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The Ca2þ Pumps of the Endoplasmic Reticulum and Golgi Apparatus

Ilse Vandecaetsbeek, Peter Vangheluwe, Luc Raeymaekers, Frank Wuytack, and Jo Vanoevelen

Laboratory of Ca2þ-transport ATPases, Department of Molecular Cell Biology, K.U.Leuven, B-3000 Leuven, Belgium Correspondence: [email protected]

The various splice variants of the three SERCA- and the two SPCA-pump genes in higher ver- tebrates encode P-type ATPases of the P2A group found respectively in the membranes of the endoplasmic reticulum and the secretory pathway.Of these, SERCA2b and SPCA1a represent the housekeeping isoforms. The SERCA2b form is characterized by a luminal carboxy termi- nus imposing a higher affinity for cytosolic Ca2þ compared to the other SERCAs. This is medi- ated by intramembrane and luminal interactions of this extension with the pump. Other known affinity modulators like phospholamban and sarcolipin decrease the affinity for Ca2þ. The number of proteins reported to interact with SERCA is rapidly growing. Here, we limit the discussion to those for which the interaction site with the ATPase is specified: HAX-1, calumenin, histidine-rich Ca2þ-binding protein, and indirectly calreticulin, cal- nexin, and ERp57. The role of the phylogenetically older and structurally simpler SPCAs as transporters of Ca2þ, but also of Mn2þ, is also addressed.

ll cells invest a considerable part of their pumps can be discerned in Eumetazoa: the Atotal energy budget in active transport to SERCA-,theSPCA-,andthePMCA-type.Where- keep up transmembrane (TM) ion gradients as ancestral representatives of each type are (Rolfe and Brown 1997). Prokaryotes already recognized in some Eubacteria and Archaea, it evolved P-type ion-transport ATPases/ion is also remarkable that some Eukaryotes have pumps to that aim (Axelsen and Palmgren apparently lost either SERCA or SPCA pumps. 1998). The name P-type refers to the transient Yeast for instance lacks SERCA pumps whereas transfer of the g-phosphate group of ATP to a plants thrive well without SPCAs (Mills et al. highly conserved aspartate group in the enzyme 2008). The SERCA pumps, which are found in forming a phospho-intermediate. This auto- the endoplasmic reticulum (ER) or in the sar- phosphorylation is an important step in the coplasmic reticulum (SR) of eukaryotic cells pump’s catalytic cycle (Kuhlbrandt 2004). and the evolutionary older secretory pathway Based on amino-acid sequence comparisons ATPases (SPCA) found in the Golgi apparatus, and on the exon/intron layout of the corre- are closely related to each other and together 2þ sponding genes, three types of P-type Ca belong to the P2A subfamily. They form the

Editors: Martin D. Bootman, Michael J. Berridge, James W. Putney, and H. Llewelyn Roderick Additional Perspectives on Calcium Signaling available at www.cshperspectives.org Copyright # 2011 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a004184 Cite this article as Cold Spring Harb Perspect Biol 2011;3:a004184

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topic of this review. The plasma-membrane 500 mM) luminal ER Ca2þ concentration. The Ca2þ-pumps (PMCA), on the other hand, ER not only serves as a useful Ca2þ store for appear to be phylogenetically the oldest of the the release of Ca2þ that activates an impressive three and form the P2B-subfamily branch. number of cellular activities (e.g., contraction, PMCAs are addressed in an article by Brini fertilization, insulin release, etc.) but it also and Carafoli (2009). Some further information creates the luminal environment necessary for on the evolution of the three types of ATPases almost all local enzyme activities (such as was recently reviewed by Palmgren and Axelsen protein folding and synthesis of lipids and ste- (1998) and Vangheluwe et al. (2009). Of the roids) and that controls cell fate (proliferation, three families, only SERCA pumps translocate apoptosis, growth, or differentiation) (Wuytack two Ca2þ ions and hydrolyze one ATP for each et al. 2002). catalytic turnover. They possess two Ca2þ- The muscle variant SERCA2a removes the transport sites: site I and site II; the numbers Ca2þ stimulus for contraction by pumping specify the sequence of filling of the respective myoplasmic Ca2þ into the SR and thereby sites. The single Ca2þ-binding site of the SPCA determines the Ca2þ load of the SR, which in and PMCA pumps structurally corresponds to turn determines the amount of Ca2þ that can site II of SERCA (Toyoshima 2009). be released for the next contraction. Together, SERCA2a is a major determinant of the speed and force of cardiac contraction and relaxation 2þ THE UBIQUITOUS SERCA2 Ca PUMP (Periasamy and Huke 2001). SERCA2 expres- SERCA2 Splicing Variants sion is reduced in end-stage heart failure, contributing to an impaired contractility of Vertebrates generate multiple SERCA isoforms the heart (Hasenfuss et al. 1994). as a result of alternative processing of the Ablation in mice of the two Atp2a2 alleles is transcripts of three paralogous SERCA genes incompatible with life (Periasamy et al. 1999). (ATP2A1-3) (Brini and Carafoli 2009). Inverte- But in light of the central role SERCA2a exerts brates typically have only a single SERCA gene in the heart, it is quite surprising that in an that is orthologous to the vertebrate housekeep- inducible cardiac-specific knock-out mouse ing SERCA2. The two major vertebrate SERCA2 model at 4 weeks following Atp2a2 gene dele- protein isoforms are the housekeeping SER- tion, cardiac function remained near normal CA2b and the more specialized SERCA2a in spite of the drop of the myocardial SERCA2 isoform. The latter is found in slow skeletal levels below 5% of controls (Andersson et al. muscle and cardiac muscle, but is also expressed 2009). However, end-stage heart failure devel- in lower amounts in smooth muscle and in oped at 7 weeks. These results show the remark- neuronal cells (Vandecaetsbeek et al. 2009a). able power of a compensatory (albeit ultimately Recently novel SERCA2c (Dally et al. 2006) failing) response to such a major acute re- and SERCA2d (Kimura et al. 2005) isoforms duction in SERCA2 function (Andersson et al. were discovered in the heart, but are expressed 2009). The effect of heterozygous knock-out at low levels and their physiological meaning of Atp2a2 in mice is also paralleled by com- remains to be further explored. pensatory responses, with only slight impact on cardiac contractility and relaxation without eliciting cardiac disease (Periasamy et al. 1999; Physiological Role of SERCA2 Ji et al. 2000). With age, these heterozygotes The housekeeping SERCA2b Ca2þ pump serves are prone to develop squamous cell tumors, a dual role. By translocating Ca2þ from the which supports the notion that altered Ca2þ cytosol into the lumen of the ER, it restores homeostasis plays a significant role in cancer the cytosolic Ca2þ concentration to its low (Liu et al. 2001; Prasad et al. 2005). Likewise, resting level (circa 100 nM). At the same time, humans lacking one functional ATP2A2 allele SERCA2b maintains a sufficiently high (circa do not develop cardiomyopathy (Tavadia et al.

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Intracellular Ca2þ Pumps

2001), but the effect of reduced Ca2þ uptake even if the overall sequence similarity is low activity is manifested in keratinocytes, where it (Fig. 1). Three cytosolic domains can be recog- triggers the onset of the skin disorder of Darier nized in the P-type ATPases: a nucleotide- (Sakuntabhai et al. 1999). binding (N), phosphorylation (P), and actuator Whereas previous studies suggest that (A) domain (Fig. 1). ATP binds on the N- changes in SERCA2 expression levels are rea- domain, whereas the P-domain drives ATP sonably well tolerated in the heart (Ji et al. hydrolysis leading to phosphorylation of a 2000; Tavadia et al. 2001), other studies point highly conserved aspartate in the P-domain. to a more critical regulation of the apparent The A-domain then contains a conserved gluta- affinity of the Ca2þ pump for cytosolic Ca2þ mate that catalyzes the dephosphorylation of ions (MacLennan and Kranias 2003; Vande- the P-domain (Kuhlbrandt 2004; Vangheluwe caetsbeek et al. 2009a; Sipido and Vangheluwe et al. 2009). The large headpiece is intimately 2010). For normal cardiac function, the affinity connected with and partially embedded in the of SERCA2a in the cardiac SR needs to be con- TM region that contains the ion-binding sites. trolled within a tight window (Vangheluwe et al. This connection assures tight coupling between 2005a; Vandecaetsbeek et al. 2009a). Genetic ATPhydrolysis in the cytosolic domains and ion manipulations in mouse that lead to the expres- transport across the membrane. Surprisingly, sion of the high Ca2þ-affinity variant SERCA2b the overall structure of the TM region is also in the cardiomyocyte instead of the normal highly conserved with only subtle differences SERCA2a, triggers cardiac hypertrophy and accounting for ion specificity (Gadsby 2007). heart failure (Ver Heyen et al. 2001; Vangheluwe The accessibility of the TM Ca2þ-binding sites et al. 2006b). Likewise, in humans (Haghighi in SERCA1a is controlled by both a cytosolic et al. 2003), but not in mice (Luo et al. 1994), and a luminal gate, which are under control of the increased Ca2þ affinity resulting from the the phosphorylation and dephosphorylation absence of phospholamban (PLN, i.e., an affin- events, respectively, in the headpiece (Moller ity modulator of the pump, discussed below) et al. 2005; Toyoshima 2008; Toyoshima 2009). triggers heart failure (Haghighi et al. 2003). Moreover, a feedback mechanism associated On the contrary, a chronic reduction in the with ion binding guarantees that ATPhydrolysis Ca2þ affinity triggered by a higher activity of can only occur when ions are bound. This tight PLN is also associated with dilated cardiomyop- coupling assures that first the cytosolic gate athy in humans (Haghighi et al. 2001; Schmitt closes and Ca2þ ions are occluded before ATP et al. 2003; Haghighi et al. 2006). hydrolysis and opening of the luminal gate can occur (Moller et al. 2005; Toyoshima 2008; Toyoshima 2009). This allows Ca2þ ions The Ca2þ-Pumping Mechanism to be pumped against an almost 10000-fold Ten years ago, the first high-resolution crystal gradient across the ER/SR membrane (Toyosh- structure of the fast-twitch skeletal-muscle ima 2009). isoform SERCA1a was published (Toyoshima et al. 2000). Since then, we have been spoilt by Structure of the Ubiquitous high-resolution crystal structures of SERCA1a SERCA2b Pump in nine different conformations, yielding de- tailed molecular insights of the Ca2þ-pumping Although the ubiquitous SERCA2b pump process (reviewed in Moller et al. 2005; Toyosh- shares an overall 85% sequence identity with ima 2008; Toyoshima 2009). In addition, struc- SERCA1a, which points to a common Ca2þ- tures of other archetypical P-type ATPases pumping mechanism (Toyoshima 2009), three (Naþ/Kþ-ATPase [Morth et al. 2007; Shinoda related properties discriminate the SERCA2b et al. 2009] and Hþ-ATPase [Pedersen et al. isoform from SERCA1a or SERCA2a: the char- 2007]) were reported. The basic structure of acteristic two-fold higher affinity for cytosolic these P-type ATPases is very well conserved, Ca2þ ions, the lower maximal turnover rate

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I. Vandecaetsbeek et al.

Figure 1. Interesting structural similarities between SERCA2b and Naþ/Kþ-ATPase. (A) The PLN NMR struc- ture (Seidel et al. 2008) and the carboxyl terminus of SERCA2b (Vandecaetsbeeket al. 2009b) modeled on the E2 crystal structure of rabbit SERCA1a (2AGV) (Obara et al. 2005). (B) Crystal structure of the pig renal Naþ/Kþ- ATPase a-subunit (2ZXE) (Shinoda et al. 2009) in the E2 conformation, together with its regulatory b- and g-subunits. Interesting similarities exist between the binding sites of the regulatory b- and g-subunits on the Naþ/Kþ-ATPase and, respectively, the 2b-tail and PLN on the SERCA1a pump. Orange: A-domain; Blue: P- domain; Green: N-domain; Gray: TM-domain. PLN, phospholamban; SLN, sarcolipin; 2b-tail, SERCA2b carboxyl terminus.

and the presence of a unique carboxy-terminal TM7 and TM10 of the Ca2þ ATPase, a relatively extension (2b-tail) comprising an additional immobile part of the pump. A groove between TM segment (TM11) and a luminal exten- luminal loops L5-6 and L7-8 is opened at the sion (LE) (Lytton et al. 1992; Verboomen et al. luminal side of TM11, for the descent of LE. 1994; Dode et al. 2003; Vandecaetsbeek et al. This displacement allows that the peptide con- 2009b). Functional measurements on SERCA2b sisting of the last four, crucial amino-acids at mutants and SERCA1a-2b chimeras revealed the pump’s carboxyl terminus (1039-MFWS) that both of these regions contribute to the reaches a luminal binding pocket that is formed functional effect of the 2b-tail (Verboomen by the five luminal loops of the pump (Vande- et al. 1994; Vandecaetsbeek et al. 2009b). Based caetsbeek et al. 2009b). This intramolecular on the known SERCA1a crystal structures and interaction stabilizes the pump in the Ca2þ- the solved NMR structure of TM11, a struc- bound E1 conformation with high-affinity tural model for SERCA2b was proposed that is binding sites facing the cytosol. Mathematical backed up by extensive mutagenesis results modeling confirmed that this could explain (see Fig. 1A in Vandecaetsbeek et al. 2009b). Ac- the increased apparent affinity for Ca2þ cording to that model, TM11 is interacting with (Vandecaetsbeek et al. 2009b). Moreover, the

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experimentally observed slower E1-P to E2-P Phospholamban and Sarcolipin and E2-P to E2 transitions (Dode et al. 2003) are tightly coupled to extensive rearrangements The related small TM proteins PLN and sarcoli- of the proposed luminal docking site of the pin (SLN) are the best-studied regulators of the 2b-tail (Vandecaetsbeek et al. 2009b). How the SERCA pump (reviewed in MacLennan and short TM11 a-helix alters the enzymatic prop- Kranias 2003; Vangheluwe et al. 2006a; Bhu- erties at the distant and relatively immobile pathy et al. 2007; Periasamy et al. 2008). In TM helices TM7 and TM10, remains to be contrast to the 2b-tail, these proteins interact clarified. with the pump to reduce the apparent affinity for cytosolic Ca2þ ions, which inhibits overall Ca2þ transport (Lee 2003; MacLennan and Kra- nias 2003). In vivo, PLN is mainly coexpressed Regulators of the ER Ca2þ Pump with SERCA2a in the heart, smooth muscle, Given its central position in cellular Ca2þ and slow-twitch skeletal-muscle fibers. During homeostasis, the activity of SERCA2 is prone the b-adrenergic response in cardiac muscle, to tight regulation. At least a dozen of different phosphorylation of PLN by protein kinase A proteins were suggested to regulate SERCA2 and/or Ca2þ-calmodulin kinase II (CaMKII) activity (previously reviewed in Vangheluwe promotes dissociation of the complex, which et al. 2005a; Vandecaetsbeek et al. 2009a). This reverses the inhibition of SERCA2a (reviewed suggests that as for the intracellular Ca2þ in MacLennan and Kranias 2003). Dissociated channels inositol-1,4,5-trisphosphate receptor PLN also exists in a stable but inactive, pen- (IP3R) or the ryanodine receptor (RyR) (Fos- tameric state, which is promoted by phosphor- kett et al. 2007), SERCA2 might form a multi- ylation (Kimura et al. 1997). PLN-SERCA2a protein complex varying in composition in dif- dissociation causes a dramatic increase in SR ferent cell types. However, because of its smaller Ca2þ transport leading to improved cardiac size and the requirement to undergo major contraction and relaxation (Luo et al. 1994). conformational changes during its enzymatic Studies in numerous PLN animal models fur- cycle, formation of a macromolecular SERCA ther showed its central role in cardiac contractil- complex is probably more restricted. ity (reviewed in MacLennan and Kranias 2003). It is of some concern that studies on Moreover, human PLN mutations leading to the effect of putative SERCA modulators often either a chronic increase like L39stop (Haghighi rely on overexpression, which on itself can et al. 2003) or decrease like R14del (Haghighi lead to ER stress via the unfolded protein et al. 2006) or R9C (Schmitt et al. 2003) of response (UPR) that includes up-regulation of the apparent Ca2þ affinity of the pump trigger SERCA2b expression and activity (Caspersen the onset of dilated cardiomyopathy and heart et al. 2000). In addition, the effect of these failure at a young age. In line with the effect of modulators is almost never confined to SERCA the SERCA2a!b isoform switch (Vangheluwe because they are nearly always part of the Ca2þ et al. 2006b), these studies further indicate signalome also affecting Ca2þ release channels. that regulating the Ca2þ affinity of the pump Finally, direct interaction of these regulators is of vital importance to maintain normal car- with the pump is often documented by im- diac function and development (Vangheluwe munoprecipitation, which for TM proteins et al. 2006a). This appears to be more important is technically very challenging. The thriving in humans than in mice (Haghighi et al. 2003; literature of putative SERCA regulators should MacLennan et al. 2003; Zhao et al. 2006). therefore be viewed with caution as long as the More recent studies suggest that the regulation interaction site is not properly identified. of the pump by PLN phosphorylation is crucial Here, we will only focus on those regulators for maintaining some cardiac reserve to prevent for which the binding site on the Ca2þ pump heart failure (Schmitt et al. 2009). This is in line is defined and well-documented (Fig. 2). with an increased morbidity and mortality in

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A B

E1 HAX-1 E2 HAX-1

E595-V594 E595-V594 K397-P401

PLN

K328 R324 L321

2b-tail

F92 V89 N1035-S1037 SLN CRT/CLNX F73 F88 A853-E892 W77 L1-2 A853-E892 C887 CALU CALU V74-P92 V74-P92 C887 L1-2 HRC L7-8 HRC L7-8 C875 C875 ERp57 ERp57

Figure 2. Interaction sites of different SERCA regulators. Different interaction sites are depicted on the crys- tal structure of rSERCA1a in the E1 conformation (1SU4) (Toyoshima et al. 2000) (A) and in E2 (2AGV) (Obara et al. 2005) (B). Note that PLN and SLN only interact in E2, and the 2b-tail predominantly in E1, and therefore are only depicted in the respective conformations. CALU, Calumenin; PLN, phospholamban; SLN, sar- colipin; HAX-1, HS1-associated protein; CRT, calreticulin; CLNX, calnexin; ERp57, endoplasmic reticulum thiol-disulfide oxidoreductase; HRC, histidine-rich Ca2þ-binding protein; 2b-tail, SERCA2b carboxyl terminus.

heart failure patients with a lower response to N-domain of SERCA2a (in the region 397- b-agonists (Wu et al. 2004; Kobayashi et al. 401) and a lysine in the cytosolic region of 2008). PLN (K3) (James et al. 1989). To date, evidence PLN inhibits the SERCA2a and SERCA2b for at least three sites of close association isoforms to the same extent (Verboomen et al. between SERCA1a and PLN was provided by 1992), thus occupying a different affinity-regu- robust homobifunctional crosslinking: between lating site on the Ca2þ pump than the 2b-tail V89C positioned on TM2 of SERCA1a with (see Fig. 1A in Vandecaetsbeek et al. 2009b). V49C (Toyoshima et al. 2003), between L321C In fact, extensive crosslinking, site-directed mu- at the cytosol-membrane boundary of SER- tagenesis and structural modeling studies have CA1a TM4 with N27C (Toyoshima et al. shown that residues in both the cytoplas- 2003), and between K328C in the cytosolic mic and the TM portions of PLN are involved domain with Q23C (Morita et al. 2008). Addi- in direct interaction with SERCA2a (Fig. 2B) tional heterobifunctional crosslinks were ob- (James et al. 1989; Kimura et al. 1996; Asahi served between the SERCA2a isoform and et al. 1999; Asahi et al. 2001; Toyoshima et al. PLN, but unexpectedly and in apparent contrast 2003). First proof of the direct interaction be- with earlier studies, no such crosslinks were tween SERCA and PLN came from a homo- observed involving K3 of PLN (Chen et al. bifunctional crosslink between a lysine in the 2003). Phosphorylation of PLN or high Ca2þ

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concentrations lead to the (partial) dissocia- having similar regulatory properties (Traaseth tion of the PLN-SERCA2a complex preventing et al. 2008). The aromatic residues of the highly crosslinking (Chen et al. 2007; Morita et al. conserved luminal extension RSYQYof SLN are 2008). Together, these studies showed that the functionally relevant (Odermatt et al. 1998) and interaction of the PLN TM region occurs in a would interact with aromatic residues on the hydrophobic cleft only present in the Ca2þ-free face of luminal loop L1-2 of SERCA (possibly E2 conformation that is formed by TM2,4,6,9 with the side chains of F73, W77, F88 or F92), (Toyoshima et al. 2003). This interaction occurs opposite to that which constitutes the luminal at the border between the highly mobile interaction site of the 2b-tail (Fig. 2) (Hughes (TM1-6) and the immobile (TM7-10) parts of et al. 2007). TM1 undergoes a strong upward the pump and inhibits the closing of the cleft movement during the enzymatic cycle, which during the transition from E2 to E1. The pro- might be affected by this interaction. Notably, found effect of PLN phosphorylation on the this SLN luminal tail is also crucial for proper functional and physical interaction with the integration of SLN in the membrane (Gramo- Ca2þ pump already indicates that the cytosolic lini et al. 2004). interaction with the N-domain could be equally PLN and SLN would fit together side-by- important. This is further corroborated by the side into the same TM cleft TM2,4,6,9, leading functional effect of mutating the cytosolic to a tighter functional interaction (Fig. 2B) domain of PLN (reviewed in MacLennan et al. (Asahi et al. 2003). This would explain the 2003). Phosphorylation would partially un- super-inhibitory properties of the PLN-SLN wind the cytosolic region, indicating an order- heterodimers observed in vitro (Asahi et al. to-disorder transition (Metcalfe et al. 2005; 2002). Given the functional importance of the Karim et al. 2006), which would prevent more cytosolic domain of PLN and luminal extension distant interactions such as a crucial H-bridge of SLN, an additional stabilization of the com- between R324 and Q26 (Traaseth et al. 2006; plex might arise from their combined inter- Traaseth et al. 2008). Togetherthis would loosen action with the pump (Hughes et al. 2007). So the interaction or even cause a complete dis- far, there is no clear evidence for this super- sociation of the PLN-SERCA2a complex. inhibition under physiological circumstances Although several lines of evidence indicate in the atria of the heart where both SERCA that monomeric PLN is the active species regulators are found (Bhupathy et al. 2007; Peri- (Kimura et al. 1997), recent structural observa- asamy et al. 2008; Vandecaetsbeek et al. 2009a). tions indicate that PLN pentamers might also Surprisingly, the proposed positions of the interact with the pump, although at a different 2b-tail and PLN/SLN on the Ca2þ pump strik- site (close to TM3) than the monomer. It re- ingly mirrors the observed interaction site of mains unknown whether this serves a physio- the Naþ/Kþ-ATPase b- and g-subunits (Fig. logical function (Stokes et al. 2006). 1) (Toyoshima et al. 2003; Morth et al. 2007; SLN appeared to act as the functional coun- Vandecaetsbeek et al. 2009b). Although these terpart of PLN in fast-twitch skeletal-muscle. modulators evolved independently from each But SLN is also found together with PLN in other, they seem to occupy similar binding sites the atria of the heart (Minamisawa et al. 2003; on the corresponding pump sharing similar Vangheluwe et al. 2005b; Babu et al. 2007a), molecular mechanisms. In all cases, the func- where it modulates the activity of the SERCA2a tional effect is related to a combined interaction pump and is under control of b-adrenergic of a TM region and luminal or cytosolic exten- stimulation (Babu et al. 2007b), presumably sions with the pump, which might stabilize one via CaMKII-dependent phosphorylation of T5 of the conformational intermediates of the (Bhupathy et al. 2009). By analogy, the conser- enzyme (Vandecaetsbeek et al. 2009b). Notably, vation in sequence, structure and dynamics the site of interaction of the g-subunit was between SLN and PLN suggest that SLN would determined from the E2 Naþ/Kþ-ATPase crys- fit into the same hydrophobic groove as PLN tal structure (Morth et al. 2007; Shinoda et al.

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2009), but in contrast to earlier modeling of an ER distribution on cotransfection with PLN on SERCA1a (Toyoshima et al. 2003) and PLN (Vafiadaki et al. 2007), but not on cotrans- the g-subunit on Naþ/Kþ-ATPase (Li et al. fection with SERCA1a or SERCA2 (Vafiadaki 2004), the binding occurs on TM9, at the out- et al. 2009a). Interaction of HAX-1 in the outer side of the proposed cleft. membrane of the mitochondria and with the ER-based SERCA could be possible at the ER-mitochondrial nexus sites, which are con- Antiapoptotic Proteins HAX-1 and Bcl-2 sidered crucial for eliciting apoptosis. HAX-1 The HS1-associated protein HAX-1 (35 kDa) is overexpression in HEK-293 cells results in a an integral membrane protein normally resid- posttranscriptional downregulation of SERCA2 ing in the outer mitochondrial membrane protein levels. The resulting lower ER Ca2þ con- (Suzuki et al. 1997; Vafiadaki et al. 2009b). It tent could explain the antiapoptotic role of interacts with a multitude of proteins. It was HAX-1 (Vafiadaki et al. 2009a). In addition, proposed that depending on the available in- because of its association with PLN and teraction partners, the subcellular localization SERCA2 on one hand, and interaction with and functional properties of HAX-1 might caspase-9 on the other hand, HAX-1 might vary among different tissues (Vafiadaki et al. link two Ca2þ-regulated processes in the heart: 2009b). Recently, PLN was identified via yeast contractility and cell survival (Han et al. 2006). two-hybrid screen and GST-pull-down experi- These observations on HAX-1 are remark- ments as a novel interaction partner of HAX-1 ably parallel to the effects of Bcl-2, another (Vafiadaki et al. 2007). The site of the HAX-1 antiapoptotic protein (reviewed in Vafiadaki and PLN interaction is well documented and et al. 2009b; Vandecaetsbeek et al. 2009a). is confined to the regions 203-245 of HAX-1 Bcl-2 is also located in the mitochondria and and 16-22 of PLN, overlapping with the PLN can be found in the ER, where it is able to in- phosphorylation sites (Vafiadaki et al. 2007). teract with SERCA2. However, the putative The direct association between HAX-1 and interaction site of Bcl-2 on the pump remains PLN was further established in vivo (Zhao to be defined, and how Bcl-2 affects ER Ca2þ et al. 2009). HAX-1 serves an inhibitory role reuptake remains somewhat controversial. Ex- on basal contractility of the heart by stabilizing perimental evidence supports different alter- the PLN monomers and lowering the apparent natives: a) the interaction between SERCA Ca2þ affinity of SERCA2a. Notably, this effect and Bcl-2 inactivates the pump, presumably is reversed during b-adrenergic stimulation by destabilizing the protein (Dremina et al. (Zhao et al. 2009). 2004), b) Bcl-2 would regulate the SERCA The HAX-1 GST-pull-down experiments expression levels (Kuo et al. 1998; Vanden also detected SERCA2a, which implies that Abeele et al. 2002), and c) Bcl-2 could inactivate PLN can interact simultaneously with HAX-1 SERCA by extraction of the ATPase from and SERCA2a, notably with similar binding caveolae-related domains in the SR (Dremina affinities (KD of 0.70 mM and 1 mM, respectively et al. 2006). (Kimura and Inui 2002; Vafiadaki et al. 2007). The HAX-1 interaction is confined to residues SERCA Complexes Involving Luminal Proteins 575-594 in the SERCA2 N-domain, enclosing Calreticulin, Calnexin, and ERp57 an accessible and highly conserved loop, on the opposite site of the proposed cytosolic PLN Two of the earliest proposed SERCA2b interac- interaction region 397-401 (Fig. 2) (Vafiadaki tors are the lectin molecular chaperones: the et al. 2009a). Whether this interaction also 46-kDa ER luminal Ca2þ-binding calreticulin occurs in the physiological setting of the heart (CRT) and its 90-kDa homolog the type-I ER remains to be investigated. integral protein calnexin (CLNX). Both pro- The preferential mitochondrial localization teins contain a globular N-domain involved of HAX-1 in HEK-293 cells can be changed to in glucose or oligo-saccharide binding, an

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extended P-domain mediating ERp57 binding would be inhibited and remain so as long as and an acidic Ca2þ-binding C-domain (Micha- ERp57 is bound (Li and Camacho 2004). The lak et al. 2009). The C-domain of CRT can bind conclusion that reduced C875 and C887 in 25 mol of Ca2þ with low (2 mM) affinity L7-8 are required for full SERCA2 activity is dif- (Baksh and Michalak 1991) and thus CRT com- ficult to reconcile with the observation that plexes over half of all ER luminal Ca2þ. Luminal mutations of either or both of the cysteine resi- Ca2þ buffering by CLNX is much less pro- dues resulted in a loss of transport without loss nounced because it contains much less Ca2þ- of Ca2þ-dependent ATPase activity in SERCA1 binding sites and its acidic carboxyl terminus (Daiho et al. 2001). Note that these cysteine res- protrudes into the cytosol. The direct interac- idues are conserved in SERCA1-3, and that tion between these luminal ER Ca2þ buffers the C875G mutation is a known Darier mutant and the Ca2þ pump and release channels might (Ruiz-Perez et al. 1999). Finally, we want to represent an elegant feed-back system that con- remark that ERp57 does not require interac- trols ER Ca2þ filling (John et al. 1998; Roderick tions with CLNX and CRT to recognize its sub- et al. 2000). strate (Zhang et al. 2009) and that CRT binds to 2þ According to some early reports Ca - SERCA2a oxidatively damaged by H2O2 treat- loaded CRT or CLNX would interact with the ment, which leads to SERCA degradation via a N-linked carbohydrates inserted on residues proteasome-dependent pathway (Ihara et al. 1035-NFS in the isoform-specific luminal 2005). extension of SERCA2b (Fig. 2A) (John et al. 1998). Although this is a consensus N-glycosy- SERCA-Calumenin Interaction lation site (N1035), glycosylation was never experimentally observed (John et al. 1998; Calumenin (CALU; 50 kDa) is a ubiquitously Roderick et al. 2000; Vandecaetsbeek et al. expressed protein, conserved from invertebrates 2009b). The lack of glycosylation does however to vertebrates, which is found in the lumen of not a priori exclude CLNX or CRT binding the ER and SR (Sahoo et al. 2009). Because of to SERCA because these ER chaperones can its nonconsensus ER-retention signal, the pro- occasionally also bind nonglycosylated targets tein can escape from the ER and even be (Roderick et al. 2000; Ireland et al. 2008). The secreted (Vorum et al. 1999). CALU belongs to interaction with CRT or CLNX would exert an the CREC family, which members share multi- inhibitory effect on the Ca2þ-wave propagation ple EF-hand Ca2þ-binding motifs (Honore in Xenopus oocytes (John et al. 1998; Roderick 2009). CALU binds in its Ca2þ-loaded form to et al. 2000). However, mutants in this site retain the luminal domain of SERCA2 and presum- normal Ca2þ-dependent ATPase-activity when ably also the other SERCAs. GST-pull-down overexpressed in COS cells (Vandecaetsbeek experiments with the different luminal loops et al. 2009b). According to the SERCA2b molec- of the pump showed that CALU interacts ular model, the 2b-tail is buried in luminal with L7-8 of the ATPase (presumably region loops of the pump making its interaction with 853-892, Fig. 2), i.e., close to or overlapping other proteins less likely (Vandecaetsbeek et al. with the ERp57 interaction area, but apparently 2009b). on the other side of the 2b-tail interaction site. ERp57, a member of the PDI family with CALU prefers the Ca2þ-bound E1 conforma- thio-oxidoreductase activity catalyzing disul- tion of SERCA, and when bound decreases fide-bond formation of glycoproteins (Ni and the apparent Ca2þ affinity of the ATPase (Sahoo Lee 2007) is recruited into the SERCA2b- et al. 2009). Overexpression of CALU in rat neo- chaperone complex and establishes a disulfide natal cardiomyocytes reduced SR Ca2þ uptake bridge between C875 and C887 in L7-8 of and decreased fractional release. Thus, inter- SERCA2 (Fig. 2) (Li and Camacho 2004). action with the ryanodine receptor RyR2 is According to the proposed model, SERCA2 also suggested from these experiments. CALU with an oxidized loop (S-S bridge is present) would be essential during the early stages of

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development, similar to other Ca2þ-binding ER (Arvanitis et al. 2007). This dual interaction chaperone proteins like CRT, and ERp57. Much would ensure a cross-talk between SR Ca2þ lower levels of CALU than calsequestrin are uptake and release in the heart (Pritchard and present in the adult heart. Kranias 2009). However, the functional effect Of note, the longest luminal loop L7-8 of of HRC on SERCA2a is less clear. Overexpres- SERCA2 apparently is the interaction site of sev- sion of HRC in mouse results in depressed car- eral regulators (Fig. 2): the 2b-tail (Vandecaets- diomyocyte Ca2þ uptake (Gregory et al. 2006), beek et al. 2009b), ERp57 (Li and Camacho indicating that HRC would inhibit SERCA2 2004) and CALU (Sahoo et al. 2009). Also, the activity. The fact that such inhibition would extracellular loop L7-8 of the Naþ/Kþ-ATPase occur at low SR Ca2þ, when high activity should a-subunit is functionally interacting with the be more appropriate to refill the SR, is some- extracellular region of the b-subunit (Morth what counter-intuitive. Direct measurements et al. 2007). The long L7-8 wouldpredominantly of SERCA activity and cardiomyocyte SR Ca2þ serve a regulatory function, because Ca2þ trans- handling in the presence and absence of HRC port is supported with a much shorter L7-8, are needed to clarify this further. as in the closely related SPCA Ca2þ pump (Vangheluwe et al. 2009). This loop may regulate the Ca2þ-binding affinity of SERCA2 through Other SERCA Isoforms modulation of the Ca2þ-binding pocket in SERCA1 TM8 (a true Ca2þ-affinity effect) or via stabili- zation of an intermediate of the pump exerting SERCA1 represents a highly specialized pump a kinetic effect on the apparent Ca2þ affinity isoform which, with the notable exception of (Vandecaetsbeek et al. 2009b). brown adipose tissue (de Meis 2003), that is, a cell type embryologically closely related to muscle (Enerback 2009), appears to be almost Histidine-Rich Ca21-Binding Protein exclusively expressed in fast skeletal muscle Another luminal Ca2þ-binding protein that fibers of all vertebrates from fish to mammals. interacts with SERCA2 is the histidine-rich Expression of SERCA1 is spatially controlled Ca2þ-binding protein (HRC; 170 kDa), which by the type of innervation the muscle fiber shows an inhibitory interaction with the lumi- receives (Hamalainen and Pette 1997). Humans nal domain of SERCA2 where it binds to L1-2 and some large animals tolerate the absence (region 74-90, Fig. 2) (Arvanitis et al. 2007). of SERCA1 reasonably well as is seen in some Note that this site potentially overlaps with the forms of human Brody myopathy (Odermatt binding site of SLN or the luminal extension et al. 1996) and in congenital pseudomyotonia of the 2b-tail (Hughes et al. 2007). HRC binds in Chianina cattle (Drogemuller et al. 2008), Ca2þ with high capacity, but low affinity (Hof- but the lack of SERCA1 is lethal in mice (Pan mann et al. 1989; Picello et al. 1992). HRC et al. 2003) and zebra fish (Hirata et al. 2004). shares similarities with calsequestrin, the major The transcript of the ATP2A1 gene can be SR Ca2þ buffer protein, but is much less abun- processed into two different SERCA1 mRNAs dant (1% of skeletal muscle SR) (Damiani et al. coding for an adult SERCA1a and for SERCA1b, 1997; Pritchard and Kranias 2009). Using dif- a form found only in neonatal or regenerating ferent regions HRC binds in a Ca2þ-dependent muscle (Zador et al. 2007). In SERCA1b, a manner with the SERCA pump and with tria- highly-conserved octapeptide (-DPEDERRK) din, which is part of the RyR Ca2þ-release com- replaces the carboxy-terminal Gly residue of plex (Pritchard and Kranias 2009). If the Ca2þ SERCA1a. The physiological and functional load in the SR is low, HRC would interact relevance of this extension remains unknown with SERCA. If HRC becomes saturated with (Maruyama and MacLennan 1988; Zador et al. Ca2þ, it dissociates from SERCA and inter- 2007). Insertion of the aberrant isoform into acts with triadin to modulate Ca2þ release the ER reduces the ER Ca2þ concentration and

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induces apoptosis (Chami et al. 2000; Chami cardiomyocytes, although the expression levels et al. 2001). of the various splice variants must be rather low (Dally et al. 2009). Of these, SERCA3f was found close to the plasma membrane and to SERCA3 be up-regulated in human failing heart (Dally SERCA3 represents the last described and most et al. 2009). enigmatic member of the SERCA family. It In human platelets, SERCA3 is thought to shows a limited cell-specific and differentia- reside in membranes of an acidic lysosome- tion-stage dependent expression pattern and a related Ca2þ store, from which it can possibly bewildering number of splice variants. At least bereleasedviaNAADP-gatedtwo-porechannels six different variants in human (SERCA3a-f ) (Calcraft et al. 2009; Brailoiu et al. 2010) whereas are known, three in mice (SERCA3a-c) and SERCA2b is confined to the so-called dense two in rats (SERCA3a,b/c) (Dally et al. 2009). tubular system. The latter store is derived from High expression of SERCA3 is found in various the ER and its Ca2þ can be discharged by IP3R- types of blood cells including lymphocytes, mediated Ca2þ-release (Juska et al. 2008). On platelets, and mast cells, in endothelial cells, in Ca2þ depletion, each of both types of stores acti- epithelia of the intestinal or respiratory tract vates its own store-operated Ca2þ-entry mecha- and in cerebellar Purkinje neurons (Wuytack nism (SOCE) (Redondo et al. 2008b), although et al. 1994; Baba-Aissa et al. 1996a). It should in the case of the acidic store SOCE appears to be be mentioned, however, that in these cells more pronounced (Rosado et al. 2004). SOCE SERCA3 is always coexpressed with the house- thereby relies on the formation of macromolec- keeping SERCA2b isoform (Papp et al. 1991; ular complexes involving the respective SERCA Wootton and Michelangeli 2006). isoforms. Complexes of SERCA3 and IP3R-2 All six SERCA3 splice variants present a 5- in the acidic store and of a transient receptor to 10-fold lower apparent affinity for cytosolic potential channel TRPC1–TRPC6 heterodimer Ca2þ than SERCA2b (Chandrasekera et al. in the adjacent plasma membrane have been 2009). The obvious question that then arises is shown (Redondo et al. 2008a). On depletion of what the meaning is of the coexpression in a the acidic Ca2þ stores in platelets with thrombin cell of the high-affinity SERCA2b with a low- or with a combination of thapsigargin and ion- affinity SERCA3. Especially, SERCA3 knock- omycin, SERCA3 also forms complexes with out mice do not display any overt phenotype, STIM1 and Orai1 (Lopez et al. 2008). further questioning the physiological impor- Yet another indication for a specific role of tance of SERCA3. SERCA3 in cellular Ca2þ signaling is found in Cells belonging to the hematopoietic line- its specific up-regulation during cell differentia- age and epithelial or endocrine secretory cells tion. Differentiation of vascular endothelium are endowed with a complex Ca2þ-signaling (Mountian et al. 1999), myeloid cells (Launay network (Guse et al. 1993). SERCA3 would et al. 1999) or colon epithelial cells (Gelebart here help to shape spatiotemporal cytosolic et al. 2002) is accompanied by an up-regulation Ca2þ oscillation patterns (Arredouani et al. of SERCA3 rather than of SERCA2b. Con- 2002). A differential subcellular localization of versely, on malignant transformation colon cells SERCA3 versus SERCA2, whereby SERCA3 loose their SERCA3 expression (Brouland et al. would then most likely face an environment 2005) and both Epstein-Barr virus-mediated with locally higher Ca2þ concentration would immortalization of B-lymphocytes with its also help in this respect. In epithelial cells, accompanying lymphomagenesis and normal SERCA3 resides in a distinct subcellular local- B-lymphocyte activation in lymph nodes are ization positioned more at the basal region of also paralleled by SERCA3 down-regulation the cell (Lee et al. 1997; Petersen 2003). A com- (Dellis et al. 2009). plex subcellular distribution of various SERCA3 A number of reported germ-line mutations splice variants was also described in human in the ATP2A3 gene may predispose to cancer

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development (Korosec et al. 2008; Korosec et al. 169600), an acantholytic skin disease (Hu et al. 2009). Presumably, haploinsufficiency of this 2000; Sudbrak et al. 2000). gene underlies this predisposition. Remarkably, A novel paralogue, ATP2C2, was found in one of these mutants is also more frequently the genome of higher vertebrates. Its protein found in type II diabetic patients (Varadi et al. product SPCA2 was characterized independ- 1999). ently by two groups (Vanoevelen et al. 2005; Normal SERCA3 activity in vascular endo- Xiang et al. 2005). Its expression pattern sug- thelium (Liu et al. 1997) and in respiratory epi- gests a more specific cellular role. thelium (Kao et al. 1999) is important for relaxation of the adjacent smooth muscle as Structural Aspects of SPCAs shown by defects in the relaxation in SERCA3 KO mice. The reported higher resistance of SPCAs differ from SERCAs mainly by the pres- SERCA3 versus SERCA2b to oxidative damage ence of only one ion-binding site (correspond- might be considered as a meaningful adaptation ing to site II in SERCA1). The structure of this in these local environments (Grover et al. 2003). site and its access pathway is probably affected by more distant residues and the packing of the TM helices allowing also for the transport SPCAs of Mn2þ with high affinity (Wei et al. 1999; The SPCAs, together with the SERCAs, are Wei et al. 2000; Van Baelen et al. 2001; Vanghe- responsible for loading the Golgi complex and luwe et al. 2009). In SPCAs, the E1 conforma- the secretory compartment with Ca2þ. In con- tion is stabilized with respect to E2, explaining trast to SERCAs, SPCAs are also equipped to the observation that SPCAs have much higher transport Mn2þ and thus supply this essential apparent affinity for the transported ions than trace metal to the Golgi lumen. A number of SERCAs (Dode et al. 2006). Compared to comprehensive reviews have been published SERCA1a, structures of the two SPCA isoforms recently by our group (Vanoevelen et al. 2007; are more compact as shown by the shorter lumi- Vangheluwe et al. 2009) and by others (Dhitavat nal and cytosolic loops (Fig. 3) (Vangheluwe et al. 2004; Foggia and Hovnanian 2004; Brini et al. 2009). As indicated above, at least some and Carafoli 2009). of these longer loops of the SERCA pump repre- sent specific binding sites for regulatory pro- teins. The homology models of SPCA1 and Short History SPCA2 look almost identical (Fig. 3). Only The archetypal member of the SPCA family was minor differences are apparent, especially in independently discovered in yeast (Saccharomy- the amino terminus and carboxyl terminus. In ces cerevisiae) by two laboratories and named Pmr1, the amino terminus contains an EF- 2þ Plasma membrane ATPase-related, or Pmr1. hand-like motif that binds Ca and is crucial 2þ Smith et al. (Smith et al. 1985) cloned PMR1 for Ca transport (Wei et al. 1999). Although by complementation of “super-secreting” yeast the EF-hand like motif in hSPCA1 is even 45 2þ mutants (ssc) while Serrano et al. (Serrano more degenerate compared to PMR1, Ca - et al. 1986) identified the same gene by hybrid- overlay experiments on the GST-purified amino ization with a PMA1 (plasma-membrane Hþ- terminus of hSPCA1 also indicated the binding 2þ ATPase) probe. Later on, homologs were studied of Ca (Vanoevelen, unpublished). in many animal species and in other fungi because of its value for biotechnology (efficient Expression Pattern secretion of heterologously expressed proteins). SPCA1 In humans, the ATP2C1 gene-encoding SPCA1 was mapped to chromosome 3 and SPCA1 is the housekeeping Ca2þ and Mn2þ gained interest when it proved to be the pump of the secretory pathway because it is gene that causes Hailey-Hailey disease (OMIM expressed in all cell types studied. However,

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Figure 3. Comparison between the rSERCA1a, hSPCA1, and hSPCA2 structures. Homology models of hSPCA1 (B) and hSPCA2 (C) based on the E2 rSERCA1a structure (A) (1WPG) (Toyoshima et al. 2004). Homology models were obtained from the SWISS-MODEL repository (Kiefer et al. 2009). SPCA1 and SPCA2 are very similar, but in general more compact than SERCA1a. The longer loops in SERCA are indicated in red and are predominantly found in the N-domain and in the luminal loops.

different laboratories described different rela- that the terminal exon of SPCA1b overlaps with tive expression levels in various tissues. Woot- the coding region of the neighboring gene Aste- ton et al. (Wootton et al. 2004) observed roid 1 whose open reading frame is oriented in much higher mRNA and protein expression in the opposite direction with respect to that of rat brain and testis than in other tissues whereas ATP2C1. this difference was not observed in the corre- The yeast Pmr1 is localized in the Golgi sponding tissues of humans (Hu et al. 2000; apparatus possibly restricted to some of its Vanoevelen et al. 2005). subcompartments (Antebi and Fink 1992). The human ATP2C1 gene transcript is al- SPCA from Caenorhabditis elegans heterolo- ternatively spliced, giving rise to different pro- gously expressed in COS-1 cells (Van Baelen tein products. Although there has been some et al. 2001) and the human SPCA1 expressed confusion about the various splice variants, in CHO cells (Ton et al. 2002) showed a local- Fairclough et al. presented a unifying study ization largely coinciding with Golgi markers. describing four isoforms (Fairclough et al. It is now well established that both overex- 2003). The corresponding proteins are termed pressed SPCA and the endogenous SPCAs in SPCA1a-d and only differ in their carboxyl a whole range of cell types are present in the termini. Three splice variants SPCA1a, b, and Golgi compartment (reviewed in Missiaen et al. d are functional whereas SPCA1c, which is 2007). truncated within the last TM segment, is non- In human spermatozoa, SPCA1 displays an functional and rapidly degraded (Dode et al. unusual subcellular distribution: it is found in 2006). Exploring the ATP2C1 gene structure in the area behind the nucleus extending into the the database points to the interesting peculiarity midpiece. SPCA1 is believed to be the only

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intracellular Ca2þ pump in these cells because SPCA2 both functional and immunocytochemical tests failed to show the presence of SERCAs (Harper Screening of the genome databases shows that et al. 2005). A similar picture arises from besides the ancestral housekeeping ATP2C1 sea-urchin sperm cells, which lack SERCAs. gene, a second paralogue, ATP2C2, emerged Their SPCAs are located in the zone occupied in the genomes of vertebrates higher than by the single giant mitochondrion where also fish. The corresponding gene is also lacking in the main ATPases involved in Ca2þ-store filling invertebrates. are situated (Gunaratne and Vacquier 2006, In human tissues, SPCA2 expression is more 2007). restricted than that of SPCA1, suggesting a more In the fly (Drosophila melanogaster), three specialized physiological function of the for- SPCA splice-variants (SPoCk-A; SPoCk-B; mer. Its mRNA is most abundant throughout SPoCk-C) are expressed. Of these isoforms, the gastrointestinal tract, in trachea, thyroid, only SPoCk-A is targeted to the Golgi appara- salivary gland, mammary gland and in prostate tus. The subcellular localization of SPoCk-B (Vanoevelen et al. 2005). It is striking that and SPoCk-C is less clear and unexpected tar- SPCA2 is most abundantly expressed in cells geting to, respectively, the ER and the peroxi- possessing a highly active secretion system like somes was reported (Southall et al. 2006). the mammary gland cells during lactation Furthermore, expression of the SPoCk-C variant (Faddy et al. 2008) and the mucin-secreting was shown to be sexually dimorphic (South- goblet cells in human colon (Dmitriev et al. all et al. 2006). 2005; Vanoevelen et al. 2005). This indicates Expression analysis in developing mouse an important role for SPCA2 in protein secre- brain showed that SPCA1 expression is promi- tion. However, reported SPCA2 expression in nent and at constant levels during the entire keratinocytes and hippocampal neurons does development of brain cortex, hippocampus, not fit this picture. These data on mRNA ex- and cerebellum. In spite of the apparently pression should however be confirmed at the unchanged expression levels, SPCA-associated protein level. So far, the presently available Ca2þ-ATPase activity increased with the stage antibodies could only show SPCA2 expression of development (Sepulveda et al. 2008). in cultured hippocampal neurons (Mattiazzi SPCA1 was localized in Golgi stacks of the et al. 2005), in the colon (Vanoevelen et al. soma and the initial part of the primary 2005), in the secretory acini of the mouse mam- dendritic trunk in main cortical, hippocampal mary gland (Faddy et al. 2008) and in neutro- and cerebellar neurons, and is present from phil granulocytes (Baron et al. 2009). the earliest postnatal stages onward. Although The precise subcellular localization of SPCA1 expression has been reported in dif- SPCA2 is not completely unambiguous. In ferent glial cultures (Murin et al. 2006), other human goblet cells, both SPCA2 and SPCA1 efforts to show SPCA- or SERCA-pump expres- colocalized with Golgi markers in a compact sion in glial cells in nervous tissue were unsuc- structure near the apical pole of the nucleus cessful (Baba-Aissa et al. 1996b; Sepulveda (Vanoevelen et al. 2005). In addition, on he- et al. 2007; Sepulveda et al. 2008). Because glial terologous expression in COS-1 cells, SPCA2 cells express high levels of the Mn2þ-dependent appeared predominantly in the Golgi area glutamine synthetase (Wedler and Denman (Missiaen et al. 2007). In cultured mouse hip- 1984), the low levels of SPCAs argues against a pocampal neurons, however, SPCA2 staining role of SPCAs in Mn2þ uptake. However, in showed a punctate distribution in the cell body rat brain SPCA1 is upregulated following and in the dendrites (Xiang et al. 2005). Al- Mn2þ exposure (Zhang et al. 2005), which though in neurons the Golgi apparatus does in would be compatible with a role in Mn2þ detox- general appear as a more fragmented structure, ification, as also observed in yeast (Lapinskas SPCA2 only partially colocalized with the trans- et al. 1995). Golgi marker TGN38. It was therefore argued

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that in hippocampal neurons SPCA2 is, at least SPCA1 also seems to be an important com- partially localized in downstream, post-Golgi ponent of Ca2þ signaling in insulin-secreting segments of the secretory pathway (Xiang cells (Mitchell et al. 2004). Knock-down of et al. 2005). Taken together, the available data SPCA1 diminished Ca2þ uptake into the ER indicate that SPCA2 can be found in the Golgi and in dense-core secretory vesicles, increased complex and in more downstream compart- Ca2þ influx through L-type Ca2þ channels ments of the secretory pathway. and increased the response to glucose. The time course of glucose-induced Ca2þ oscilla- tions was also modified (Mitchell et al. 2004). Role of SPCAs in Cellular Physiology The same approach in cell lines expressing Insights from PMR1 Mutants in Yeast misfolded proteins revealed defects in protein processing and degradation (Ramos-Castaneda Although homozygous null mutations in the et al. 2005). Furthermore, SPCA1 deficiency ATP2C1 gene encoding SPCA1 seem to be lethal rendered cells hypersensitive to ER stress. in mammals (Okunade et al. 2007), they are tol- Down-regulating SPCA1 in neurons com- erated in lower eukaryotes, including fungi and promises differentiation. The affected neurons C. elegans (Rudolph et al. 1989; Cho et al. 2005), displayed increased numbers of neurites of re- where compensatory mechanisms presumably duced length as compared to control cells. suffice to allow viability. An attractive model Additionally, Golgi Ca2þ-signalling was dis- for understanding such mechanisms is the yeast turbed and trafficking of proteins through the orthologue Pmr1. PMR1 mutants in yeast dis- Golgi was also hampered (Sepulveda et al. 2þ play pleiotropic changes in Ca -dependent 2009). It is also known that both expression growth (Antebi and Fink 1992), secretion of and activity of SPCA1 changes on ischemic unprocessed proteins (Antebi and Fink 1992), events in the brain (Pavlikova et al. 2009). outer-chain glycosylation (Rudolph et al. 1989), Mn2þ tolerance (Lapinskas et al. 1995), salt tolerance (Park et al. 2001), cell shape Studies in Other Model Organisms (Cortes et al. 2004), virulence (Bates et al. Knockdown of SPCA1 in C. elegans rendered the 2005) and viability (Agaphonov et al. 2007). worms highly sensitive to Ca2þ-deficient and The characterization of the diverse PMR1- Mn2þ-enriched conditions and made them mutant phenotypes in yeast has been invalu- more resistant to oxidative stress (Cho et al. able in providing the basis for studies on the 2005). These defects are reminiscent of the mu- role of metazoan SPCA orthologues. Some of tant phenotype observed in yeast, as discussed these studies will be discussed in the following earlier. parts. Using a genetically transmissible RNA- interference strategy in Drosophila, Southall et al. also showed aberrant Ca2þ signaling com- Studies in Cell Systems bined with defective neuropeptide-stimulated Van Baelen et al. used RNA interference to diuresis in the Malpighian tubes of transgenic understand the role of SPCA1 in HeLa cells flies (Southall et al. 2006). (Van Baelen et al. 2003). Luminal [Ca2þ] mea- Expression levels and activity of SPCAs surements using Golgi-targeted aequorin change in response to altered physiological showed that endogenous SPCA1 was responsi- needs. In response to changes in glucose concen- ble for Ca2þ uptake in a subcompartment of tration, SPCA1 expression levels significantly the Golgi. On knock-down, the frequency of increased in smooth muscle cells cultured in histamine- induced baseline Ca2þ-oscillations high-glucose medium versus normal medium. was reduced, indicating that in these cells a Functional consequences consisted of increased SPCA1-related Ca2þ-store may affect cytosolic ATPase activity and altered thapsigargin-in- Ca2þ signals. sensitive AVP (arginine-vasopressin)-induced

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cytosolic Ca2þ transients. These results indicate SPCAs and Human Disease that SPCA can play a role in Ca2þ uptake within Hailey-Hailey disease (OMIM 169600) is an smooth muscle cells (Lai and Michelangeli autosomal-dominant skin disease caused by 2009). the loss of one functional copy of the ATP2C1 Expression of SPCA1 and especially SPCA2 gene encoding SPCA1 (Hu et al. 2000; Sudbrak rapidly adapts to lactation. SPCA2 is up-regu- et al. 2000). It is characterized by an increased lated 35-fold whereas SPCA1 expression only propensity for the formation of erosive and rises two-fold. These results clearly suggest an oozing skin lesions in the flexural areas (Hailey important role for SPCA2 specifically (in addi- and Hailey 1939) from the second decade of life tion to PMCA2) in the transport of high on. In recent years, a large number of causative amounts of proteins and Ca2þ into milk (Faddy mutations have been described (Cialfi et al. et al. 2008). Conversely, on mammary gland 2009). One cannot miss the remarkable parallels involution the expression level of both pumps between the inactivation of one allele of the is reduced 80–95% in an early phase and subse- ATP2A2 or ATP2C1 genes causing very similar quently up-regulated again to meet normal dermatological problems, respectively, Darier physiological needs (Reinhardt and Lippolis and Hailey-Hailey disease (Dhitavat et al. 2008). 2004). However, in contrast to keratinocytes of The description of the phenotype of Darier patients, keratinocytes of Hailey-Hailey SPCA12/2 mice has shown the important patients show an abnormal response to extra- housekeeping function of SPCA (Okunade cellular Ca2þ. Apparently, Darier keratinocytes et al. 2007). Homozygous mutant mice died behave normally in this respect because in utero before gestation day 10.5. The animals SPCA1 is up-regulated and can compensate showed growth retardation and had an open for the partial loss of SERCA2 function (Foggia rostral neural tube. At the subcellular level, et al. 2006). the Golgi membranes were dilated, expanded Very recently, ATP2C2 in addition to the in amount and with fewer stacked leaflets. CMIP (c-maf inducing protein) gene has ge- In addition, the number of Golgi-associated netically been linked to both a human devel- vesicles was increased although processing opmental disorder termed specific language and trafficking of proteins in the secretory impairment (SLI) and to phonological short- pathway was apparently normal. Apoptosis term memory. Detailed analysis indicates that was increased and a large increase of cytoplas- both genes are independenly involved. This mic lipids was observed, consistent with study provides molecular evidence for a role of impaired handling of lipids by the Golgi com- phonological short-term memory in language plex. The authors introduced the concept of acquisition (Newbury et al. 2009). Golgi stress to summarize these defects (Oku- nade et al. 2007). Adult SPCA1 heterozygous mice were found to have an increased incidence CONCLUSIONS of squamous cell tumors of epithelial cells in the skin and esophagus (Okunade et al. 2007). SERCA and SPCA pumps help to establish and In addition, SERCA2 heterozygous mice maintain low cytosolic and high luminal free developed such tumors (Graef et al. 2001). Ca2þ concentration in respectively the ER and The development of squamous cell tumors the organelles of the secretory pathway. Fail- in aged ATP2A2þ/2 and ATP2C1þ/2 mice ure to keep this vital Ca2þ gradient results in indicates that SERCA2 and SPCA1 haploinsuffi- ER stress, Golgi stress and cell death. It is thus ciency predisposes murine keratinocytes to physiologically important to maintain the neoplasia. The possible links between Ca2þ- activity of the pump, which is mainly accom- transporting proteins and cancer have been plished by meticulously controlling the affinity reviewed in detail by Monteith et al. (Monteith of the pump for Ca2þ. To that extent, the cell et al. 2007). has at its disposal several SERCA isoforms

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displaying differences in Ca2þ affinity and of Asahi M, Green NM, Kurzydlowski K, Tada M, MacLennan affinity modulators of the pump, such as phos- DH. 2001. Phospholamban domain IB forms an interac- tion site with the loop between transmembrane helices pholamban and sarcolipin. Furthermore, mul- M6 and M7 of sarco(endo)plasmic reticulum Ca2þ titudes of additional SERCA2 modulators ATPases. Proc Natl Acad Sci 98: 10061–10066. were recently identified, although more work Asahi M, Kimura Y, Kurzydlowski K, Tada M, MacLennan DH. 1999. Transmembrane helix M6 in sarco(endo)- is needed to clarify their functional and physio- plasmic reticulum Ca2þ-ATPase forms a functional logical roles. interaction site with phospholamban. Evidence for The role of the SPCA pumps in the secretory physical interactions at other sites. J Biol Chem 274: pathway is less well understood, but a remark- 32855–32862. Asahi M, Kurzydlowski K, Tada M, MacLennan DH. 2002. able property of SPCA is its ability to transport Sarcolipin inhibits polymerization of phospholamban 2þ 2þ Mn . Transport of Mn from the cytosol to to induce superinhibition of sarco(endo)plasmic re- 2þ the lumen of the secretory pathway organelles ticulum Ca -ATPases (SERCAs). J Biol Chem 277: 26725–26728. provides these with a necessary cofactor for sev- Asahi M, Sugita Y, Kurzydlowski K, De Leon S, Tada M, eral of the resident enzymes and may be impor- Toyoshima C, MacLennan DH. 2003. Sarcolipin regulates tant for Mn2þ detoxification of the cells. sarco(endo)plasmic reticulum Ca2þ-ATPase (SERCA) by binding to transmembrane helices alone or in association with phospholamban. Proc Natl Acad Sci 100: 5040– 5045. ACKNOWLEDGMENTS Axelsen KB, Palmgren MG. 1998. Evolution of substrate spe- cificities in the P-type ATPase superfamily. 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The Ca2+ Pumps of the Endoplasmic Reticulum and Golgi Apparatus

Ilse Vandecaetsbeek, Peter Vangheluwe, Luc Raeymaekers, Frank Wuytack and Jo Vanoevelen

Cold Spring Harb Perspect Biol 2011; doi: 10.1101/cshperspect.a004184 originally published online February 9, 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 /Calmodulin-Dependent Protein Kinase 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