]. Therefore, the net effect of Cd2+ on the actin cytoskeleton may be due to several competing factors: (i) Binding to Ca2+ sites on G-actin monomers to enhance polymerization; (ii) activation of Ca2+-dependent proteins such as gelsolin and CaMK-II to effect decreases in polymerization; (iii) effects of kinases and apoptotic intermediates on actin filaments; and (iv) disruption of focal adhesions, in turn disrupting anchorage of actin filaments (see below).

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As Cd2+ has been shown to cause cytoskeletal disruption in several cell types, alterations in Ca2+ signaling and protein function may play significant roles in this disruption, which may either be a downstream consequence of apoptotic signals or an upstream activator of apoptosis. A more comprehensive review on the effects of Ca2+ on Cd-mediated cytoskeletal disruption in mesangial cells can be found in [125].

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6.2. Microtubules

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Microtubles (MTs) have a role in mediating mitosis, intracellular trafficking, maintenance of cell shape, and cellular motility. Microtubles consist of tubulin monomers (a, b) arranged in helical protofilaments. Microtubule assembly requires the heterodimer to bind 2 molecules of GTP, allowing for MT assembly through microtubule organizing centers (MTOC), with growth occurring fastest at the polarized ends. Phosphorylation and dephosphorylation of microtubule associated proteins (MAPs) may also modulate MT assembly [126]. Calmodulin binds to tubulin in a 2:1 M ratio, though this binding does not inhibit CaM activity [127]. Calmodulin has a dual role in mediating tubulin polymerization; in the presence of MAPs it has been shown to have an inhibitory effect, but in the absence of MAPs it can enhance the rate of polymerization of purified tubulin. These effects are dependent on the presence of Ca2+, and it is proposed that these effects are due to sequestration of Ca2+ by CaM and association with MAPs; EGTA and parvalbumin have the same effect [128]. Interestingly, this effect is independent of direct binding of CaM to MAPs. CaMK-II increases phosphorylation of a- and b-tubulin. Transient increases in [Ca2+]i resulted in localization of CaMK-II to MT dendrites, resulting in spine and synaptic remodeling, contributing to the plasticity of synpases [129]. Although CaMK-II has a role in MT remodeling, it does not activate MAP1a,b, or MAP2c at Ser-316, which control MT bundling [130]. To date, there is very little indication for a role of CaMK-II in changes to MT dynamics. Cadmium causes disassembly of microtubule complex in cultured Swiss 3T3 cells [131] and inhibited in vitro polymerization at concentrations of 0.5 mM Cd2+ [132]. However, Hamel et al. [133] showed that Cd2+ supported polymerization and enhanced polymer stability bringing to question the effect of Cd2+ on MTs. Further work needs to be done to clarify the role of Cd2+ on MT stability and if this process is mediated by changes to [Ca2+]i, CaM, and CaMK-II in a non-neural context.

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6.3. Cadherins

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Cadherins are transmembrane proteins involved in adherens junctions. They contain an extracellular Ca2+-binding domain, a transmembrane domain, and an intracellular domain that binds to catenins and the actin cytoskeleton [134]. There are three major forms of cadherins, dependent on the location: E-cadherin (epithelial), N-cadherin (neural) and P-cadherin (placental). Calcium ions have an important role in maintaining the structural stiffness of cadherins, with higher extracellular Ca2+ levels resulting in maintenance of adherens junctions. E-cadherin is a major extracellular target of Cd2+. Prozialeck [134] has shown that Cd2+ can displace Ca2+ from the extracellular domain of E-cadherin, causing activation of downstream signaling cascades. Based on time studies, it is probable that Cd is acting on the extracellular domain of E-cadherin to produce these results. Cadmium can compete with Ca2+ for the extracellular domain of cadherins [135], resulting in loss of cell–cell adherens junctions, an effect that was similar to that of Ca2+ depletion [136]. Cadmium can also alter the localization of E-cadherin, N-cadherins and b-catenin in proximal convoluted tubule cells [137]. Cadmium

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increases E-cadherin processing through c-secretase in T47D breast cancer cell lines [138]. The roles of CaM and CaMK-II in altering cadherin structure are unclear. Although cadherin function is primarily mediated through homotypic interactions of the extracellular domains, [139] have shown that IQGAP1, a member of the Rho GTPase family associates with both the actin cytoskeleton and CaM, potentially linking CaM function to E-cadherin. Therefore, given the link between CaM/ CaMK-II and other structural proteins, they may have a significant but undetermined role in affecting adherens junctions.

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6.4. Focal adhesions and intermediate filaments

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Focal adhesions (FAs) mediate contact between the extracellular matrix environment and the actin cytoskeleton, and play a critical role in regulating cell proliferation, apoptosis and migration [140]. Upon integrin clustering, the focal complex forms, resulting in recruitment of paxillin, talin, vinculin, a-actinin and focal adhesion kinase (FAK), which can subsequently recruit the cytoskeleton to FAs. Clustering activates FAK at the autophosphorylation site Tyr397, resulting in activation and recruitment of other kinases such as Src, to mediate changes in function [141,142]. To date, very little work has been done on the effects of Cd on focal contacts. We have recently shown that Cd2+ can disrupt focal contacts with disruption of the actin cytoskeleton and FAK signaling, directing phospho-Tyr925-FAK into a membrane fraction; the effect was dependent upon CaMK-II [143]. Immunofluorescence of vinculin also indicated that CaM may have a role in focal adhesion disruption in mesangial cells. Changes to CaM and CaMK-II mediate this effect, possibly due to changes in actin dynamics. This is in general agreement with Lek et al. [144] who showed an increase of CaM-dependent integrin adhesions in activated leukocytes. Further work must be done in other cell types to confirm that focal adhesions are a target of cadmium toxicity. Whether this effect is due to CaMK-II-dependent changes in the actin cytoskeleton, or possibly a consequence of suppression of an apoptotic pathway upon inhibition of CaMK-II, remains to be determined. Intermediate filaments also maintain cellular morphology and are responsible for cellular attachment, subcellular organization and signal transduction from the plasma membrane to the nucleus. Very few studies have focused on the role of Cd on intermediate filaments. Vimentin is an intermediate filament that regulates cellular attachment and subcellular organization, and proteolytic degradation of vimentin has been linked to apoptosis [145]. Interestingly, Cd treatment with 100 lM CdCl2 resulted in increased in vimentin protein and mRNA expression during a Cd-recovery phase [146]. In a neuroblastoma cell line, Cd2+ treatment for 30 min resulted in loss of morphology and disappareance of vimentin from a soluble cellular fraction [147]. This process was not dependent on MAPKs, caspases, or proteosomal degradation. Vimentin translocated into an insoluble fraction starting at 200 lM CdCl2 exposure, but this effect decreased at higher concentrations. The presence of vimentin in an insoluble fraction may indicate translocation of vimentin to the cytoskeleton, which is also seen with FAK [143]. This indicates that though MAPKs may not play a role, other CaMK-II substrates may alter localization of vimentin and (or) affect downstream factors that change vimentin expression. We have also seen a change in the filamentous structure of vimentin in rat mesangial cells, with Cd2+ treatment causing a collapse of the filaments to a perinuclear region and loss of a vimentin network within the cytoplasm. Interestingly, this change was shown to be abrogated by inhibition of CaMK-II with KN-93, but was unaffected by antagonism of CaM with TFP, despite the presence of an intact actin cytoskeleton (Fig. 3, unpublished data). As CaM is an upstream regulator of CaMK-II, it would be of interest

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Fig. 3. Effect of Cd2+ on cellular filaments. Immunohistochemical staining of vimentin and the actin cytoskeleton indicates that intermediate filaments localize to a perinuclear region upon Cd treatment. Rat mesangial cells were stained with Alexa Fluror 488-anti-vimentin antibody (green), rhodamine-phalloidin directed against F-actin (red), and the nuclear stain DAPI (blue); three-colour overlays are shown. (A) Control cells treated with serum-free medium alone showed an intact actin cytoskeleton and the presence of a vimentin network. (B) Treatment with 10 lM CdCl2 for 6 h caused vimentin to collapse and become disordered in a perinuclear region. (C) Cells pre-treated with 5 lM TFP to antagonize CaM showed no effect on vimentin localization upon Cd2+ treatment, although (D) inhibition of CaMK-II by 10 lM KN-93 partially prevented loss of the network structure of vimentin. Magnification in each panel is 400. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

to determine the CaM-independent and CaMK-II dependent effects of Cd2+ on intermediate filaments. CaMK-II is binds to vimentin, and subsequently phosphorylates vimentin at Ser38 and Ser82 sites [148]. The phosphorylation regulates dynamic vimentin filament assembly and disassembly in cultured cells [149]. Taken together, these results indicate that the effects of Cd on intermediate filaments should be more thoroughly explored, especially in the context of CaM and CaMK-II signaling.

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7. Conclusions and future prospects

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The biophysicochemical similarities of Cd2+ and Ca2+ allows Cd2+ to displace Ca2+ in some Ca2+-binding proteins, and to disrupt Ca-mediated signaling pathways. This ‘‘ionic mimicry’’ of Cd2+ may have a central role in mediating Cd toxicity, possibly through important changes in the activation of CaM and CaMK-II. It is difficult to evaluate the importance of CaM and CaMK-II independently of one another, as both respond to similar stimuli and CaM is an upstream activator of CaMK-II. Nevertheless, CaMK-II does have unique modes of activation, such as methionine oxidation in its autoregulatory domain. Although a large number of studies have investigated the role of [Ca2+]i, CaM, and CaMK-II in mediating changes to apoptosis or cellular morphology, relatively few have shown an effect of Cd on these parameters. Of particular interest are the effects of CaMK-II and CaM in mediating Cd-dependent cell death pathways, such as apoptosis, necrosis or autophagy. Studying downstream signaling cascades other than the MAPK pathways could determine if CaM or CaMK-II have a central role in mediating Cd toxicity. Additionally, the role of Cd on lesser studied cytoskeletal proteins, such as intermediate filaments and

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focal adhesion proteins, could provide more information on toxic mechanisms and the role of apoptosis. Does cytoskeletal disruption lead to apoptosis, or does apoptosis initiate cytoskeletal disruption in the context of Cd2+? Another important factor that must be considered is the effect of extracellular versus intracellular Cd2+ on these mechanisms. Rapid alterations in Ca2+-signaling pathways occur upon Cd2+ treatment, in what seems to be insufficient time for appreciable Cd2+ uptake to occur, indicating an effect on cell surface receptors or channels, but their identity remains elusive. Further determination of the short-term and long-term factors that are affected by spatial and molecular interactions of Cd2+ and Ca2+ will provide more insight into toxic mechanisms. While avoidance is key to minimizing Cd toxicity, and therapeutic strategies beyond general chelation therapy for treating Cd intoxication are not well established, further molecular strategies for ameliorating Cd toxicity might be considered based upon the interactions described here, and notably upon suppressing activation of the CaMK-IIdependent pathways.

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Conflict of interest

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The authors declare that there are no conflicts of interest.

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Q3

1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 1166 1167 1168 1169 1170 1171 1172 1173 1174 1175 1176 1177 1178 1179 1180 1181 1182 1183 1184 1185 1186 1187 1188 1189 1190 1191 1192 1193 1194 1195 1196 1197 1198 1199 1200 1201 1202 1203 1204 1205 1206 1207 1208 1209 1210 1211 1212

CBI 6977


27 January 2014 12 1213 1214 1215 1216 1217 1218 1219 1220 1221 1222 1223 1224 1225 1226 1227 1228 1229 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1242 1243 1244 1245 1246 1247 1248 1249 1250 1251 1252 1253 1254 1255 1256


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Cadmium toxicity.

Cadmium toxicity.

Cadmium-induced enteropathy: comparative toxicity of cadmium chloride and cadmium-thionein.

Cadmium toxicity to freshwater algae.

Combined effects of cadmium and salinity on juvenile Takifugu obscurus: cadmium moderates salinity tolerance; salinity decreases the toxicity of cadmium.

Cadmium toxicity and treatment: An update.

Effect of cadmium toxicity on Vertebrates.

Hydrogen sulfide modulates cadmium-induced physiological and biochemical responses to alleviate cadmium toxicity in rice.

Calcium signaling mediates the response to cadmium toxicity in Saccharomyces cerevisiae cells.

Studies on the toxicity and metabolism of cadmium-thionein.

Chronic toxicity of cadmium in Pteris vittata, a roadside fern.

Protective effect of phenobarbital on cadmium toxicity in mice.

Effects of vitamin B12 on cadmium toxicity in rats.

Cadmium toxicity in planktonic organisms of a freshwater food web.

The interaction of cadmium-binding proteins (Cd-bp) and progesterone in cadmium-induced tissue and embryo toxicity.

Dietary strategies for the treatment of cadmium and lead toxicity.

Influence of some factors on cadmium pharmacokinetics and toxicity.

[Long term toxicity of cadmium administered in very small doses to the rat: distribution of cadmium, zinc and copper].

Silicon-induced reversibility of cadmium toxicity in rice.

Hepatoprotective activity of Moringa oleifera against cadmium toxicity in rats.

Cadmium toxicity in silversmith: Safety is never too much!

Cadmium toxicity in the free-living nematode, Caenorhabditis elegans.

Cadmium.

Cadmium block of calcium current in frog sympathetic neurons.