Role of Store-Operated Calcium Entry During Meiotic Progression and Fertilization of Mammalian Oocytes

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Role of Store-Operated Calcium Entry During Meiotic Progression and Fertilization of Mammalian Oocytes Francisco Javier Martı´n-Romero,* Aida M. Lo´pez-Guerrero,* Ignacio S. A´lvarez,† and Eulalia Pozo-Guisado* Contents 1. Introduction 2. Ca2þ as an Essential Intracellular Messenger for the Oocyte 2.1. Ca2þ transporters and Ca2þ-binding proteins 2.2. Reorganization of the ER during maturation and fertilization of oocytes 2.3. Ca2þ signaling during maturation of mammalian oocytes 2.4. Experimental evidence supporting an early role for Ca2þ signaling at fertilization 3. SOCE in Somatic Cells 3.1. Stromal interaction molecule 1 3.2. SOCs: ORAIs and TRPCs 3.3. STIM1 and the remodeling of the ER 3.4. Additional modulators of SOCE 4. Modulation of SOCE During Cell Cycle 4.1. SOCE downregulation during mitosis of somatic cells 4.2. Downregulation of SOCE in Xenopus oocytes 4.3. SOCE is an active Ca2þ influx pathway in mature mammalian oocytes 5. Possible Role of SOCE in Fertilization 5.1. Molecular markers of SOCE activation: STIM1 relocalization 5.2. SOCs in mammalian oocytes 6. Modulation of SOCE During Oocyte Maturation 7. Future Objectives and Conclusions 7.1. Finding oocyte-specific members of “CRACsome” 7.2. Modulation of SOCE by posttranslational modifications References

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* Department of Biochemistry and Molecular Biology, School of Life Sciences, University of Extremadura, Badajoz, Spain Department of Cell Biology, School of Life Sciences, University of Extremadura, Badajoz, Spain

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International Review of Cell and Molecular Biology, Volume 295 ISSN 1937-6448, DOI: 10.1016/B978-0-12-394306-4.00014-9

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2012 Elsevier Inc. All rights reserved.

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Abstract Calcium signaling is essential for many cellular events, including muscle contraction, secretion of hormones and neurotransmitters, and fertilization of oocytes. For the appropriate maturation and fertilization of mammalian oocytes, the influx of extracellular calcium through plasma membrane Ca2þ channels is required. Although the molecular pathway of the Ca2þ entry in other cell types has been reported, Ca2þ channels involved in the regulation of Ca2þ influx in oocytes have remained unknown for a long time. In this review, we summarize recent findings regarding the occurrence of store-operated calcium entry (SOCE) in mammalian oocytes and the expression and localization profiles of STIM1 and ORAI1, two important proteins that control SOCE. As we discuss here, STIM1, as an endoplasmic reticulum Ca2þ sensor, and ORAI1, the major plasma Ca2þ channel involved in SOCE, might help to explain the role of Ca2þ entry in mammalian oocyte maturation and fertilization. Key Words: Oocyte, Calcium signaling, Oocyte maturation, Fertilization, SOCE, STIM1, ORAI1. ß 2012 Elsevier Inc.

1. Introduction Primary oocytes develop in the mammalian ovary until they become arrested in the prophase of the first meiotic division. By the time of sexual maturity, this meiotic arrest is released by a preovulatory surge of gonadotrophins, and the oocytes progress into the second meiosis. There is a subsequent meiotic arrest at the metaphase of the second meiotic division (MII oocytes), and this progress between first and second meiosis is called oocyte maturation, which can be mimicked in vitro for some mammalian species when the immature oocytes are isolated from surrounding cumulus cells. Oocyte maturation requires a striking nuclear alteration with the extrusion of the first polar body, but it is also characterized by significant cytoplasmic changes, such as modifications of mitogen-activated protein kinase (MAPK) activity or the increase of the expression of several Ca2þtransport systems, including inositol 1,4,5-trisphosphate receptors (InsP3Rs) and sarco(endo)plasmic Ca2þ-ATPase. Only ovulated MII oocytes which are fertilized by the sperm undergo a second meiotic resumption and the subsequent first mitotic division. In the mammalian oocyte, Ca2þ waves, that is, transient and repetitive increases of the cytosolic free Ca2þ concentration ([Ca2þ]i), are triggered by the sperm-specific phospholipase C zeta (PLCz), which is released to the oocyte cytosol at the time of sperm–oocyte fusion. PLCz activates the phosphoinositide pathway in the oocyte and triggers the release of Ca2þ to the oocyte cytoplasm from the endoplasmic reticulum (ER) through InsP3Rs, generating the fertilization Ca2þ wave.

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This wave is propagated by a Ca2þ-induced Ca2þ release (CICR) mechanism when InsP3Rs in the vicinity of the sperm fusion point are activated by a local increase of cytosolic Ca2þ concentration. The subsequent pumping out of Ca2þ and sequestering into the ER, mediated by Ca2þ pumps, restores Ca2þ basal levels in the cytoplasm. This repetitive signaling lasts for several hours, helped by a Ca2þ-wave pacemaker located in the cortex of the oocyte, until Ca2þ oscillations stop at the time of pronuclei formation. In mammals, extracellular Ca2þ is essential for both oocyte maturation and fertilization, indicative of the requirement of extracellular Ca2þ entry. However, the molecular nature of the Ca2þ channels involved in those events and their regulation have been elusive. Store-operated Ca2þ channels (SOCs) constitute major candidates for these activities because (i) they are expressed in mammalian oocytes, (ii) there is a correlation between store-operated Ca2þ entry (SOCE) and oocyte maturation, and (iii) the fertilization Ca2þ wave leads to the depletion of intracellular Ca2þ stores (mainly the ER), thus requiring a refilling system, a mission that can be accomplished by the collaboration between SOCs and ER–Ca2þ pumps. SOCs are plasma membrane (PM) Ca2þ channels activated by stromal interaction molecule 1 (STIM1), a transmembrane protein located in the ER. STIM1 contains an EF-hand domain close to the N-terminus of the protein that senses intraluminal Ca2þ. Upon depletion of intraluminal Ca2þ levels, STIM1 oligomerizes and relocalizes in ER–PM junctions, where the cytosolic domain of STIM1 activates SOCs, increasing [Ca2þ]i and letting Ca2þ pumps to refill Ca2þ stores. Due to the lack of knowledge regarding the molecular nature of the components that rules SOCE, the role of this Ca2þ entry pathway in mammalian oocyte maturation and fertilization has not been evaluated in detail until recently. This review summarizes recent findings that suggest a direct involvement of STIM1 and SOCs in Ca2þ signaling in mammalian oocytes, giving an explanation for previous early reports showing the requirement of extracellular Ca2þ during oocyte maturation and fertilization.

2. Ca2þ as an Essential Intracellular Messenger for the Oocyte The cytosolic free Ca2þ concentration ([Ca2þ]i) in resting cells is in the 80–150 nM range. For the oocyte, like for any other eukaryotic cell, the variation of this concentration is critical for many cellular events because [Ca2þ]i constitutes an intracellular messenger. Thus, the transport of Ca2þ through channels and pumps is tightly regulated to ensure a controlled temporal and spatial variation of this messenger. The available sources of Ca2þ in order to increase [Ca2þ]i are mainly the extracellular milieu, with a

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total [Ca2þ] of 1–2mM, and the ER, with a [Ca2þ] in the high micromolar range (Barrero et al., 1997), together with Golgi vesicles and mitochondria to a lesser extent. Therefore, [Ca2þ]i increase is mediated by the activation of Ca2þ channels located in the PM or in the ER membrane. This [Ca2þ]i increase is transient because Ca2þ transport systems restore basal levels of cytosolic Ca2þ through the pumping out to the extracellular milieu or by the pumping into ER. Repetitive and transient oscillations of [Ca2þ]i in oocytes, known as calcium waves, are essential during fertilization (Cuthbertson and Cobbold, 1985), and they drive important events such as the exocytosis of cortical granules, the blocking of polyspermy, and the resumption meiosis (Cran et al., 1988; Hyslop et al., 2004). However, this Ca2þ signaling is not important at fertilization only but also during maturation of the oocytes. To better understand the role of [Ca2þ]i in these processes, we shall first describe some of the major Ca2þ transport systems in the mammalian oocyte.

2.1. Ca2þ transporters and Ca2þ-binding proteins The ER constitutes the major intracellular Ca2þ store for the oocyte. In mature mammalian oocytes, the ER is distributed in cortical ER clusters, and it is assumed that this particular distribution of the ER acts as a cortical pacemaker responsible for generating Ca2þ waves at fertilization (Dumollard et al., 2002; Kline et al., 1999). The presence of two types of Ca2þ channels, InsP3Rs and ryanodine receptors (RyR), in the ER membrane of the mammalian oocytes is well documented (Machaty et al., 1997; Mehlmann et al., 1996; Stricker, 1999; Wang et al., 2005; Yue et al., 1995). When InsP3Rs or RyRs are activated, they contribute to the release of Ca2þ from the ER lumen, increasing [Ca2þ]i. Although there are three InsP3R isoforms, encoded by three different genes, oocytes express mainly the InsP3R type 1 (Fissore et al., 1999; Parrington et al., 1998) which is sensitive to InsP3 and to cytosolic Ca2þ in the 100–300-nM range (Patterson et al., 2004). The InsP3R type 2 has also been found in human oocytes, with a distribution that overlaps with InsP3R1 (Balakier et al., 2002; Goud et al., 1999). The role of RyR has been at the center of a debate with opposing conclusions. RyR seemed to be essential in echinoderms only, with a secondary role when compared with InsP3R in the case of mammalian oocytes (Galione et al., 1993; Miyazaki et al., 1993; Whitaker, 2006). However, Sousa et al. suggested that a cooperation between the ryanodine-sensitive and ryanodine-insensitive stores takes place in the human oocyte to maintain the sperm-induced Ca2þ oscillations (Sousa et al., 1996). Those authors proposed the “two-store oscillation model,” that is, every cytosolic Ca2þ spike is triggered by the Ca2þ discharge from cortical InsP3-sensitive stores, and it is transmitted to the inner part of the oocyte by inducing CICR from ryanodine-sensitive stores (Tesarik, 2002; Tesarik and Sousa, 1996).

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For the oocyte, as well as for most eukaryotic cells, the continuous increase of [Ca2þ]i triggers Ca2þ-mediated processes such as the activation of Ca2þ-dependent proteases that may lead to cell death. To avoid this permanent high level of [Ca2þ]i, several Ca2þ transport systems are activated, mainly the PM Ca2þ-ATPase (PMCA), which extrudes Ca2þ into the surrounding milieu, and the sarco(endo)plasmic reticulum Ca2þATPase (SERCA), which pumps Ca2þ ions into the ER lumen. Another PM system involved in Ca2þ transport is the Naþ/Ca2þ exchanger (NCX) that regulates cytosolic Ca2þ concentration by coupling the extrusion of Ca2þ with the import of extracellular Naþ. The presence of the NCX in oocytes was revealed by modifying the Naþ gradient across the PM of the oocyte while monitoring cytosolic Ca2þ (Carroll, 2000; Pepperell et al., 1999). In this way, it was demonstrated that a Naþ/Ca2þ exchange takes place in mouse oocytes. This exchange is sensitive to Naþ depletion in the media or to bepridil, an inhibitor of the Naþ/Ca2þ exchange. Moreover, the sensitivity of the exchanger is higher in immature oocytes (Carroll, 2000), a result which suggests that the expression of the NCX decreases during oocyte maturation. Later, Macha´ty et al. demonstrated the presence of the NCX transcript in immature and mature porcine oocytes by endpoint RT-PCR, and they immunolocalized the protein in the PM of the oocyte (Machaty et al., 2002b). However, this exchanger plays no major role in the maintenance of Ca2þ homeostasis in the mouse oocyte, because mouse oocytes can recover from Ca2þ increases in the reverse mode (Carroll, 2000). In the lumen of the ER, there are additional proteins with an important role in Ca2þ signaling for the oocyte, such as the Ca2þ-binding proteins calreticulin and calsequestrin. Calreticulin is found in the oocyte cortex, similarly to the location profile of InsP3R, whereas calsequestrin shows a more diffuse distribution throughout the oocyte ER, like that of the RyRs (Balakier et al., 2002). In addition, calnexin, an integral ER chaperone, was found in human oocytes with a distribution profile similar but not identical to that reported for calreticulin in human MII oocytes (Balakier et al., 2002). Interestingly, calreticulin colocalizes with other Ca2þ-sensitive proteins, such as STIM1, which is a key protein in the regulation of Ca2þ influx (Gomez-Fernandez et al., 2009). Finally, the presence of L- and T-type voltage-operated Ca2þ channels (VOCCs) has been confirmed in a variety of nonmammalian oocytes (Leclerc et al., 2000; Ouadid-Ahidouch, 1998; Tomkowiak et al., 1997). These VOCCs, gated by depolarization of PM, were found to be active and to play a role during oocyte maturation in molluscs (Cuomo et al., 2005; Moreau et al., 1996; Tomkowiak et al., 1997), in ascidians (Cuomo et al., 2006), amphibians (Ouadid-Ahidouch, 1998), and mammals (Lee et al., 2004; Tosti, 2006; Tosti et al., 2000).

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2.2. Reorganization of the ER during maturation and fertilization of oocytes Mammalian primary oocytes develop in the ovary until they become arrested at prophase of the first meiosis I (prophase I; Moor et al., 1981). At this stage, the oocyte shows a prominent nuclear envelope called germinal vesicle (GV). The arrest at prophase I can last for several years in the case of human oocytes. The signal that releases the meiotic arrest is the luteinizing hormone in mammals, which triggers the maturation of the oocyte still in the ovary, although in some species maturation can be initiated when the immature oocyte is isolated from the follicle (Edwards, 1965). This maturation is the transition between prophase I and metaphase of the second meiosis (MII), and the oocyte remains arrested at the MII stage when ovulated. Oocyte maturation can be followed by evident nuclear modifications, such as the germinal vesicle breakdown (GVBD), which corresponds to prometaphase I. In the transition from the first to the second meiosis, the oocyte extrudes the polar body that remains attached to the mature oocyte (or MII oocyte). Finally, the resumption of the second meiosis is triggered by the fusion of the oocyte with the sperm. During maturation, there are also important cytoplasmic events, including the remarkable reorganization of the ER. The ability of the mature oocyte to regulate the cytosolic Ca2þ increase depends on biochemical and structural changes of the ER during oocyte maturation (Kline, 2000), and it is thought to play an essential role in the ability to generate long-lasting Ca2þ oscillations in the mature oocyte at fertilization. The organization of the ER has been studied mostly using electron microscopy, dicarbocyanine (DiI) dyes, or antibodies against markers of the ER, such as InsP3R or calreticulin. The DiI signal and the immunofluorescence with ER-specific antibodies are found uniformly distributed throughout the cytosol of mouse oocytes arrested in the GV stage. Thus, it is accepted that most of the ER is accumulated in inner sections of the immature oocyte, without the presence of major clustering or polarity (Mehlmann et al., 1995, 1996). Shortly after the breakdown of the nuclear envelope, the ER accumulates in the center of the oocyte surrounding the developing meiotic spindle and keeps this localization during the spindle migration to the oocyte cortex (FitzHarris et al., 2007). In fully mature oocytes, the ER shows prominent clusters, of 1–2mm in diameter, in the cortex (Mehlmann et al., 1995), where InsP3Rs accumulate (Kline et al., 1999; Mehlmann et al., 1996) together with other ER-resident proteins, such as STIM1 or calreticulin (Gomez-Fernandez et al., 2009). Interestingly, there is a developmental clustering of the cortical ER in mammalian oocytes which correlates well with meiotic maturation, suggesting that the abundance and clustering of InsP3Rs in the cortical ER of the mature oocyte may help in the propagation of Ca2þ release from the ER, mediated by a CICR mechanism. In addition, the differential

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distribution of Ca2þ transporters in mature oocytes (InsP3Rs and RyRs) led to the proposal that differential Ca2þ propagation occurs in the mature oocyte in response to sperm (Tesarik et al., 1995). The lower levels of InsP3R and its particular scattered distribution in the interior of the immature oocyte are responsible for the lower Ca2þ release rate when they are stimulated with sperm. In sum, the profound reorganization of the ER brings the most important Ca2þ storage to the close proximity of the PM, where sperm–oocyte fusion takes place. ER clusters are continuous with the reticular ER network in mouse oocytes, and these structures remain stable and continuous during the time of fertilization-induced Ca2þ transients or after InsP3 injection (Kline et al., 1999). However, ER clusters disappear at the completion of meiosis II, and the ER aggregates around the mitotic spindle in the first mitotic division (FitzHarris et al., 2003). Consequently, after activation of bovine oocytes by ionomycin, ryanodine, or fertilization, RyR distribution decreases significantly to undetectable levels (Yue et al., 1998). In a similar manner, InsP3R clustering decreases after fertilization, and these receptors diffuse into the central region of the bovine oocyte (Wang et al., 2005). Because a sustained increase of cytosolic Ca2þ leads to the fragmentation of ER tubules in somatic cells (Subramanian and Meyer, 1997), one possibility that can explain the diffusion of the ER-resident Ca2þ transporters after fertilization is that the rise of cytosolic Ca2þ in the oocyte, triggered by the sperm fusion, may induce the loss of InsP3R and RyR clustering due to the fragmentation of the cortical network of the ER (Stricker, 2006). An alternative detailed explanation was given by FitzHarris et al., since they proved that ER organization was dependent on the levels of the cyclindependent kinase 1 (CDK1) and cyclin B, and that the CDK1–cyclin B degradation, triggered by Ca2þ transients, facilitates the removal of ER clusters from the oocyte cortex (FitzHarris et al., 2003). Nevertheless, the reorganization of the ER after the fertilization helps in the cessation of Ca2þ oscillations in mammalian oocytes (Kline, 2000), although ER clusters seem to be nonessential because they disperse before Ca2þ oscillations stop (Day et al., 2000; Jones et al., 1995a).

2.3. Ca2þ signaling during maturation of mammalian oocytes Calcium plays an important role in oocyte maturation, because Ca2þ oscillations occur during meiotic resumption of mammalian oocytes released from antral follicles and they are required for in vitro maturation (Carroll and Swann, 1992; Carroll et al., 1994; De Felici et al., 1991; Deng et al., 1998). These Ca2þ oscillations are blocked by microinjected heparin, an antagonist of InsP3Rs, suggesting that spontaneous Ca2þ oscillations during maturation are InsP3 dependent, although there is another Ca2þ

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release mechanism in mouse oocytes which is not sensitive to InsP3, but sensitive to thimerosal (Carroll and Swann, 1992; Deng et al., 1998). It has been reported that during maturation of mammalian oocytes, there is an increase of the Ca2þ store size. This was based on the fact that mature oocytes release higher levels of Ca2þ that immature oocytes in response to ionomycin and thapsigargin (Fujiwara et al., 1993; Jones et al., 1995b; Tombes et al., 1992), and it was postulated that one feature of the oocyte maturation is the increase of the Ca2þ-sequestering capacity. However, Mehlmann and Kline demonstrated that the ER of immature oocytes can release as much Ca2þ in response to InsP3 as that of fully mature oocytes when InsP3Rs are sensitized with thimerosal (Mehlmann and Kline, 1994). Therefore, it was demonstrated that immature oocytes do not store lower levels of Ca2þ than mature oocytes, but that the maturing oocytes acquire greater competence for releasing Ca2þ in response to InsP3. This is in agreement with the reported increasing expression of InsP3R during maturation of oocytes. There is a twofold increase in this expression during maturation (Mehlmann et al., 1996), and it is believed that this upregulation, together with changes in the ER organization, may contribute to the differential Ca2þ release between immature and mature oocytes. For instance, in immature oocytes, the response to sperm is greatly attenuated when compared with mature oocytes. Whereas the fertilization of MII oocytes triggers a long-lasting series of Ca2þ waves, in immature oocytes, the response is limited to a single Ca2þ spike, followed by two or three low-level Ca2þ transients (Cheung et al., 2000; Jones et al., 1995b), that is, the ability to generate cytosolic Ca2þ oscillations in response to sperm fusion increases in the final stages of the oocyte maturation (see Fig. 8.1; Cheung et al., 2000). 2.5

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Figure 8.1 Calcium oscillations in oocytes triggered by sperm fusion. The ratio F340/F380 was monitored in zona pellucida (ZP)-free immature oocytes (left) or in ZP-free mature oocytes (right) loaded with fura 2 and incubated with capacitated sperm. Multiple Ca2þ oscillations induced by sperm in MII oocytes are absent in immature oocytes, where a single rise of cytosolic Ca2þ or a low number of Ca2þ transients is observed.

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During this maturation progress, InsP3R1 becomes phosphorylated at MAPK/ERK target sites, a posttranslational modification that regulates receptor activity, and remains phosphorylated in MII oocytes (Lee et al., 2006a). This phosphorylation is required for the generation of Ca2þ oscillations because the incubation of oocytes during maturation with inhibitors of the MAPK cascade impairs the capability of generating fertilization-like Ca2þ oscillations (Matson and Ducibella, 2007). However, the use of inhibitors of the MAPK cascade could affect other Ca2þ transport systems, such as SOCE which requires the ERK1/2-mediated phosphorylation of STIM1, a key mediator of this Ca2þ entry pathway, for the full activation of PM SOCs (Pozo-Guisado et al., 2010). Indeed, the lack of SOCE activation at fertilization due to the inhibition of ERK1/2 could underlie the results reported by Matson and Ducibella (2007), as will be discussed in more detail below. InsP3R1 shows a spatial regulation that is dependent on the maturation progress. In GV oocytes, InsP3R1 is found throughout the cytoplasm, but enriched in small clusters (<1mm) located around the cortex (Fissore et al., 1999; Mehlmann et al., 1996). However, InsP3Rs are present in large clusters (1–2mm in diameter) in the cortex of the mature oocyte except in the surroundings of the meiotic spindle (Kline et al., 1999; Mehlmann et al., 1996). As stated for InsP3Rs, RyRs show a very weak and diffuse distribution in GV oocytes, whereas the expression is greater in MI and MII oocytes. RyRs are found mainly in the cortex of MI and MII oocytes and are associated to cortical granules in bovine oocytes from the MI stage through fertilization, suggesting that RyRs may play a key role in cortical granule release (Wang et al., 2005; Yue et al., 1998). The activity of these receptors was studied by means of the injection of ryanodine, which triggered a slight increase of cytosolic Ca2þ in GV oocytes, and a series of significant Ca2þ spikes in mature oocytes (Yue et al., 1998). Thus, the sensitivity of the Ca2þ-releasing system increases during maturation of the oocyte due to the increased density and clustering of InsP3Rs and RyRs at the oocyte cortex, close to the sperm–oocyte fusion point, in order to enhance Ca2þ release from the ER at fertilization. Spontaneous Ca2þ oscillations in mammalian oocytes during meiotic maturation occur every 2–3min when GV oocytes are released from their follicles and resume meiosis, but these Ca2þ transients are not observed when oocytes do not maturate spontaneously in vitro and become arrested (Carroll et al., 1994). There are some conflicting data regarding the time and duration of this extracellular Ca2þ dependence during maturation. Some researchers found that a transient increase of the [Ca2þ]i might play an essential role in GVBD, and that the chelation of extracellular calcium with EGTA blocks in vitro maturation of mouse and hamster oocytes (Homa, 1995; Racowsky, 1986; Whitaker and Patel, 1990). On the contrary, Tombes et al. described GVBD as being Ca2þ independent, but they

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reported that the metaphase of the first meiosis is strongly dependent on the presence of extracellular Ca2þ (Tombes et al., 1992). Indeed, the inhibition of Ca2þ uptake with verapamil or tetracaine impaired mouse oocyte maturation (Powers and Paleos, 1982). Therefore, it can be argued that Ca2þ entry may play an essential role during oocyte maturation. We still do not know, however, the molecular pathway of this Ca2þ entry during oocyte maturation. In this regard, an excellent review highlights the involvement of VOCCs during oocyte maturation (Tosti, 2006). For instance, an inward Ca2þ current is detected in mouse GV oocytes, and during meiotic maturation, a gradual depolarization (35 to 17mV) takes places in these oocytes, suggesting that there is an increase of VOCCs during oocyte growth before nuclear maturation, and that those channels might have a role in the onset of maturation (Murnane and DeFelice, 1993). GV- or GVBD-arrested oocytes, incompetent for meiosis resumption, showed no presence of P/Q-, N-, and L-type Ca2þ channels in contrast to nonarrested and competent GV/GVBD oocytes, further demonstrating a correlation between meiotic competence and VOCC expression during early stages of meiotic resumption (Lee et al., 2004). However, Tosti et al. found that L-type VOCCs were active at GV stage only, and that their activity decreased at late phases of meiotic maturation (Tosti et al., 2000).

2.4. Experimental evidence supporting an early role for Ca2þ signaling at fertilization At fertilization, there is a PM fusion between sperm and oocyte, and this fusion releases the sperm-specific PLCz from the sperm to the oocyte cytosol (Saunders et al., 2002). PLCz activates the phosphoinositide pathway in the oocyte by means of the release of InsP3 and 1,2-diacylglycerol (DAG) via the hydrolysis of phosphatidyl 4,5-bisphosphate (PIP2). Released InsP3 binds to its specific receptor located at the ER membrane, the InsP3R. This receptor regulates the release of Ca2þ from the ER lumen upon activation by InsP3, increasing the [Ca2þ]i in the oocyte cytoplasm (Carroll, 2001; Halet et al., 2003; Lee et al., 2006b; Malcuit et al., 2006; Swann et al., 2004; Whitaker, 2006). Because InsP3Rs are sensitive to a moderate increase of the [Ca2þ]i above resting levels, the initial release of Ca2þ from the ER has the ability to stimulate further Ca2þ release through InsP3Rs located in the surroundings of the initial Ca2þ spike, a physiological response known as CICR. As a result, a “fertilization Ca2þ wave” is generated in the oocyte. As stated above, the abundance of InsP3Rs in the cortex of the oocyte and the diffuse distribution of RyRs throughout the cytoplasm (Balakier et al., 2002) support the “two-store model” (Tesarik and Sousa, 1996). Based on this model, the initial and restricted limited Ca2þ release is mediated by InsP3Rs, which show a low threshold for CICR activation. This local increase of the cytosolic Ca2þ propagates the

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fertilization wave by triggering a massive Ca2þ discharge from the two types of stores (enriched in InsP3Rs or in RyRs) located throughout the oocyte (Tesarik, 2002; Tesarik and Sousa, 1996). The increase of [Ca2þ]i induces the subsequent activation of the PMCA and SERCA in order to restore cytosolic Ca2þ levels by Ca2þ extrusion and Ca2þ uptake into ER, respectively. In sum, sperm fusion triggers a transient cytosolic Ca2þ rise followed by a rapid decrease of the cytosolic free Ca2þ concentration. This initial spike of Ca2þ lasts for 2–3min in mammalian oocytes and reaches the micromolar range. However, the continuous activity of the PLCz releasing InsP3 and the following activation of InsP3Rs induce several Ca2þ discharges from the ER, generating transient and repetitive increases of the cytosolic Ca2þ concentration in the fertilized oocyte (Cran et al., 1988; Cuthbertson and Cobbold, 1985; Kline, 1988; Kline and Kline, 1992a). Each of the subsequent Ca2þ discharges starts from intracellular stores located in the oocyte cortex, mediated by a CICR mechanism, when [Ca2þ]i, which shows a slow but significant increase between two sequential spikes, reaches the threshold of CICR activation (Tesarik, 2002). This signaling triggers cortical granule exocytosis and drives the exit from metaphase arrest of oocytes in meiosis II. There is a fascinating interplay between protein phosphorylation and Ca2þ signaling in mammalian oocytes, because the spatiotemporal pattern of cytosolic Ca2þ oscillations has a strong influence on the activation of downstream kinases directly involved in the egg activation. For instance, GFP-tagged protein kinase C (PKC) was found to translocate from the cytosol to the PM during each fertilization-induced Ca2þ transient, and this translocation was mediated by the C2 domain of the kinase (Halet et al., 2004). Another example of this close relationship between Ca2þ oscillations and kinase activation is the resumption of cell cycle at fertilization. Sperm-induced Ca2þ oscillations trigger the activation of Ca2þ/calmodulin kinase II (CaMKII), which phosphorylates Emi2, an inhibitor of the meiosis progression, required for maintaining cell-cycle blockade. Phosphorylated Emi2 is a substrate of the Polo-like kinase (Plx1kinase), and the phosphorylation of Plx1-target sites of Emi2 triggers its degradation by the proteasome. Thus, the anaphase-promoting complex (APC/C) loses its major inhibitor, Emi2, and drives the degradation of cyclin B1, the regulatory component of maturation promoting factor (MPF), consisting of p34cdc2 kinase and cyclin B (Hansen et al., 2006; Liu and Maller, 2005; Miller et al., 2006; Nixon et al., 2002; Rauh et al., 2005). However, cyclin B1 degradation is transitory, and protein levels can recover between Ca2þ spikes. Therefore, multiple Ca2þ spikes are needed to achieve complete cyclin degradation and ensure the exit from meiosis. Ca2þ oscillations continue until the MAPK pathway is completely inactivated (Moos et al., 1996), which is the time of the pronuclei formation (4–5h after fertilization; Deguchi et al., 2000; Jones et al., 1995a). This cessation is due to the nuclear

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localization signal of the PLCz (Swann et al., 2006). Therefore, by the time of pronuclei formation, PLCz is accumulated into formed pronuclei (Larman et al., 2004; Sone et al., 2005; Yoda et al., 2004). This feature of PLCz, together with the corresponding cessation of Ca2þ oscillations, indeed constituted further evidence in support of PLCz as the Ca2þ oscillation-inducing sperm factor. It is accepted that the ER is a major source of Ca2þ in these cytosolic spikes in mammalian oocytes. However, Ca2þ influx is required to preserve Ca2þ spiking during mammalian oocyte fertilization, as this signaling ceases in Ca2þ-free extracellular medium (Igusa and Miyazaki, 1983; Kline and Kline, 1992b). In addition, it was early reported that the continuous Ca2þinflux plays a role in refilling the ER, maintaining Ca2þoscillations in mammalian oocytes during fertilization (Mohri et al., 2001). This extracellular Ca2þ dependence is not shared by other species, and it is known that Ca2þ waves propagate in Ca2þ-free solutions in the sea urchin egg (Crossley et al., 1988; Schmidt et al., 1982). Moreover, not all the events associated with the resumption of meiosis require extracellular Ca2þ. For instance, cortical granule discharge is not sensitive to extracellular Ca2þ removal, but it is blocked by intracellular Ca2þ chelators (Tombes et al., 1992). Although extracellular Ca2þ is required for the fertilization of mammalian oocytes, the molecular pathway for Ca2þ entry in this process remains unknown. SOCE is a strong candidate for regulating Ca2þ entry at fertilization, since this is an active pathway in mammalian oocytes (Gomez-Fernandez et al., 2009; Halet et al., 2004; Machaty et al., 2002a; McGuinness et al., 1996) including human oocytes (Martin-Romero et al., 2008). However, little is known regarding the role of SOCE at fertilization.

3. SOCE in Somatic Cells In many cell types, it is well established that Ca2þ spikes or waves triggered by diverse stimuli are dependent on Ca2þ entry through the PM. This entry pathway replenishes Ca2þ levels within intracellular stores to maintain the rapid rate of cytosolic Ca2þ spiking. This mechanism was originally proposed by James Putney Jr. in 1986. The model described the depletion of intracellular Ca2þ stores as activating a Ca2þ entry pathway from the extracellular space to the pool, due to the activation of the phosphoinositide pathway. Conversely, when the pool is filled, the pathway is closed. For this reason, this entry pathway was originally called “capacitative calcium entry.” The term “store-operated calcium entry” (SOCE) is now commonly used, because it indicates the retrograde signaling by which PM Ca2þ channels are controlled by Ca2þ levels within the ER (Putney, 1986, 2007). However, despite the importance of SOCE for Ca2þ

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signaling, the molecular nature of many of the components involved in the control of SOCE has remained elusive for more than two decades.

3.1. Stromal interaction molecule 1 In 2005, two independent groups reported that the protein STIM1 is an essential component of the molecular machinery governing SOCE (Liou et al., 2005; Roos et al., 2005). Consequently, the knockdown of STIM1 expression reduced SOCE in a variety of cell lines, including HEK293, SH-SY5Y, Jurkat T, HeLa cells, and mammalian oocytes (Koh et al., 2009; Liou et al., 2005; Roos et al., 2005), whereas the overexpression of STIM1 enhanced SOCE (Roos et al., 2005). STIM1 was described a few years earlier as a single-transmembrane protein with an EF-hand domain close to the N-terminus (Manji et al., 2000; Williams et al., 2001, 2002; see Fig. 8.2). The predicted location for STIM1 is the membrane of the ER, with the EF-hand domain within the luminal space of the ER acting as the intraluminal Ca2þ sensor (Liou et al., 2005; Zhang et al., 2005). Upon

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Figure 8.2 STIM1 protein domains and clustering of STIM1 under store-depletion conditions. (A) The Ca2þ-binding EF-hand domain and the sterile alpha motif (SAM) are located within the ER, close to the N-terminus. In the cytoplasmic region, we find the following domains: two coiled-coil domains (CC1 and CC2), Serine/Proline-rich (S/P) domain, Lysine-rich (K) domain, and CAD (CRAC activation domain), also called SOAR (STIM1–ORAI1 activation region). TM, transmembrane domain. (B) HEK293 expressing STIM1-GFP were incubated in Hank’s balanced salt solution (HBSS) containing Ca2þ (left panel) or in Ca2þ-free HBSS with 1mM thapsigargin (right panel) and visualized under wide-field fluorescence microscopy. The treatment with thapsigargin leads to the rapid clustering of STIM1-GFP (Pozo-Guisado et al., 2010).

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depletion of intraluminal Ca2þ levels, the sterile alpha motif (SAM) interaction domain, adjacent to the EF-hand domain, mediates the oligomerization of STIM1 (Liou et al., 2007), and STIM1 is rapidly redistributed into discrete puncta that are located underneath, but not inserted into, the PM, that is, STIM1 relocalizes in puncta-like ER–PM junctions (Liou et al., 2007; Muik et al., 2008; Smyth et al., 2008; Fig. 8.2). The localization of STIM1 has been a point of intense debate during the past years. Earlier reports proved that a considerable fraction of STIM1 is in the PM under store-depletion conditions (Manji et al., 2000; Spassova et al., 2006; Williams et al., 2002; Zhang et al., 2005). For this reason, it was suggested that STIM1 translocates from ER to PM, in response to store depletion (Zhang et al., 2005). However, other reports demonstrated that STIM1 protein does not translocate to the PM, and that STIM1 in the ER approaches and interacts with SOCs in the PM upon depletion of Ca2þ stores (Wu et al., 2006; Xu et al., 2006). STIM1 movement in the resting state is mediated through the coiledcoil and Ser/Thr-rich C-terminal domains in the cytoplasmic region of STIM1, whereas the inducible puncta formation requires the SAM domain, which is found in the ER lumen (Baba et al., 2006). STIM1 clustering and relocalization are required for the activation of SOCs, which are located in the PM. STIM1 is a phosphoprotein (Manji et al., 2000), but the physiological role of the phosphoresidues remained elusive for several years. Recently, it was shown that Ser486 and Ser668 are probable targets of the CDK1 activity, and that phosphorylation of those residues underlies the inactivation of SOCE during mitosis in somatic cells (Smyth et al., 2009). Ser575, Ser608, and Ser621 were shown to be targets of the ERK1/2 activity, and the phosphorylation of those residues is required to achieve full activation of SOCE (Pozo-Guisado et al., 2010).

3.2. SOCs: ORAIs and TRPCs SOCs carry a Ca2þ-selective, nonvoltage-gated, inwardly rectifying current, also known as the Ca2þ release-activated Ca2þ current (ICRAC). The elusive molecular nature of these SOCs (or CRAC channels) was unraveled in 2006 with the discovery of ORAI1 (also known as CRACM1), a PM fourtransmembrane spanning protein that constitutes the CRAC channel (Feske et al., 2006; Soboloff et al., 2006b; Vig et al., 2006; Zhang et al., 2006). Some mechanistic details of SOC activation are still under study, but it is accepted that STIM1 multimerization triggers the binding to ORAI1 (Yeromin et al., 2006) to form active channels. The C-terminal domain of STIM1 activates ORAI1 by a physical interaction between coiled-coil domains in both proteins (Muik et al., 2008). Studies focused on the minimal domain of STIM1 required for the activation of ORAI1 reported that a highly conserved domain of about 100 amino acids, denominated CAD (CRAC activation domain) or

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SOAR (STIM1–ORAI1 activation region), binds directly to ORAI1, gating the channel (Park et al., 2009; Yuan et al., 2009). In addition, STIM1 couples to some members of the family of transient receptor potential canonical (TRPC) channels (Worley et al., 2007; Yuan et al., 2007), such as TRPC1, TRPC4, and TRPC5, and determines their function as SOC. For TRPC1, an electrostatic gating mechanism has been reported involving the interaction of two negatively charged aspartates in TRPC1 and the conserved polybasic domain close to the C-terminus of STIM1 (Zeng et al., 2008). STIM1 does not bind to TRPC3 and TRPC6, but regulates their function by the heteromultimerization of TRPC3 with TRPC1 and TRPC6 with TRPC4 (Yuan et al., 2007). For this reason, the laboratory of Shmuel Muallem proposed that the term SOCs can be used for all those channels that are regulated by STIM1 and require the store depletion-mediated clustering of STIM1. Moreover, heteromeric interactions of TRPCs can generate SOCs with different properties, and TRPC1 also associates with ORAI1 in a ternary complex STIM1–ORAI1–TRPC1 (Ambudkar et al., 2007). Finally, SOCs can be activated by alternative mechanisms. For instance, ORAI1 can be activated by the secretory pathway Ca2þ-ATPase, SPCA2, independent of both ER Ca2þ store levels and STIM1. Although SPCA2 usually acts as Ca2þ pump in Golgi, the binding of SPCA2 to ORAI1 activates the channel, promoting tumorigenesis (Feng et al., 2010), a recently described novel function for ORAI1.

3.3. STIM1 and the remodeling of the ER STIM1 is an ER-resident protein with a diffuse distribution when stores are full, but with a major movement in the membrane of the ER in resting cells (Baba et al., 2006). The reason for this behavior is unknown, although the close relationship between SOCE and microtubules could help to explain whether this is related to STIM1. Many different microtubule plus-end tracking proteins (þTIPs) associate with growing microtubule plus ends and control microtubule dynamics. STIM1 is a microtubule-tracking molecule because it directly binds to the microtubule þTIP EB1 (Grigoriev et al., 2008). STIM1 uses a short polypeptide motif (Thr-Arg-Ile-Pro) close to the C-terminus for its localization to microtubule tips in an EB1-dependent manner (Honnappa et al., 2009) and forms EB1-dependent comet-like accumulations at the sites where microtubule ends are in contact with the ER (Grigoriev et al., 2008). Moreover, STIM1 overexpression stimulates ER extension because ER tubules attach to and elongate together with the EB1-positive ends of growing microtubules. On the contrary, depletion of STIM1 and EB1 decreases ER protrusion, a piece of experimental evidence that further demonstrates the role played by STIM1 in ER remodeling (Grigoriev et al., 2008).

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Depletion of intracellular stores induces the dissociation of STIM1 from EB1, and this dissociation is a requirement for the puncta-like ER–PM junctions and the subsequent SOCE activation (Sampieri et al., 2009). Indeed, the use of microtubule-depolymerizing drugs, such as nocodazole, strongly inhibits SOCE and the associated Ca2þ release-activated Ca2þ current (ICRAC). Because this inhibition can be reversed by the overexpression of EYFP-STIM1, this result argued for the inhibitory effect being related to STIM1 function (Smyth et al., 2007). Although the molecular motif within STIM1 that binds to EB1 is known, it is not clear how STIM1 forms the complex with EB1 for the binding to microtubules, and it would be no surprise if additional unknown members of the cytoskeleton are found to play a possible role in the STIM1-mediated remodeling of the ER. Closely related to the activity of STIM1 as microtubule-tracking molecule is the finding that STIM1 rules the insertion of TRPC1 into lipid rafts at the PM, suggesting that STIM1 is directly involved in the transport of SOCE-associated proteins to the PM and the controlled insertion of these proteins into lipid rafts (Alicia et al., 2008; Vaca, 2010).

3.4. Additional modulators of SOCE Many of the molecular components involved in SOCE regulation are found in lipid rafts, domains with high concentrations of cholesterol and sphingolipids, which are known to facilitate the assembly of signaling complexes. For instance, TRPC1 is assembled in a complex with caveolin-1 (Cav-1), a cholesterol-binding protein involved in the generation of caveolar lipid rafts. The binding of Cav-1 to TRPC1 is mediated by a binding domain in the TRPC1 N-terminus, and the deletion of this domain induces a dominant suppression of SOCE (Brazer et al., 2003). Moreover, using mice deficient in Cav-1, it was shown that Cav-1 is essential for the localization and protein– protein interactions between TRPC1 and TRPC4 (Murata et al., 2007), and the disruption of lipid rafts severely affects SOCE (Lockwich et al., 2000; Pani et al., 2008). Clustering of STIM1 in ER–PM junctions and activation of TRPC1-dependent SOCE are determined by lipid raft domains (Pani et al., 2008), and this facilitates the functional interaction of STIM1 with SOCs in order to activate SOCE. Recently, Alicia et al. found that the association of STIM1 with TRPC1 favors the insertion of TRPC1 into lipid rafts, where TRPC1 functions as a SOC. In contrast, TRPC1 associates with other members of the TRPC family in the absence of STIM1, with the associations acting as receptor-operated channels (ROCs; Alicia et al., 2008), providing further evidence for the dual role of TRPC1 as ROC or SOC, depending on its association with STIM1 in lipid rafts. Because the number of components known to regulate SOCE is still rising, the term store-operated calcium influx complex has been proposed to refer all those components (Vaca, 2010). Recent reports point to

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additional modulators of SOCE, such as SERCA ( Jousset et al., 2007; Manjarres et al., 2010; Sampieri et al., 2009), the aforementioned microtubule end-binding protein EB1 (Grigoriev et al., 2008; Sampieri et al., 2009), or the Ca2þ-binding protein calmodulin (CaM). The Ca2þ influx mediated by SOCs can be suppressed by the increase of cytosolic Ca2þ concentration. This Ca2þ-dependent inactivation is a negative feedback regulation that inactivates SOCs when cytosolic Ca2þ levels become higher. This inhibition is mediated by CaM (Vaca, 1996) that binds to both STIM1 and ORAI1 for this channel inactivation (Mullins et al., 2009; Parvez et al., 2008). A recent report shed some light on the molecular mechanism of the SOCE inhibition mediated by CaM. Srikanth et al. found that CRACR2A, a 45-kDa protein containing two EF hands, interacts with both STIM1 and ORAI1 when Ca2þ levels are low, but that this interaction is attenuated when cytosolic Ca2þ levels increase over resting levels. At low cytosolic Ca2þ levels, CRACR2A enhances the binding of STIM1 to ORAI1 and thereby promotes SOCE. Finally, ORAI1 residues involved in CRACR2A binding have been described as those previously shown to bind CaM (Mullins et al., 2009). As a result, it was proposed that the binding of Ca2þ/CaM and Ca2þ-free CRACR2A to ORAI1 is competitive, and the dissociation of CRACR2A allows the binding of Ca2þ/CaM to ORAI1, leading to SOCE inactivation (Srikanth et al., 2010). Like STIM1, the closely related protein STIM2 is a transmembrane protein found in the ER membrane. STIM2 has an EF-hand domain within the ER that senses intraluminal Ca2þ levels, and upon store depletion, STIM2 translocates into puncta and interacts with STIM1. Although it was initially described that STIM2 interferes with STIM1 and blocks its function as SOC activator when overexpressed in a variety of cell lines, such as HEK293, PC12, A7r5, and Jurkat T cells (Soboloff et al., 2006a), a possible physiological function of STIM2 is to keep intraluminal Ca2þ levels within tight limits, because STIM2 activates Ca2þ influx when the Ca2þ ER drops slightly below resting levels (Brandman et al., 2007). As a consequence, it has been suggested that STIM2 is involved not only in SOCE but also in the control of cell proliferation in HEK293 cells (El Boustany et al., 2010), and that STIM2 is essential for the Ca2þ influx observed in neurons during ischemia (Berna-Erro et al., 2009).

4. Modulation of SOCE During Cell Cycle 4.1. SOCE downregulation during mitosis of somatic cells Many cellular events are downregulated during mitosis to ensure the correct progress of cell division. The large Ca2þ influx triggered by the activation of the histamine H1 receptor in HeLa cells during interphase is suppressed in

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mitotic cells, and only an initial Ca2þ rise, derived from the Ca2þ release from intracellular stores, is observed (Volpi and Berlin, 1988). In these mitotic cells, thapsigargin, a SERCA inhibitor, does not stimulate Ca2þ influx, and the coupling between depletion of intracellular stores and Ca2þ influx is lost (Preston et al., 1991). Additionally, there is a complete lack of STIM1 rearrangement into puncta in response to Ca2þ-store depletion in mitotic HEK293 cells (Smyth et al., 2009). This is not due to a different expression level of STIM1 because this level remains unaltered in mitotic HeLa or HEK293 cell lysates, but the expression of ORAI1 is reduced in mitotic cells by 25–50% (Smyth et al., 2009). However, Orai1 siRNA in asynchronous cells decreases ORAI1 levels to a greater extent but inhibits Ca2þ entry to a lesser extent. Although the mechanism by which mitotic suppression of SOCE occurs remained unknown for a long time, Smyth et al. demonstrated that phosphorylation of STIM1 at Ser 486 and Ser 668 suppresses SOCE during cell division, this finding being the first demonstration of a specific role for STIM1 phosphorylation (Smyth et al., 2009). However, those authors suggested that other determinants, including additional phosphorylation sites, could be involved in SOCE suppression. The interaction of STIM1 with microtubule-binding protein EB1 was mapped to a region of STIM1 between amino acids 392 and 652 (Grigoriev et al., 2008). Therefore, the possibility that phosphorylation of STIM1 at Ser 486 and Ser 668 regulates the interaction of STIM1 with EB1 remains to be studied, but it could explain the dissociation of STIM1 from microtubules during mitosis, preventing STIM1 localization to the mitotic spindle (Smyth et al., 2009).

4.2. Downregulation of SOCE in Xenopus oocytes In Xenopus, meiotic resumption, and therefore oocyte maturation, is triggered by progesterone (Maller and Krebs, 1980), which induces a signal transduction pathway that activates the maturation-promoting factor (MPF; Nebreda and Ferby, 2000) required and sufficient for GVBD and entry into meiosis. The work of the laboratory of Khaled Machaca unraveled some of the questions regarding the molecular regulation of Ca2þ signals during Xenopus oocyte maturation. In Xenopus, there is an inactivation of Ca2þ influx during oocyte meiosis (Machaca and Haun, 2000), similar to that described during mitosis of mammalian cells (Preston et al., 1991). Machaca’s group found that the activation of MPF before Ca2þ-store depletion blocks SOCE activation but not the current through SOCE channels (Machaca and Haun, 2002), that is, MPF blocks the coupling of Ca2þ-store depletion to SOCE activation. More recently, they found that STIM1 oligomerization in response to store depletion is inhibited during Xenopus oocyte meiosis (Yu et al., 2009), similar to the lack of puncta formation of STIM1 in HEK293 cells during mitosis (Smyth et al., 2009).

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It was then observed that STIM1 is phosphorylated during meiosis in several MAPK/MPF consensus sites. The MAPK cascade and MPF drive oocyte maturation, since they are activated in eggs but not in immature oocytes. Indeed, they found seven phosphorylated residues in STIM1 from eggs but no phosphorylation was detected in STIM1 from immature Xenopus oocytes (Yu et al., 2009). By mutating those residues to Ala or Glu to mimic constitutive dephosphorylation or phosphorylation, respectively, they argued that the inhibition of STIM1 oligomerization cannot be attributed to STIM1 phosphorylation, although it requires the activation of MPF kinase (Yu et al., 2009). The results with Xenopus oocytes were clearly different from those reported with mitotic HEK293 and HeLa cells (see above). Putney’s group found that constitutive dephosphorylation of residues Ser486 and Ser668 rescued SOCE in mitosis, that is, phosphorylation of those sites may underlie SOCE inhibition during mitosis (Smyth et al., 2009). However, those specific residues were not studied by Machaca’s group, so the possibility that STIM1 phosphorylation at those specific sites underlies inhibition of STIM1 function in both mitotic and meiotic cells is an attractive, and still viable, hypothesis. Additionally, there is continuous ORAI1 recycling at the PM in Xenopus oocytes during meiotic maturation, and ORAI1 becomes internalized during meiosis into a caveolin-positive endosomal vesicles (Yu et al., 2009), together with other proteins such as PMCA and b-integrin (Machaca, 2007). ORAI1 internalization inactivates SOCE and there is a strong correlation between ORAI1 internalization and current inhibition. This inhibition was observed even in oocytes expressing constitutively active STIM1 mutants, such as STIM1D76A, or the cytosolic domain of STIM1 (Yu et al., 2009). In sum, these results suggested that ORAI1 internalization is sufficient to inactivate SOCE during Xenopus oocyte maturation.

4.3. SOCE is an active Ca2þ influx pathway in mature mammalian oocytes A remarkable exception to the downregulation of SOCE during cell division is the mammalian oocyte, which undergoes prolonged Ca2þ oscillations postfertilization and maintains active SOCE. The presence of capacitative calcium entry in mammalian oocytes was proposed early on, based on the sensitivity of mouse oocytes to the SERCA inhibitor thapsigargin and to the Ca2þ ionophore ionomycin (Kline and Kline, 1992b; McGuinness et al., 1996). It was proposed that the capacitative Ca2þ entry is activated after pharmacological depletion of intracellular stores, and that this mechanism sets the frequency of spiking by modulating the required time for the refilling of intracellular stores. In addition, those early experiments suggested that sperminduced Ca2þ oscillations may deplete intracellular Ca2þ stores, thereby triggering the activation of the Ca2þ influx required for the rapid and periodic

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refilling of intracellular stores between subsequent Ca2þ spikes at fertilization (Kline and Kline, 1992b; McGuinness et al., 1996). In sum, Ca2þ influx would play a role in refilling the ER, and this influx would be required to preserve Ca2þ spiking during the fertilization of mammalian oocytes. Later, the presence of a capacitative Ca2þ entry pathway, sensitive to lanthanum, was observed in porcine oocytes after treatment with thapsigargin (Machaty et al., 2002a), and in a similar way, SOCE has been monitored in fura2-loaded mature mouse oocytes (Gomez-Fernandez et al., 2009; Halet et al., 2004; McGuinness et al., 1996) and human oocytes (Martin-Romero et al., 2008). In human oocytes, Ba2þ and Mn2þ were used as Ca2þ surrogates to study the sensitivity of divalent cation entry to SOCE blockers, such as 2-aminoethoxydiphenylborate or diethylstilbestrol, and the pharmacological inhibition of this pathway further supported the presence of active SOCE in oocytes (Martin-Romero et al., 2008). The molecular identification of endogenous STIM1 in mammalian oocytes was reported in 2009 (Gomez-Fernandez et al., 2009; Koh et al., 2009). STIM1 was found mainly in ER clusters (1–2mm in diameter) in the cortex of mouse mature oocytes. This particular distribution matches well with other Ca2þ mediators, such as calreticulin (Gomez-Fernandez et al., 2009; see Fig. 8.3) and InsP3R (Balakier et al., 2002), both segregated to the periphery of the oocyte. In porcine oocytes, Koh et al. found STIM1 predominantly in the inner regions of the cytoplasm in resting conditions (Koh et al., 2009). This major difference in the reports could reflect a speciesdependent distribution of STIM1. Therefore, additional data from other mammals are required to clarify the issue and to complete the description of the SOCE molecular machinery in mammalian oocytes. Because it is accepted that STIM1 activation is as a selective marker of SOCE (Ambudkar et al., 2007; Ong et al., 2007; Pani et al., 2008), the relocalization of STIM1 in response to ER depletion (Fig. 8.4) lends further support to STIM1 being active in MII oocytes (Gomez-Fernandez et al., 2009). Of particular interest is that STIM1–ORAI1 colocalization increases significantly upon store depletion in mouse MII oocytes (Go´mez-Ferna´ndez et al., 2011), coherent with the binding of STIM1 to ORAI1 when Ca2þ stores are depleted, and confirming that SOCE is an activatable pathway in mouse mature oocytes.

5. Possible Role of SOCE in Fertilization 5.1. Molecular markers of SOCE activation: STIM1 relocalization Although there is solid evidence for a major role for Ca2þ influx at fertilization in mammalian oocytes (Igusa and Miyazaki, 1983; Kline and Kline, 1992b; Mohri et al., 2001), the initial studies aimed at explaining how Ca2þ

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Figure 8.3 STIM1 expression and localization in mouse oocytes. (A) Western blot experiments show a single band of 80kDa that corresponds to STIM1 in mouse oocytes lysates as indicated in Gomez-Fernandez et al. (2009). As a control, we show the result of HEK293 cells expressing endogenous STIM1 (Flag-empty) or HEK293 cells overexpressing STIM1 tagged with the Flag-peptide (Flag-STIM1). (B) In MII oocytes, STIM1 (green) colocalizes with calreticulin (red), a Ca2þ-binding protein which is found within the cortical ER at this meiotic stage. The immunolocalization of STIM1 was performed with the anti-STIM1 antibody used in the panel A. Images correspond to the total projection of 1.5-mm z-sections obtained by confocal microscopy. Other experimental conditions are detailed in Gomez-Fernandez et al. (2009).

oscillations are generated in the oocyte were focused on the role of Ca2þ release from the ER. This role is now well known and indeed was noted above. However, there is still an important gap in this model. As suggested by Kline and Kline, the first sperm-induced Ca2þ transient at fertilization could deplete intracellular Ca2þ stores, therefore making the triggering of the Ca2þ influx necessary to restore those levels (Kline and Kline, 1992b). This restoration capacitates the ER to support additional oscillations. Because SOCE can be activated in mature oocytes, this Ca2þ entry pathway might replenish Ca2þ stores during Ca2þ oscillations at fertilization.

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Figure 8.4 STIM1 relocalization in mammalian oocytes. STIM1 shows a remarkable relocalization in response to pharmacological Ca2þ-store depletion in mouse MII oocytes, triggered in this case by thapsigargin. Similar results are shown under store depletion induced by ionomycin, in a Ca2þ-free medium, or by stimulation of PLC activity with m-3M3FBS. Images correspond to the total projection of 1.5-mm z-sections obtained by confocal microscopy (Gomez-Fernandez et al., 2009).

As a demonstration of this hypothesis, we reported that sperm induces relocalization of STIM1 in oocytes after sperm fusion. This relocalization has two major features. First, mobilization of STIM1 induced by sperm shows a clear difference from thapsigargin-induced mobilization, since sperm triggered STIM1 relocalization to a single small region near the PM (Gomez-Fernandez et al., 2009), that is, STIM1 distribution is highly polarized after sperm fusion. The spatially restricted distribution of STIM1 during fertilization may suggest that STIM1 accumulates close to the point of sperm–oocyte fusion, a hypothesis that needs further experimental confirmation. The protrusion of the oocyte in this cortical region of the oocyte where STIM1 accumulates at fertilization resembles the point of Ca2þwave generation, or Ca2þ-wave pacemaker, that has been functionally monitored in nonmammalian species (Dumollard et al., 2002). However, Ca2þ-wave pacemakers have been described as being located at the vegetal pole of the oocyte, and we observed that STIM1 relocates close to the mitotic spindle in many cases. In addition, this relocalization is concomitant with the generation of the first Ca2þ spikes (Fig. 8.5), confirming the early reports that hypothesized that the first sperm-induced Ca2þ transient at fertilization depletes intracellular Ca2þ stores (Kline and Kline, 1992b). STIM1 aggregation at a single point of the oocyte after oocyte–sperm fusion is not due to large modifications of the ER structure, because the ER clusters remain stable and continuous throughout the time of fertilizationinduced Ca2þ transients (Kline et al., 1999). Interestingly, the rapid STIM1 relocalization (<15min after sperm addition) strongly supports the hypothesis that SOCE plays an early role in fertilization, because it suggests the requirement of Ca2þ entry through STIM1-dependent channels (i.e., SOCs) during Ca2þ oscillations induced by fertilization. Finally, the

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Figure 8.5 Kinetics of STIM1 relocalization and Ca2þ oscillations at fertilization. STIM1 relocalization in large clusters in response to sperm stimulation occurs simultaneously to the generation of the first cytosolic Ca2þ wave (or “fertilization Ca2þ wave”), that is, within the first 15min after addition stimulation of mouse MII oocytes with capacitated sperm (Gomez-Fernandez et al., 2009).

pharmacological activation of endogenous phospholipase C in oocytes with the activator m-3M3FBS leads to the relocalization of STIM1 in a similar way to thapsigargin-treated oocytes (Gomez-Fernandez et al., 2009), further supporting the idea that STIM1 is sensitive to store depletion induced by the activation of the phosphoinositide pathway. Therefore, we propose that Ca2þ channels activated by STIM1, that is, SOCs, are involved in sustaining the Ca2þ signal initiated by the sperm fusion.

5.2. SOCs in mammalian oocytes The endogenous expression of SOCs in mammalian oocytes had not been described until very recently (Go´mez-Ferna´ndez et al., 2011). The expression of Orai1 transcripts in mouse oocytes was monitored by end-point PCR and quantitative RT-PCR, and we reported that Orai1 levels show an upregulation during maturation. However, ORAI1 protein expression was steady in the GV-MII transition. ORAI1 was found in the PM with some level of clustering in resting MII oocytes, that is, the ORAI1 distribution in the PM resembles STIM1 location in the ER (Fig. 8.6). Indeed, there is a low but significant STIM1–ORAI1 colocalization, and this spatial proximity between the two proteins in resting oocytes suggests that MII oocytes

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Figure 8.6 Immunoblot and immunolocalization of ORAI1 in mouse MII oocytes. Left panel: Western blot experiments show a single band of 50kDa that corresponds to ORAI1 in mouse oocytes lysates as indicated in Gomez-Fernandez et al. (2009). As a control, we show the result of HEK293 cells expressing endogenous ORAI1 (nontransfected) or HEK293 cells overexpressing ORAI1 tagged with the Flag-peptide (Flag-ORAI1). Right panel: In MII oocytes, ORAI1 shows a high level of clustering resembling the distribution of STIM1 in the ER. Images correspond to equatorial section (upper image) or to the total projection of 1.5-mm z-sections obtained by confocal microscopy (Go´mez-Ferna´ndez et al., 2011).

might have an increased capability of activating rapid Ca2þ influx. Moreover, STIM1–ORAI1 colocalization increases significantly (greater than threefold) in MII oocytes in response to pharmacological inhibition of SERCA, a result that strongly suggests that SOCE is mediated by ORAI1 in mature oocytes. Although other SOCs might be available and active in mammalian oocytes, such as some of the members of the TRPC family, so far there is no evidence of their participation in the regulation of SOCE in mammalian oocytes. For instance, a fragment of a trpc3 homologue transcript has been found in porcine oocytes (Machaty et al., 2002a), but definitive experimental evidence to demonstrate the molecular nature of the protein and its location is needed. Unpublished data from our laboratory revealed that transcripts Trpc1, Trpc3, and Trpc4 are expressed in mature mouse oocytes, and at least TRPC1 protein expression has been confirmed in mouse MII oocytes (A.M.L.G. and F.J.M.R, unpublished results). In sum, mature mouse oocytes express the minimal elements required for the activation of SOCE: STIM1 and ORAI1. Moreover, their distribution and colocalization are sensitive to intracellular Ca2þ stores levels.

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6. Modulation of SOCE During Oocyte Maturation The mechanisms involved in the control of Ca2þ spikes at fertilization are strictly optimized during meiotic maturation of the oocyte, that is, in the transition from immature GV to fully mature oocytes. Moreover, maturation progress is accompanied by a significant increase in the capability of the ER to release Ca2þ to the cytoplasm, as stated above, and this capability is required for the generation of repetitive cytosolic Ca2þ spiking at fertilization. Therefore, immature oocytes are not competent for this repetitive spiking when they are stimulated with the sperm, and this incompetence has been ascribed to a lesser capability to mobilize Ca2þ from intracellular stores ( Jones et al., 1995b; Mehlmann and Kline, 1994). Consequent to this idea, we found that SOCE is inactive in immature oocytes (Go´mez-Ferna´ndez et al., 2011). Although thapsigargin induces store depletion in GV, GVBD, and MI oocytes, this depletion is not coupled to the opening of a capacitative Ca2þ entry pathway. The possible reasons for the lack of SOCE in immature oocytes are still under study, but our laboratory has shown that there is an upregulation of endogenous levels of STIM1 during mouse oocyte maturation (Gomez-Fernandez et al., 2009; Go´mez-Ferna´ndez et al., 2011). This upregulation is due to a combination of transcriptional and posttranscriptional mechanisms of regulation. The level of transcripts encoding Stim1 increases sharply at the GVBD stage and decreases slightly during the GVBD–MII transition. STIM1 endogenous protein expression is very low in GV oocytes, increasing at the time of the nuclear envelope breakdown, in accordance with Stim1 transcript levels, and it remains stable during the progression to the MII stage (Go´mez-Ferna´ndez et al., 2011). The expression of Orai1 transcripts and ORAI1 protein has also been studied to explain the dynamics of SOCE in maturing oocytes. Orai1 transcript levels increase at the nuclear envelope breakdown, but ORAI1 protein levels remain steady during maturation (Go´mez-Ferna´ndez et al., 2011). It has been demonstrated that the knockdown of STIM1 leads to the inactivation of SOCE in somatic cells (Cahalan, 2009; Liou et al., 2005; Roos et al., 2005) and in mammalian oocytes (Koh et al., 2009). Thus, the low level of STIM1 in GV oocytes may explain the lack of SOCE at this particular stage, because the lack of STIM1 uncouples ORAI1 activation from Ca2þ levels within stores. In addition, STIM1 does not bind to ORAI1 in GVBD or in MI oocytes in response to thapsigargin (Go´mez-Ferna´ndez et al., 2011), in contrast to MII oocytes. It is accepted that the rearrangement of the cytoskeleton facilitates the relocalization of STIM1 in response to store depletion (Smyth et al., 2007). We have observed that there is no relocalization of STIM1 during thapsigargin-triggered store depletion in immature oocytes, and that STIM1–ORAI1 colocalization did not increase in these

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conditions (Go´mez-Ferna´ndez et al., 2011), suggesting that a defective reorganization of the STIM1–ORAI1 complex occurs in immature oocytes. Because microtubule organization strongly correlates with MAPK activity (Verlhac et al., 1994), it is possible that GV and GVBD oocytes are defective in SOCE because they do not show high MAPK levels. An additional plausible explanation for the dynamic modulation of SOCE during meiotic progression is the modulation of STIM1 by posttranslational modifications. Phosphorylation of STIM1 at ERK1/2 target sites (i.e., Ser575, Ser 608, and Ser621) enhances SOCE in somatic cells (Pozo-Guisado et al., 2010), and it is well known that ERK1/2 activity increases during oocyte maturation (Fan and Sun, 2004; Verlhac et al., 1993, 1994). Consequently, the possibility that the increasing phosphorylation of STIM1 by ERK1/2 underlies SOCE upregulation during maturation is an attractive hypothesis that we are currently studying. Also, it has recently been shown that a conformational change in STIM1 is required for full activation of SOC channels (Korzeniowski et al., 2011; Muik et al., 2011). STIM1 has an autoinhibitory domain that needs to be unfolded for its full activation and the subsequent activation of ORAI1. Whether the lack of SOCE in immature oocytes is due to the absence of this conformational modification in STIM1 or due to a constitutive dephosphorylation needs to be clarified in future studies. The absence of active SOCE in immature oocytes explains the early cessation of Ca2þ transients in immature oocytes after sperm stimulation. Because sperm fusion represents a continuous stimulation that triggers Ca2þ release from the ER, a system for restoring Ca2þ concentration within the ER is required in the oocyte. SOCE, together with the ER Ca2þ pump, is a major candidate for this role. However, in the absence of SOCE, as in immature oocytes, there is no proper replenishment of Ca2þ levels within the ER, and this leads to the generation of a low number of cytosolic Ca2þ oscillations by the immature oocyte. In a similar way, somatic cells with defective SOCE, like HEK293 cells stably expressing FlagSTIM1S575A/S508S/S621A (Pozo-Guisado et al., 2010), cannot rise [Ca2þ]i in response to a repetitive stimulation with ATP and carbachol (E.P.G. and F.J.M.R., unpublished data). Indeed, this result suggests that the inability of immature oocytes to relocalize STIM1 and ORAI1 in response to store depletion could be due to the incomplete phosphorylation of STIM1 at ERK1/2 sites in immature oocytes.

7. Future Objectives and Conclusions In this review, we have summarized some of the major contributions to the study of Ca2þ signaling during the maturation and fertilization of mammalian oocytes, with special focus on the roles of extracellular Ca2þ

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and Ca2þ entry in these processes. To the original hypothesis that suggested the requirement of extracellular Ca2þ for the proper onset and completion of fertilization, there are currently new additional elements seen as modulating Ca2þ entry in oocytes. The involvement of STIM1 and ORAI1 in the regulation of this Ca2þ entry pathway in oocytes is a recent finding that shed light on the partial scheme that is currently used to explain how Ca2þ oscillations are generated in the oocyte. As a result, we provide an updated scheme of the Ca2þ signaling in mammalian oocytes at fertilization (see Fig. 8.7). In addition, the participation of new Ca2þ transport systems in this important event increases the number of potential targets for the treatment of pathologies directly involved with the oocyte physiology. In this regard, the obstacles in many cases of human infertility are bypassed by assisted reproductive techniques, including in vitro maturation and in vitro fertilization of human oocytes. During in vitro culture, human oocytes are exposed

Figure 8.7 The role of store-operated Ca2þ entry in the Ca2þ signaling pathway at fertilization of mammalian oocytes. (1) The activation of the phosphoinositide pathway by the sperm-specific PLCz triggers a first Ca2þ release from the ER through InsP3Rs. The elevated [Ca2þ]i activates Ca2þ pumps: SERCA and PMCA, thereby leading to the emptying of intracellular stores. The partial depletion of the ER does not support subsequent Ca2þ discharges from this store, unless a capacitative Ca2þ entry pathway is activated. (2) The emptying of the ER activates STIM1 which relocates close to the plasma membrane where it activates Ca2þ influx through ORAI1. This Ca2þ entry pathway (SOCE) replenishes Ca2þ levels within ER and allows the generation of repetitive Ca2þ spikes when the phosphoinositide pathway is activated.

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to high levels of reactive oxygen species (ROS), mainly due to spontaneous generation of ROS by enriched culture media containing photodynamic sensitizers, such as flavins, in combination with atmospheric oxygen (Guerin et al., 2001; Michelson, 2000). SOCE is a major target of oxidative stress, and we have shown that micromolar concentrations of extracellular H2O2 induce a significant deregulation of [Ca2þ]i in human oocytes, activating Ca2þ influx through SOCs in a store-independent mode (Martin-Romero et al., 2008). Although a common strategy to counteract this oxidative stress is the addition of nonenzymatic antioxidants to the culture medium, this strategy should be implemented only after a detailed study of the pharmacological sensitivity of Ca2þ-transport systems to these antioxidants, especially to polyphenolic agents. For instance, curcumin inhibits SOCE in Jurkat T cells (Shin et al., 2011), and other polyphenols such as diethylstilbestrol inhibit SOCE in platelets (Dobrydneva et al., 2010) and human oocytes (Martin-Romero et al., 2008). Therefore, the use of these agents may put in risk the outcome of in vitro maturation or fertilization by impairing Ca2þ signaling. This is a major reason to continue with the description of the complete set of channels involved in Ca2þ signaling at fertilization and oocyte maturation, and hence of oocytes’ sensitivity to the wide range of drugs that may be used during in vitro culture.

7.1. Finding oocyte-specific members of “CRACsome” The study of the regulation of SOCE requires finding the molecular partners of STIM1 and ORAI1 that modulate Ca2þ influx. As has already been mentioned above, members of the TRPC family, CRACR2A, CaM, and ERK1/2, are transiently bound to STIM1 and modulate its ability to bind to ORAI1 (Mullins et al., 2009; Pozo-Guisado et al., 2010; Srikanth et al., 2010). One is probably still far from having a complete list of SOCE modulators, and future studies are required for the full description of the macromolecular complex that rules SOCE, the “CRACsome.” However, this line of investigation would appear to constitute one of the most promising fields in the study of Ca2þ signaling, as reflected in the rapid increase in the number of members associated to this pathway. It is important though to focus particularly on the description of this complex in diverse cell types, because it is reasonable to expect to find important differences in the composition and activity of this complex amongst cell types with a differential dependence on Ca2þ signaling and Ca2þ entry. Although the use of established cell lines facilitates the study of these molecular complexes, the distinctiveness of the mammalian oocyte requires specific studies in this cell type because substantial differences have been reported in the regulation of SOCE between oocytes and somatic cells, such as the upregulation of SOCE during the M-phase of the cell cycle or the presence of a high degree of STIM1 clustering in resting oocytes. Because of

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the tight association between SOCE and the cell cycle, it should not be surprising for there to be a marked difference in the number of molecular partners regulating STIM1 function during interphase, mitosis, and meiosis. We have already mentioned the functional differences in STIM1 and SOCE regulation in those cell cycle phases, but there still lacks confirmation of the molecular interaction between STIM1/ORAIs/TRPCs and regulatory proteins in oocytes.

7.2. Modulation of SOCE by posttranslational modifications The finding that STIM1 is a target of ERK1/2 activity in vitro and in vivo (Pozo-Guisado et al., 2010) gives rise to new questions regarding the modulation of STIM1 activity in mature oocytes, where outstanding upregulated ERK1/2 activity is found. The pharmacological inhibition of the MAPK cascade in maturing oocytes has a strong impact on the amplitude and duration of Ca2þ oscillations in the fertilized oocyte after maturation (Matson and Ducibella, 2007). Thus, it is possible that ERK1/ 2 may phosphorylate STIM1 in mature oocytes thereby promoting SOCE, although this hypothesis needs further experimental confirmation. We do know that suppression of this phosphorylation by mutation of ERK1/2-target serine residues to alanine in STIM1 suppresses the capability of somatic cells to generate repetitive Ca2þ oscillations in response to purinergic stimulation (E.P.G. and F.J.M.R., unpublished data). This result strongly suggests that phosphorylation of STIM1 at these sites is required to completely activate SOCE. The study of the dynamics of the phosphorylation state of ERK1/2 target sites in STIM1 will clarify this issue. Also, PKC activation has been described as being involved in the modulation of Ca2þ oscillations in mammalian oocytes. Hyperactivation of PKC with phorbol esters or the overexpression of PKCa has a strong impact on Ca2þ oscillations dynamics, promoting these oscillations, whereas PKC inhibitors decreased the number of Ca2þ oscillations in fertilized oocytes (Halet et al., 2004). Consequently, it was suggested that conventional PKCs may control SOCs (Halet, 2004; Halet et al., 2004). However, it was later reported that phosphorylation of SOCs by PKC suppresses SOCE and the function of ORAI1 as a Ca2þ channel (Kawasaki et al., 2010), suggesting that alternative targets of PKCs may control Ca2þ oscillations in fertilized mammalian oocytes. The finding of PKC targets in the mature oocyte should clarify the role of this kinase in the modulation of Ca2þ signaling. Furthermore, the description of phosphatases involved in this regulation will add to the knowledge of the interplay between kinases and Ca2þ oscillation dynamics. Additional posttranslational modifications have been described for STIM1, such as the S-glutathionylation at cysteine 56 in response to oxidative stress (Hawkins et al., 2010). This modification activates a

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constitutive Ca2þ influx independent of the level of Ca2þ within intracellular stores, and it is a plausible explanation for the deregulation of [Ca2þ]i that was observed in human oocytes under oxidative insults (MartinRomero et al., 2008). This specific residue Cys56, together with Cys49, is also involved in the binding to the ER oxidoreductase ERp57, a protein that regulates SOCE through the intraluminal domain of STIM1 (Prins et al., 2011) and a potential modulator of STIM1 to be included in the list of SOCE regulators. In sum, what these posttranslational modifications have shown is that modulation of SOCE can be carried out by many other as yet unidentified molecular components, in addition to the well-established role of ORAIs and TRPCs.

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