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Organellar Calcium Buffers

Daniel Prins and Marek Michalak

Department of Biochemistry, School of Molecular and Systems Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2H7 Correspondence: [email protected]

Ca2þ is an important intracellular messenger affecting many diverse processes. In eukaryotic cells, Ca2þ storage is achieved within specific intracellular organelles, especially the endo- plasmic/sarcoplasmic reticulum, in which Ca2þ is buffered by specific known as Ca2þ buffers. Ca2þ buffers are a diverse group of proteins, varying in their affinities and capacities for Ca2þ, but they typically also carry out other functions within the cell. The wide range of organelles containing Ca2þ and the evidence supporting cross-talk between these organelles suggest the existence of a dynamic network of organellar Ca2þ signaling, mediated by a variety of organellar Ca2þ buffers.

INTRACELLULAR Ca2þ DYNAMICS that they also serve other roles within the cell. These roles include catalyzing the correct fold- a2þ serves as an intracellular messenger in ing of other cellular proteins, regulating Ca2þ various cellular processes, including muscle C release and retention, and communicating in- contraction, expression, and fertilization formation about Ca2þ levels within organelles (Berridge et al. 2003). To use Ca2þ, the cell to other proteins. requires a readily mobilizable source of Ca2þ, the majority of which is found within the lumen of the (ER) and/or sar- ENDOPLASMIC RETICULUM coplasmic reticulum (SR), but is also located in the , peroxisomes, mitochon- The ER is a multifunctional organelle within the dria, and endolysosomal compartments. It is eukaryotic cell that serves as the single largest not surprising that Ca2þ levels are of central im- Ca2þ store inside nonstriated muscle cells. The portance in dictating the function of proteins ER is also responsible for functions as diverse that reside in intracellular organelles. Although as synthesis and posttranslational mod- some Ca2þ exists as free ions within these com- ification, lipid and steroid metabolism, and partments, much of it is buffered by specific drug detoxification (Michalak and Opas 2009). proteins, simply known as Ca2þ buffers. How- Within the ER lumen, the total concentration ever, these proteins are diverse in terms of struc- of Ca2þ is approximately 1 mM, with free ture, oligomerization, affinity and capacity for Ca2þ in the range of approximately 200 mM Ca2þ, and physical basis for binding Ca2þ and the remainder buffered via ER resident pro- ions, one commonality across Ca2þ buffers is teins (Michalak and Opas 2009). Most ER Ca2þ

Editors: Martin D. Bootman, Michael J. Berridge, James W. Putney, and H. Llewelyn Roderick Additional Perspectives on available at www.cshperspectives.org Copyright # 2011 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a004069 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004069

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D. Prins and M. Michalak

buffering proteins also serve as ER chaperones showed that the tip of the P-domain protrusion or folding enzymes, responsible for correctly accounts for the binding site of ERp57, an protein folding that are transiting through oxidoreductase-folding enzyme (Frickel et al. the ER. 2002). The C-domain of calreticulin is enriched in negatively charged amino acid residues respon- Calreticulin sible for its Ca2þ-buffering capabilities (Naka- Calreticulin, a 46-kDa ER luminal resident pro- mura et al. 2001b). It binds Ca2þ with high tein, is responsible for buffering up to 50% of capacity (25 mol of Ca2þ per mol of protein) 2þ ER Ca in nonmuscle cells (Nakamura et al. and low affinity (Kd ¼ 2 mM) (Nakamura et al. 2001a; Nakamura et al. 2001b). Structurally, 2001b). The conformation of this region is calreticulin consists of three distinct domains: highly dependent on variations in Ca2þ concen- N, which is the amino-terminal and implicated trations within a physiological range (Corbett (together with the P-domain) in et al. 2000). SAXS studies indicate that the C- function; P, which is central, proline-rich, and domain of calreticulin may be globular (Nor- a structural backbone; and C, which is the gaard Toft et al. 2008). Ca2þ binding stabilizes carboxy-terminal and critical for Ca2þ buffer- the C-domain into a more compact, a-helical ing. The N-domain of , which is ho- conformation; the Ca2þ concentration required mologous to calreticulin, is primarily b-sheet to induce this change, 400 mM, is well within and globular, with high homology to the struc- the range of concentrations to which calreticu- ture of plant , suggesting a role in the lin would be exposed physiologically (Villamil binding of monoglucosylated substrates to cal- Giraldo et al. 2009). reticulin as part of its chaperone role (Schrag et al. 2001). Recent work using small angle Calreticulin Gain-of-Function X-ray scattering (SAXS) showed that the N- and Loss-of-Function domain of calreticulin itself is indeed globular and fits well onto modeled calnexin (Norgaard Understanding the roles calreticulin and Ca2þ Toft et al. 2008). The N-domain conformation play at cellular and organismal levels requires is dynamic and is stabilized by accounting for both its role as a chaperone binding (Saito et al. 1999; Conte et al. 2007) and as an ER luminal Ca2þ buffer. Cell culture and the binding of Ca2þ at a high-affinity site and animal models of calreticulin deficiency (Corbett et al. 2000; Conte et al. 2007), though (loss-of-function) and overexpression (gain- this binding does not affect its affinity for oligo- of-function) have shown how tight control of saccharides (Conte et al. 2007). protein folding and Ca2þ homeostasis, as ex- The P-domain of calreticulin is proline- erted by calreticulin, are necessary for proper rich, which suggests that it may show confor- function and development. mational flexibility. Its sequence contains two In mice, calreticulin deficiency (loss-of- pairs of repeated amino acid sequences, 1 and function) is lethal at embryonic day 14.5 be- 2, in the order 111222 (Fliegel et al. 1989). The cause of impaired cardiogenesis, manifested P-domain adopts an extended conformation as abnormally thin ventricular walls and im- with antiparallel b-sheets between the repeated proper myofibrillogenesis (Mesaeli et al. 1999). amino acid sequences; the domain as a whole The insufficiency in this pathway can be traced protrudes out from the N- and C-domains to a lack of nuclear translocation of NF-AT3 (Ellgaard et al. 2001a; Ellgaard et al. 2001b). The (nuclear factor of activated T-cells), which is ac- extended protrusion requires a b-hairpin turn tivated by calcineurin, a Ca2þ-dependent phos- at amino acid residues 238 to 241; small angle phatase. crt2/2 cells showed no cytoplasmic X-ray scattering (SAXS) analyses indicate that Ca2þ spike in response to the agonist bradyki- this is in a spiral-like conformation (Norgaard nin, indicating that the IP3 pathway to stimu- Toft et al. 2008). TROSY-NMR experiments late release of Ca2þ from the ER was affected

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Calcium Buffers

(Mesaeli et al. 1999). Embryonic lethality could implicated in cardiac development, suggesting be rescued via heterologous expression of a con- that calreticulin may play multiple roles in con- stitutively active mutant of calcineurin in the trolling downstream gene transcription (Hat- heart, demonstrating that calreticulin’s role in tori et al. 2007). cardiogenesis depends on its regulation of intra- cellular Ca2þ dynamics from the ER lumen Immunoglobulin Binding (Guo et al. 2002). Calreticulin may regulate the 2þ Protein BiP/GRP78 IP3RinaCa -dependent manner (Camacho and Lechleiter 1995; Naaby-Hansen et al. BiP (immunoglobulin binding protein), also 2001). Furthermore, in a cell culture model, car- known as GRP78, similarly to calreticulin, is diomyocytes derived from crt2/ – embryonic an ER luminal resident protein known to play stem cells showed lower rates of myofibrillar an important role in binding to unfolded pro- development (Li et al. 2002), thought to involve teins and assisting in the attainment of the cor- transcriptional pathways regulated by Ca2þ rect conformations. Its most prominent roles (Lynch et al. 2006). The critical role of Ca2þ sig- are as a regulator of the unfolded protein re- naling is underscored by the observation that sponse, a player in ER stress, and a crucial com- myofibrillar development could be rescued in ponent of the protein translocation machinery crt2/ – cells by transient ionomycin treatment (Dudek et al. 2009). BiP/GRP78 deficiency (Li et al. 2002). Taken together, these investiga- (loss-of-function) is extremely detrimental and tions show that the absence of calreticulin is lethal at embryonic day 3.5 in mice (Luo et al. severely affects Ca2þ-regulated pathways, via 2006). In addition to its protein binding func- both calreticulin’s Ca2þ buffering and its regula- tions, BiP/GRP78 serves as an important lumi- tion of protein folding. nal Ca2þ buffer, likely responsible for buffering Calreticulin overexpression (gain-of-func- approximately 25% of the total ER Ca2þ load tion) is also detrimental to the maintenance of (Lievremont et al. 1997). As BiP/GRP78 is Ca2þ homeostasis and the molecular pathways expressed at a higher level than is calreticulin, it regulates. Overexpressing calreticulin within its Ca2þ binding should be considered low ca- the lumen of the ER increases the amount of pacity, approximately 1–2 mol of Ca2þ per mol Ca2þ that can be released after inhibition of of protein, and low affinity (Lievremont et al. SERCAvia thapsigargin, showing that calreticu- 1997; Lamb et al. 2006). BiP/GRP78 contains lin does in fact buffer readily mobilizable Ca2þ an ATPase domain through which it harnesses within the ER (Mery et al. 1996). Furthermore, energy to fold its client proteins (Dudek et al. overexpression of calreticulin delays the process 2009). Intriguingly, the affinity of BiP/GRP78 of store-operated Ca2þ entry if ER luminal for Ca2þ is altered by its binding to ATP or depletion is incomplete but not when depletion ADP,suggesting interplay between ER Ca2þ fill- is complete, again suggesting that calreticulin ing and the chaperone activity of BiP/GRP78 buffers a significant amount of Ca2þ within (Lamb et al. 2006). Indeed, prolonged di- the lumen (Fasolato et al. 1998). At a cellular minishment of ER Ca2þ stores can abrogate in- level, augmented calreticulin levels increase the teractions between BiP/GRP78 and its client susceptibility of SERCA2a to oxidative stress proteins (Suzuki et al. 1991) and its ATPase (Ihara et al. 2005). In the murine heart, targeted activity is increased when Ca2þ levels are low overexpression of calreticulin and concomitant (Kassenbrock and Kelly 1989). BiP/GRP78 increased ER Ca2þ capacity results in impaired also plays a role in the protein translocation gap junctions, aberrant Ca2þ handling, and ar- machinery, both in binding to unfolded pro- rhythmia, culminating in heart block and death teins to maintain and prevent their misfolding (Nakamura et al. 2001a; Hattori et al. 2007). (Dudek et al. 2009) and, importantly, in closing Interestingly, calreticulin overexpression also the Sec61 channel to maintain the ER Ca2þ per- results in impaired synthesis of MEF2C (myo- meability barrier both before and after translo- cyte enhancer factor 2C), a transcription factor cation (Haigh and Johnson 2002; Alder et al.

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D. Prins and M. Michalak

2005). BiP/GRP78 is also a critical component blocks apoptosis, whereas siRNA knockdown of the unfolded protein response (Rutkowski of GRP94 eliminates the antiapoptotic effect and Kaufman 2004) and regulates ER associated of HCV E2 (Lee et al. 2008). In pancreatic can- degradation (ERAD) (Hebert et al. 2009). In cer patients, heightened expression of GRP94 summary, BiP/GRP78 is a crucial ER Ca2þ buf- correlated with a worsened prognosis because fer, accounting for about one quarter of the ER’s of GRP94’s antiapoptotic effect (Pan et al. buffering capacity, and also shows Ca2þ-de- 2009). Hypoxic conditions are known to up- pendent regulation of chaperone activity. regulate GRP94, underscoring its importance during tumor development (Paris et al. 2005). GRP94 has been shown to regulate apoptosis GRP94 via stabilization of Ca2þ homeostasis (Bando GRP94 (glucose regulated protein of 94-kDa, et al. 2004), suggesting that its antiapoptotic endoplasmin, CaBP4) is an ER resident protein effects are a consequence of its Ca2þ buffering with a Ca2þ buffering role (Macer and Koch rather than its peptide-binding activity. GRP94 1988); (Van et al. 1989). It binds Ca2þ with also protects against cell death induced by ische- high capacity (15 to 28 mol of Ca2þ per mol mia/reperfusion injuries (Bando et al. 2003). of protein) (Macer and Koch 1988; Van et al. 1989). Ca2þ binding can be further divided Protein Disulfide Isomerase into four sites of higher affinity (Kd ¼ 2.0 mM) and eleven sites of lower affinity (Kd ¼ Protein disulfide isomerase (PDI) is an ER lu- 600 mM) (Van et al. 1989; Ying and Flatmark minal protein that is capable of isomerizing 2006). Structurally, GRP94 undergoes a confor- disulfide bonds on proteins transiting through mational change to be less a-helical in the pres- the ER. It has long been known to bind Ca2þ ence of 100 mMCa2þ (Van et al. 1989; Ying and (Macer and Koch 1988) with high capacity Flatmark 2006). GRP94 binds to ER luminal (19 mol of Ca2þ per mol of protein) (Lebeche peptides and this binding is increased in the et al. 1994); (Lucero et al. 1994). Heterologous absence of Ca2þ, consistent with its role as a expression of PDI in Chinese hamster ovary response to ER stress (Ying and Flatmark 2006; cells increased the Ca2þ stored within ER micro- Biswas et al. 2007). Moreover, GRP94 binding somes (Lucero et al. 1998). Structurally, the to ATP induces a conformational change and carboxy-terminal region of PDI is enriched in subsequent dimerization. This enables recogni- paired acidic residues; removal of these residues tion of an immature client protein, whereas significantly reduces the amount of Ca2þ that attainment of the correct folding by the client PDI can bind (Lucero and Kaminer 1999). In protein leads to yet another shape change in general, PDI was enzymatically more active in GRP94 causing release of the substrate (Im- the presence of increased Ca2þ (Lucero and mormino et al. 2004; Rosser et al. 2004). In- Kaminer 1999), again showing modulation of triguingly, GRP94 is protective in cardiac enzyme activity by ER Ca2þ levels. pathologies, reducing cardiomyocyte necrosis in response to artificially induced Ca2þ over- ERp72, a PDI-Like Protein load or simulated ischemic insult (Vitadello et al. 2003). Furthermore, GRP94 expression is ERp72, an ER luminal protein with thiore- increased in hearts undergoing prolonged atrial doxin-like motifs, is homologous to the rat pro- fibrillation, hypothesized to have a protective tein CaBP2 (calcium-binding protein 2) (Van role against injury (Vitadello et al. 2001). et al. 1993). Its primary function appears to be GRP94 also plays a role in apoptosis, particu- as a molecular chaperone (Nigam et al. 1994) larly when related to perturbations in Ca2þ where it isomerizes disulfide bonds (Rupp homeostasis. The hepatitis C virus E2 protein et al. 1994). Though it does bind Ca2þ, the blocks apoptosis by inducing overexpression chaperone activity of ERp72 is unaffected by of GRP94: artificially increasing GRP94 levels Ca2þ concentrations (Rupp et al. 1994) and

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Calcium Buffers

overexpression of ERp72 does not increase ER is high capacity, with calculated values of mol Ca2þ stores, suggesting its protein folding ac- of Ca2þ bound per mol of cardiac tivity is more important than its Ca2þ binding ranging from 18 (Slupsky et al. 1987) to 60 (Park (Lievremont et al. 1997). et al. 2004). calsequestrin binds The ER, as the principal intracellular Ca2þ more Ca2þ than its counterpart: store in nonstriated muscle cells, has evolved up to 80 mol of Ca2þ per mol of protein for numerous proteins with the capability to buffer skeletal muscle calsequestrin compared to Ca2þ with variable capacities and affinities. 60 mol per mol of protein for cardiac muscle Most Ca2þ-buffering proteins also serve as key calsequestrin at saturating concentrations of modulators of protein folding, both upstream, Ca2þ (Park et al. 2004); (Wei et al. 2009b). as in calreticulin, which acts on unfolded pro- Ca2þ binding to both isoforms of calsequestrin teins to ensure their correct folding, and down- significantly affect the conformation of the pro- stream, as in BiP/GRP78, a key player in the tein, making it much more compact and playing unfolded protein response. In addition, most a role in oligomerization (Ikemoto et al. 1972; Ca2þ buffers are capable of dynamic responses Mitchell et al. 1988; He et al. 1993). to variations in ER Ca2þ levels, particularly The crystal structure of calsequestrin re- with respect to conformation. It is therefore vealed the presence of three almost identical clear that ER Ca2þ buffering capacity is inex- domains, each of which shows high homology tricably linked to other cellular processes that to Escherichia coli thioredoxin motifs, suggest- are the responsibility of the ER. ing that calsequestrin may be yet another Ca2þ- binding protein with the ability to fold other proteins (Wang et al. 1998). In vivo, skeletal SARCOPLASMIC RETICULUM muscle calsequestrin consists of long, ribbon- Ca2þ STORES like polymers that were described via electron The sarcoplasmic reticulum (SR) is an organ- microscopy (though not yet identified as calse- elle, closely related to the ER, that is found in questrin) as early as 1970 (Franzini-Armstrong cardiac, skeletal, and smooth muscle (Michalak 1970). In the presence of Ca2þ, calsequestrin and Opas 2009). Its major function is in regula- forms two different types of dimers, front-to- tion of Ca2þ fluxes responsible for muscular front and back-to-back. Both types are stabi- contraction by serving as the principal intracel- lized by salt bridges and Ca2þ ions binding lular Ca2þ store within muscle cells; total SR into the negatively charged pocket between two Ca2þ levels, similarly to the ER, are in the milli- copies of the protein (Wang et al. 1998). Back- molar range (Michalak and Opas 2009). to-back dimerization of skeletal calsequestrin The most abundant Ca2þ-binding protein occurs first; at a lower Ca2þ level (10 mM) within the SR is calsequestrin, a high capacity whereas at a higher Ca2þ concentration (1 mM), Ca2þ binding protein. There are two isoforms calsequestrin forms front-to-front dimers fol- of calsequestrin, skeletal muscle (calsequestrin- lowed by formation of linear polymers (Wang 1, or Casq1) and cardiac muscle (calsequestrin- et al. 1998). Electron tomography shows that 2, or Casq2) (Murphy et al. 2009). Interestingly, calsequestrin polymers are physically connected although fast-twitch muscle contains almost to the junctional region of the SR membrane in exclusively calsequestrin-1 isoform, slow-twitch muscle cells (Franzini-Armstrong 1970; Wagen- muscle fibers also contain some calsequestrin-2 knecht et al. 2002). Polymerization behavior (Murphy et al. 2009). Calsequestrins across nu- differs between the two calsequestrin isoforms: merous species show high (.75%) homology in vitro in the presence of 1 mM Ca2þ, calse- (Beard et al. 2004); moreover, the two isoforms questrin-1 is mostly polymerized whereas calse- show high homology to each other (Wei et al. questrin-2 is primarily monomeric or dimeric 2009b). Binding of Ca2þ to calsequestrin is (Park et al. 2003; Wei et al. 2009b). Calseques- based on extensive stretches of acidic amino trin-2’s polymerization may be inhibited by its acids within the carboxy-terminal region and longer carboxy-terminal tail interfering with

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D. Prins and M. Michalak

the Ca2þ-binding pocket (Park et al. 2004; Wei culminating in sudden death (Terentyev et al. et al. 2009b). These differences in polymeriza- 2006). The exact mechanisms linking mutated tion are thought to be related to the varying cardiac muscle calsequestrin to impaired Ca2þ Ca2þ capacities of the two isoforms, though it handling phenotypes vary from mutation to is unclear if polymerization affects Ca2þ capac- mutation. One human mutant of calsequestrin, ity or vice versa (Wei et al. 2009b). G112þ5X, is a frame-shift mutation leading to Calsequestrin is also known to interact with premature termination; this protein is incapa- the RyR. These interactions are thought to be ble of binding Ca2þ (di Barletta et al. 2006) or mediated by the transmembrane proteins junc- polymerizing (Terentyev et al. 2008). A different tin and triadin, though recent results suggest mutant of cardiac calsequestrin associated with that only junctin may be crucial for the regula- CPVT, R33Q, shows normal Ca2þ binding, but tion of RyR proteins by calsequestrin in skeletal has lost the capability to inhibit RyR on empty- muscle (Wei et al. 2009a). Interactions between ing of SR Ca2þ stores, both at rest and after stim- calsequestrin and the RyR depend on the lumi- ulation (Terentyev et al. 2006; Terentyev et al. nal Ca2þ concentration (Gyorke et al. 2004). In 2008). The R33Q mutation also impairs front- cardiac systems, calsequestrin-2 interacts with to-front dimerization, but not to such an extent triadin to inhibit RyR2 channel opening, possi- as to abrogate polymerization (Valleet al. 2008); bly regulated by SR luminal Ca2þ (Terentyev by contrast, the L167H mutation completely et al. 2007). Interactions between calsequestrin eliminates polymer formation (Valle et al. and RyR provide a range of sensitivity over 2008). The D307H mutation almost entirely el- the range of physiological Ca2þ concentration iminates the Ca2þ sensitivity of calsequestrin’s (Qin et al. 2008). The skeletal muscle isoform conformation and also impairs its binding to of calsequestrin also interacts with RyR pro- junctin, preventing interactions with the RyR teins, though in a different and more complex channel (Houle et al. 2004; Viatchenko- fashion than does the cardiac isoform. Cal- Karpinski et al. 2004; Kalyanasundaram et al. sequestrin-1 is known to undergo reversible 2009). From these results, it is clear that calse- phosphorylation at low Ca2þ concentrations questrin’s importance is not limited to its buf- corresponding to depleted SR Ca2þ stores. fering of Ca2þ but also its interaction with, Phosphorylated calsequestrin strongly interacts and regulation of, other constituents of the with junctin and hence inhibits the RyR1 chan- Ca2þ release pathway. This conclusion is under- nel (Beard et al. 2008). Junctin, but not triadin, scored by the fact that a 25% reduction in calse- is required for skeletal calsequestrin to exert reg- questrin levels does not affect SR Ca2þ levels, ulatory control over RyR1 channels (Wei et al. but does increase Ca2þ leak via RyR channels, 2009a). At resting SR Ca2þ levels, skeletal calse- pointing to a regulatory function of calseques- questrin inhibits RyR1; by contrast, cardiac cal- trin on RyR (Chopra et al. 2007). sequestrin activates both RyR1 and RyR2 (Wei A mouse model deficient in skeletal muscle et al. 2009b). calsequestrin (Casq1) has also been generated Mice deficient in the Casq2 gene have only (Paolini et al. 2007). The absence of calseques- 11% lower SR Ca2þ storage in cardiac muscle trin-1 is not lethal and surprisingly has only a cells (Knollmann et al. 2006). The hearts of slight effect on the contraction of skeletal mus- these mice display increased SR Ca2þ leak, espe- cles (Paolini et al. 2007). Absence of calseques- cially after catecholaminergic stimulation, caus- trin correlates to reduced Ca2þ release from ing ventricular (Knollmann et al. the SR (because of impaired Ca2þ accumulation 2006). Similarly, mutated forms of human car- near RyRs; partially compensated for by in- diac calsequestrin cause certain forms of CPVT creased expression of release channels) and (catecholamine-induced polymorphic ventric- reduced Ca2þ reuptake by the SR (because of ular tachycardia), a disease associated with pol- impaired Ca2þ buffering) (Paolini et al. 2007). ymorphic ventricular tachycardias in response Casq1 null mice have only 20% of the SR Ca2þ to adrenergic stimulation and exercise, often stores of wild-type mice, suggesting that the

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Calcium Buffers

role of skeletal calsequestrin in fast-twitch Minor SR Ca2þ Buffering Proteins muscles may be primarily its Ca2þ buffering, required to keep free luminal Ca2þ concentra- The minor SR Ca2þ buffering protein HRC tions low, thus reducing SR Ca2þ leaking (Mur- (histidine-rich Ca2þ binding protein) is a phy et al. 2009). The increased susceptibility of 165-kDa protein first identified and character- Casq1 null mice to heat stroke (Protasi et al. ized in 1989 (Hofmann et al. 1989; Hofmann 2009) is likely a consequence of increased SR et al. 1991). HRC binds Ca2þ with high capacity Ca2þ leakage in fast-twitch muscle fibers (Mur- and low affinity and, like calsequestrin, exists as phy et al. 2009). In mouse models of Duchenne a multimer within the SR lumen (Suk et al. muscular dystrophy, the most affected muscle 1999). However, in contrast to calsequestrin, fibers are associated with decreased levels of cal- which exists as higher order oligomers in the sequestrin and, consequently, impaired Ca2þ presence of increasing levels of Ca2þ, HRC dis- handling (Pertille et al. 2009). sociates from pentamers to dimers and tri- Experiments with calsequestrin overexpres- mers when Ca2þ levels are elevated (Suk et al. sion (gain-of-function) have solidified its role 1999). Moreover, unlike calsequestrin, HRC is as the key Ca2þ buffer within the lumen of less tightly folded and more sensitive to trypsin the SR. Mouse models specifically overexpress- digestion in the presence of Ca2þ (Suk et al. ing cardiac muscle calsequestrin in the heart 1999). HRC is known to be directly involved showed cardiac hypertrophy and increased in Ca2þ binding, as shown through studies quantities of Ca2þ stored within the SR, both that correlated overexpression of HRC with im- supportive of a role for calsequestrin as a Ca2þ paired SR Ca2þ uptake (Gregory et al. 2006) and buffer (Jones et al. 1998; Sato et al. 1998; increased total SR Ca2þ stores (Kim et al. 2003). Schmidt et al. 2000). Overexpression of calse- Early evidence showed that HRC, via its gluta- questrin increases SR Ca2þ stores and impairs mate-enriched carboxy-terminal region, inter- restoration of free Ca2þ levels within the SR acts with triadin in a Ca2þ-dependent manner lumen (Terentyev et al. 2003; Terentyev et al. to anchor HRC to the junctional membrane 2008), indicating that calsequestrin does buffer (Sacchetto et al. 1999; Lee et al. 2001; Sacchetto Ca2þ. Interestingly, the effects of overexpressing et al. 2001); this led to the hypothesis that HRC calsequestrin were similar to those of introduc- may also be responsible for regulating RyR ing a chemical Ca2þ buffer into the SR lumen activity through its interactions with triadin. (Terentyev et al. 2002; Terentyev et al. 2003), HRC also interacts with SERCA in cardiac indicating that calsequestrin’s functions in vivo muscle (Arvanitis et al. 2007), leading to the include both Ca2þ buffering and regulation of intriguing hypothesis that HRC may link Ca2þ the RyR proteins. release (via triadin) and Ca2þ uptake (via Calsequestrin, the primary Ca2þ buffer SERCA) in the SR lumen (Pritchard and Kranias within the SR, is a fascinating protein to con- 2009). HRC is implicated in cardiovascu- sider in terms of Ca2þ binding. Its conforma- lar disease: overexpression (gain-of-function) tion, oligomerization state, and interactions of HRC provides protection against heart dam- with other proteins all vary with physiological age induced by ischemia/reperfusion (Zhou concentrations of Ca2þ. Although it is unques- et al. 2007) whereas a S96A mutation in HRC tionably a Ca2þ buffer, equally important is has been identified in human patients to corre- its regulation of SR Ca2þ release via communi- late with decreased survival in idiopathic dilated cations with the RyR. As calsequestrin overex- cardiomyopathy (Arvanitis et al. 2008). Mice pression can be mimicked via introduction of deficient (loss-of-function) in HRC are more a nonprotein Ca2þ buffer, it seems evident that liable to develop cardiac hypertrophy when although some copies of calsequestrin are in- treated with isoproterenol (Jaehnig et al. 2006). volved in interactions with the RyR, the vast Junctate, a 33-kDa protein localized to the majority of calsequestrin is simply concerned SR membranes, is an alternative splice product with Ca2þ buffering in vivo. of the same gene that produces junctin (Treves

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D. Prins and M. Michalak

Ca2+

MITOCHONDRIA PEROXISOME NCX SARCOPLASMIC RETICULUM

CSQ IP 2+ 3 Ca Ca2+ HRC ? ? RyR Ca2+ Ca2+

Ca2+ SERCA

IP3R Ca2+ Ca2+

GRP94 ERp72 Ca2+ SERCA Ca2+ Ca2+ BiP/GRP78 Orai1 TCA CRT PDI STIM1 cycle ENDOPLASMIC RETICULUM Ca2+

2+ GRP94 Ca CRT 2+ ERGIC Ca

Ca2+ Lysosome Ca2+ IP R Regulation of gene Ca2+ 3 transcription SPCA Cab45 Ca2+

NUCLEUS CALNUC P54/NEFA

GOLGI APPARATUS

Figure 1. Organellar Ca2þ buffering and intracellular Ca2þ dynamics. Ca2þ is stored within several different organelles including the endoplasmic reticulum (ER), ERGIC, the Golgi apparatus, mitochondria, and perox- isomes. A typical Ca2þ release pathway is shown at top: an extracellular ligand binds to its receptor, leading to 2þ production of IP3, which binds to the IP3R on the ER membrane, stimulating release of Ca from the ER lumen. 2þ Note that the Golgi apparatus also contains IP3R molecules and thus may contribute to Ca release from stores; Golgi Ca2þ uptake occurs via SPCA pumps. As shown at left,Ca2þ released from the ER has several different fates, including regulation of gene transcription within the nucleus; uptake by mitochondria, which are typically closely apposed to the ER network and where Ca2þ can affect metabolism; or extrusion from the cell via Naþ/ Ca2þ exchanger plasma membrane proteins. Peroxisomes are known to maintain Ca2þ at higher levels than those of the cytoplasm, but how this gradient is developed and maintained is not yet known. Ca2þ levels are elevated in the ER, in the SR, in the ERGIC, and in the Golgi apparatus, with most Ca2þ bound to buffering proteins, as shown within these organelles. (See facing page for legend.)

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et al. 2000). It isa high capacity,moderateaffinity the Ca2þ buffering capabilities of CALNUC are Ca2þ-binding protein (Treves et al. 2000); conse- the most important and have been the most quently, overexpressing junctate in skeletal mus- extensively investigated. Cab45 is a 45-kDa cle increases total SR Ca2þ stores (Divet et al. soluble protein with six Ca2þ-binding EF- 2007). In addition to its luminal domain binding hands; interestingly, it was the first soluble pro- Ca2þ directly, in the ER, junctate interacts with tein shown to be retained in the Golgi lumen IP3R proteins and TRPC3 (transient receptor (Scherer et al. 1996), though later results show potential channel) channels to regulate Ca2þ Cab45 or its variants are also found in the cyto- homeostasis, both in response to agonists and plasm (Lam et al. 2007) and secreted by pancre- to store depletion (Treves et al. 2004). In the SR atic cancer cells (Gronborg et al. 2006). P54/ of mouse cardiomyocytes, junctate interacts NEFA (DNA binding/EF hand/acidic amino with SERCA2a, further linking it with Ca2þ han- acid rich region protein) contains two EF-hands, dling (Kwon and Kim do 2009). Overexpression but is thought to function in a regulatory role of junctate in the mouse heart leads to impaired rather than as a Ca2þ buffer (Morel-Huaux Ca2þ transients,culminatingin cardiac hypertro- etal.2002).AnotherGolgiCa2þ-bindingprotein, phy and arrhythmias (Hong et al. 2008). CALNUC, shows some homology to calreticulin andistightlyassociatedwiththeinnermembrane of theGolgiapparatus(Linetal.1998). CALNUC GOLGI Ca2þ STORES contains two EF-hand motifs, one of which has Although the ER and SR are accepted as the high affinity for Ca2þ, making the protein a low major organellar Ca2þ buffers, several other capacity, high-affinity Ca2þ buffer (Lin et al. subcellular organelles, including the Golgi ap- 1999). CALNUC is extremely abundant in the paratus, mitochondria, peroxisomes, and endo- Golgi lumen (approximately 0.4% of total Golgi somes/lysosomes, are known to maintain Ca2þ protein), suggesting that it may be the principal at significantly higher levels than those of the Golgi Ca2þ store (Lin et al. 1999). The apparent cytoplasm. affinity of CALNUC for Ca2þ has been reported The Golgi apparatus was identified as con- as 6–7 mM (Lin et al. 1999; Kanuru et al. 2009). taining Ca2þ in the millimolar range during CALNUC is tightly folded in the presence of the 1990s (Chandra et al. 1994; Pezzati et al. Ca2þ and that loss of Ca2þ exposes a large hydro- 1997). Golgi Ca2þ stores can be released in re- phobic surface (de Alba and Tjandra 2004). They sponse to InsP3-triggered pathways and were further postulate that this surface serves to shown to be developed by proteins residing modulate interactions with other proteins and within the Golgi, instead of existing solely be- that it may serve as both a Ca2þ buffer and a cause of vesicular trafficking from the Ca2þ-rich Ca2þ sensor (de Alba and Tjandra 2004). CAL- ER (Pinton et al. 1998). Ca2þ is bound within NUC has also been shown to be secreted (Lavoie the Golgi by three proteins, Cab45, P54/ et al. 2002) and may play a role in bone develop- NEFA, and CALNUC (nucleobindin), of which ment (Petersson et al. 2004).

Figure 1. (Continued) The store-operated Ca2þ entry (SOC) is also represented. In response to depleted ER Ca2þ stores, an ER luminal Ca2þ sensor, STIM1, oligomerizes and migrates to subplasmalemmal punctaewhere it communicates with Orai1. Orai1 functions as a plasma membrane Ca2þ channel that allows for Ca2þ entry from the extracellular milieu into the cytoplasm, where it is taken up by SERCA into the ER lumen. BiP/GRP78 binding protein/glucose-regulated protein of 78-kDa; CRT, calre- ticulin; ERGIC, endoplasmic reticulum/Golgi intermediate complex; GRP94, glucose-regulated pro- þ 2þ tein of 94-kDa; IP3, ; IP3R, inositol trisphosphate receptor; NCX, Na /Ca exchanger; P54/NEFA, DNA binding/EF hand/acidic amino acid rich region protein; PDI, protein disulfide isomerase; SERCA, sarcoplasmic/endoplasmic reticulum Ca2þ-ATPase; SPCA, secretory pathway Ca2þ-transport ATPase; STIM1, stromal interacting molecule 1.

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D. Prins and M. Michalak

The importance of Golgi Ca2þ signaling is covered in great detail here, but one aspect shown by the effects of its dysfunction. Hailey- worth highlighting is how mitochondria com- Hailey disease, characterized by skin blistering municate with the ER with respect to Ca2þ and lesions, is caused by mutations in the gene fluxes. Release of Ca2þ from the ER results in encoding SPCA1, the secretory pathway Ca2þ elevated cytoplasmic Ca2þ levels, after which ATPase responsible for maintenance of Golgi mitochondria take up Ca2þ resulting in elevated Ca2þ gradients (Hu et al. 2000; Sudbrak et al. matrix Ca2þ levels (Rizzuto et al. 1992). ER and 2000). Furthermore, reduced SPCA1 expression mitochondria are often tightly apposed in re- in a mouse model caused impaired neural gions known as mitochondria-associated mem- polarity (Sepulveda et al. 2009). branes (MAM); the interactions between these two organelles are regulated by cytoplasmic Ca2þ levels (Wang et al. 2000). Interestingly, ENDOPLASMIC RETICULUM GOLGI resting cytoplasmic Ca2þ levels promote disso- INTERMEDIATE COMPLEX ciation of the two organelles whereas higher There is growing evidence that the ERGIC Ca2þ levels enhance their association, suggest- (endoplasmic reticulum Golgi intermediate ing that mitochondria may act as buffers to complex) plays a role in Ca2þ storage, as would soak up Ca2þ released from the ER lumen be expected for a compartment located between (Wanget al. 2000). The Ca2þ cross-talk between two Ca2þ-enriched organelles. The ERGIC the ER and mitochondria is known to be impli- contains SERCA and significant quantities of cated in cell death and, consequently, may be a GRP94, usually thought of as an ER resident target in cancer therapy (Rizzuto et al. 2009). protein, allowing ERGIC to take up Ca2þ and buffer it (Ying et al. 2002). Calreticulin has PEROXISOMES also been detected within the ERGIC and may contribute to its Ca2þ buffering (Zuber et al. Recent results indicate that peroxisomes are 2000). capable of taking up and storing Ca2þ within ERGIC and the Golgi apparatus, as the two their lumens at concentrations much higher organelles following the ER in the secretory than those found in the cytoplasm (Raychaud- pathway, also contain Ca2þ at significantly hury et al. 2006; Lasorsa et al. 2008). However, it higher levels than those found in the cytoplasm. is not yet known how Ca2þ is stored within It is therefore intriguing that both compart- these organelles and whether there exist specific ments have been shown to take up and buffer peroxisomal Ca2þ buffering proteins. Ca2þ independently of trafficking from the ER. The proteins responsible for Ca2þ buffering ENDOLYSOSOMAL COMPARTMENT within ERGIC and the Golgi apparatus are, as with many of the previously discussed Ca2þ Recent results show that nicotinic acid adenine buffers, multifunctional and responsible for dinucleotide phosphate (NAADP) acts as a sec- communicating information about Ca2þ levels ond messenger to mobilize intracellular Ca2þ to other proteins. stores through actions on two-pore channels (TPCs) in endosomal membranes (Calcraft et al. 2009). Endosomes and lysosomes may MITOCHONDRIA thus be considered to be Ca2þ storage organ- Mitochondria, the cellular organelles responsi- elles; the importance of lysosomal Ca2þ is ble primarily for energy generation, are also shown by Niemann-Pick type C1 disease, a neu- intracellular Ca2þ stores. Within the matrix of rodegenerative lysosomal storage disease caused mitochondria, Ca2þ is stored not bound to by perturbations in lysosomal Ca2þ handling Ca2þ buffering proteins but instead precipitated (Lloyd-Evans et al. 2008). However, the mecha- 2þ out as an insoluble salt, CaPO4. The handling nism of lysosomal Ca buffering has not been of Ca2þ by mitochondria is too complex to be described.

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CONCLUSION sarcoplasmic/endoplasmic reticulum Ca2þ ATPase; SOCE, store-operated Ca2þ entry; SR, Eukaryotic cells use Ca2þ as an intracellular sig- sarcoplasmic reticulum; STIM1, stromal-inter- nal to regulate a wealth of processes; it is thus acting molecule-1. unsurprising to see that these cells have evolved equally varied proteins to buffer Ca2þ within the cell. The importance of these proteins is REFERENCES shown by consequences of their loss or muta- Alder NN, Shen Y,Brodsky JL, Hendershot LM, Johnson AE. tion, which frequently result in cardiac and/or 2005. The molecular mechanisms underlying BiP-medi- muscular phenotypes, emphasizing the impor- ated gating of the Sec61 translocon of the endoplasmic tance of Ca2þ in muscular contraction. One reticulum. J Cell Biol 168: 389–399. characteristic uniting organellar Ca2þ buffers, Arvanitis DA, Sanoudou D, Kolokathis F,Vafiadaki E, Papal- 2þ ouka V, Kontrogianni-Konstantopoulos A, Theodorakis which display such variety in their Ca binding GN, Paraskevaidis IA, Adamopoulos S, Dorn GWII, et and their responses to Ca2þ, is their multifunc- al. 2008. The Ser96Ala variant in histidine-rich calcium- tionality. Instead of being limited to serving as a binding protein is associated with life-threatening ven- 2þ tricular arrhythmias in idiopathic dilated cardiomyop- passive sponge for Ca within intracellular athy. Eur Heart J 29: 2514–2525. 2þ organelles, Ca -buffering proteins are respon- Arvanitis DA, Vafiadaki E, Fan GC, Mitton BA, Gregory sible for a variety of processes, including protein KN, Del Monte F, Kontrogianni-Konstantopoulos folding, regulation of apoptosis, and regulating A, Sanoudou D, Kranias EG. 2007. Histidine-rich Ca- 2þ binding protein interacts with sarcoplasmic reticu- Ca release pathways. It thus may be limiting lum Ca-ATPase. Am J Physiol Heart Circ Physiol 293: to name these proteins simply Ca2þ buffers, as H1581–H1589. this reduces their functions to just one, whereas Bando Y, Katayama T, Aleshin AN, Manabe T, Tohyama M. 2004. GRP94 reduces cell death in SH-SY5Y cells pertur- they typically have other roles that may trump bated calcium homeostasis. Apoptosis 9: 501–508. 2þ Ca buffering in importance. Furthermore, Bando Y, Katayama T, Kasai K, Taniguchi M, Tamatani M, the versatility of Ca2þ as a messenger suggests Tohyama M. 2003. GRP94 (94-kDa glucose-regulated that the presence of proteins that respond to protein) suppresses ischemic neuronal cell death against ischemia/reperfusion injury. Eur J Neurosci 18: 829–840. Ca2þ within so many organelles correlates to a 2þ Beard NA, Laver DR, Dulhunty AF.2004. Calsequestrin and network of Ca signaling linking subcellular the calcium release channel of skeletal and cardiac organelles, as shown in Figure 1. muscle. Prog Biophys Mol Biol 85: 33–69. Beard NA, Wei L, Cheung SN, Kimura T, Varsanyi M, Dulhunty AF. 2008. Phosphorylation of skeletal muscle calsequestrin enhances its Ca2þ binding capacity and ACKNOWLEDGMENTS promotes its association with junctin. Cell Calcium 44: 363–373. Work in our laboratory is supported by grants Berridge MJ, Bootman MD, Roderick HL. 2003. Calcium from the Canadian Institutes of Health Re- signalling: dynamics, homeostasis and remodelling. Nat search Heart (MOP-53050. MOP-15415, Rev Mol Cell Biol 4: 517–529. MOP-15291) and Stroke Foundation of Biswas C, Ostrovsky O, Makarewich CA, Wanderling S, Gidalevitz T,Argon Y.2007. The peptide-binding activity Alberta, Alberta Innovates–Heath Sciences. of GRP94 is regulated by calcium. Biochem J 405: D. Prins is supported by the Canadian Institutes 233–241. of Health Research Frederick Banting and Calcraft PJ, Ruas M, Pan Z, Cheng X, Arredouani A, Hao X, Charles Best Canada Graduate Scholarship– Tang J, Rietdorf K, Teboul L, Chuang KT, et al. 2009. NAADP mobilizes calcium from acidic organelles Master’s Award and a Studentship Award from through two-pore channels. Nature 459: 596–600. the Alberta Innovates–Health Sciences. Camacho P,Lechleiter JD. 1995. Calreticulin inhibits repet- itive intracellular Ca2þ waves. Cell 82: 765–771. Chandra S, Fewtrell C, Millard PJ, Sandison DR, WebbWW, ABBREVIATIONS USED Morrison GH. 1994. Imaging of total intracellular cal- cium and calcium influx and efflux in individual resting and stimulated tumor mast cells using ion microscopy. ER, endoplasmic reticulum; IP3, inositol- J Biol Chem 269: 15186–15194. 1,4,5-trisphosphate; IP3R, inositol-1,4,5-tris- Chopra N, Kannankeril PJ, Yang T, Hlaing T, Holinstat I, phosphate receptor; PDI, protein disulphide Ettensohn K, Pfeifer K, Akin B, Jones LR, Franzini- isomerase, RyR, ; SERCA, Armstrong C, et al. 2007. Modest reductions of cardiac

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Organellar Calcium Buffers

Daniel Prins and Marek Michalak

Cold Spring Harb Perspect Biol 2011; doi: 10.1101/cshperspect.a004069 originally published online January 12, 2011

Subject Collection Calcium Signaling

The Endoplasmic Reticulum−Plasma Membrane Primary Active Ca2+ Transport Systems in Health Junction: A Hub for Agonist Regulation of Ca 2+ and Disease Entry Jialin Chen, Aljona Sitsel, Veronick Benoy, et al. Hwei Ling Ong and Indu Suresh Ambudkar Calcium-Handling Defects and Neurodegenerative Signaling through Ca2+ Microdomains from Disease Store-Operated CRAC Channels Sean Schrank, Nikki Barrington and Grace E. Pradeep Barak and Anant B. Parekh Stutzmann Lysosomal Ca2+ Homeostasis and Signaling in Structural Insights into the Regulation of Ca2+ Health and Disease /-Dependent Protein II (CaMKII) Emyr Lloyd-Evans and Helen Waller-Evans Moitrayee Bhattacharyya, Deepti Karandur and John Kuriyan Ca2+ Signaling in Exocrine Cells Store-Operated Calcium Channels: From Function Malini Ahuja, Woo Young Chung, Wei-Yin Lin, et al. to Structure and Back Again Richard S. Lewis Functional Consequences of Calcium-Dependent Bcl-2-Protein Family as Modulators of IP3 Synapse-to-Nucleus Communication: Focus on Receptors and Other Organellar Ca 2+ Channels Transcription-Dependent Metabolic Plasticity Hristina Ivanova, Tim Vervliet, Giovanni Monaco, et Anna M. Hagenston, Hilmar Bading and Carlos al. Bas-Orth Identifying New Substrates and Functions for an Calcium Signaling in Cardiomyocyte Function Old Enzyme: Calcineurin Guillaume Gilbert, Kateryna Demydenko, Eef Dries, Jagoree Roy and Martha S. Cyert et al. Fundamentals of Cellular Calcium Signaling: A Cytosolic Ca2+ Buffers Are Inherently Ca2+ Signal Primer Modulators Martin D. Bootman and Geert Bultynck Beat Schwaller

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Role of Two-Pore Channels in Embryonic Organellar Calcium Handling in the Cellular Development and Cellular Differentiation Reticular Network Sarah E. Webb, Jeffrey J. Kelu and Andrew L. Wen-An Wang, Luis B. Agellon and Marek Michalak Miller

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Copyright © 2011 Cold Spring Harbor Laboratory Press; all rights reserved