Mini-Review |
Address correspondence to S. Papp, Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8. Tel.: (416) 978-8947. E-mail: sylvia.papp{at}utoronto.ca
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Abstract |
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Introduction |
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Ca2+ signaling |
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The pancreatic acinar cell is a model cell type used to study the effects of the spatial heterogeneity of Ca2+-handling proteins on Ca2+-dependent events and has been extensively characterized by the group of Petersen (Belan et al., 1996; Petersen et al., 1999) and others (Kasai et al., 1993; Nathanson et al., 1994; Lee et al., 1997a,b; Leite et al., 1999). The pancreatic acinar cell has special Ca2+ release sites in its apical region, termed the trigger zone, which are enriched in InsP3 receptors (Nathanson et al., 1994; Lee et al., 1997b; Petersen et al., 1999), whereas its uptake sites, enriched in SERCAs, are located in the basal region (Lee et al., 1997a; Petersen et al., 1999). In pancreatic acinar cells, the focus has been on the distribution of Ca2+ pumps and channels and their critical role in the generation of spatially complex Ca2+ waves and oscillations. We suggest here, however, that Ca2+ signal generation and regulation is an intricate process, which likely also requires input from the endoplasmic reticulum lumenal environment and its Ca2+-binding proteins (Simpson et al., 1997; Johnson and Chang, 2000).
The major Ca2+-binding protein of the endoplasmic reticulum of smooth muscle and nonmuscle cells is calreticulin (Milner et al., 1991), and its homologue in the sarcoplasmic reticulum of striated muscle is calsequestrin. Calreticulin may influence the action of both SERCAs and InsP3 receptors (Corbett and Michalak, 2000), thereby modulating Ca2+ uptake and release, respectively, and thus regulating Ca2+ signals. In particular, Camacho's group has shown that calreticulin, in the lumen of the endoplasmic reticulum, inhibits Ca2+ uptake by the SERCA2b pump, thus inhibiting the continued generation of Ca2+ waves (Camacho and Lechleiter, 1995). This may be due to a direct interaction between calreticulin and the lumenal COOH-terminal tail of the SERCA2b isoform. In support of this interaction, calreticulin has been shown to colocalize with SERCA2b (John et al., 1998). In addition, a recent report indicates that a mathematical model, developed from single cell Ca2+ dynamics, has predicted an interaction between calreticulin and the SERCA pump (Baker et al., 2002). This model suggests that calreticulin alters the pump's affinity for Ca2+, thus regulating Ca2+ oscillations. The effects of calreticulin expression on InsP3 receptor activity may also be direct. Cell subfractionation experiments have revealed that calreticulin copurifies with InsP3 binding sites (Enyedi et al., 1993), whereas double immunolabeling experiments have shown that calreticulin colocalizes with the InsP3 receptor in the acrosome, in the equatorial segment, and in cytosolic vesicles of human spermatozoa (Naaby-Hansen et al., 2001). In summary, although the strategic placement of Ca2+ pumps and channels is imperative in generating spatially complex Ca2+ signals (Johnson and Chang, 2000), it is the responsibility of Ca2+-binding proteins to provide a releasable pool of Ca2+ near the release channels, and to modulate the activity of the pumps and channels to regulate Ca2+ waves and oscillations.
The arrangement of Ca2+-handling proteins in the endoplasmic reticulum creates specialized Ca2+-handling subdomains. For example, in astrocytes and oligodendrocytes, Ca2+ wave amplification sites exist along the endoplasmic reticulum, which are enriched in calreticulin, SERCAs, and InsP3 receptors and thus exhibit elevated Ca2+ release kinetics (Simpson et al., 1997, 1998). This organization between the InsP3 receptor and calreticulin is similar to the specialization seen in the junctional sarcoplasmic reticulum in striated muscle between calsequestrin and the ryanodine receptor (Allen and Katz, 2000; Gatti et al., 2001). Calreticulin is excluded from these junctional areas, and is found in the longitudinal sarcoplasmic reticulum, from where calsequestrin is excluded (Allen and Katz, 2000). The mechanisms underlying the heterogeneous distribution of endoplasmic reticulum Ca2+-binding proteins have only recently been elucidated for calsequestrin. The term condensation is used to refer to the head-to-tail oligomerization of calsequestrin, which is responsible for creating dense cores of the protein that are heterogeneously located throughout the sarcoplasmic reticulum (Gatti et al., 2001). Other endoplasmic/sarcoplasmic reticulum resident proteins may utilize a similar mechanism to establish a nonuniform distribution.
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Multifunctionality of the endoplasmic reticulum |
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Interestingly, heterogeneity in compartmentalization may already be evident during development. In human oocytes, for example, the endoplasmic/sarcoplasmic reticulumassociated Ca2+-binding proteins are nonuniformly distributed (Balakier et al., 2002). Calreticulin is predominant in the cell cortex, whereas calsequestrin is found throughout the entire cytoplasm (Fig. 2). Such differential distribution of calreticulin and calsequestrin indicates that oocytes have two distinct Ca2+ storage compartments: one enriched in calreticulin (and the InsP3 receptor), and the other in calsequestrin (and the ryanodine receptor). Calsequestrin may localize to certain regions by the condensation mechanism, whereas calreticulin may utilize specific proteinprotein interactions to achieve its localization in the endoplasmic reticulum. Interestingly, calnexin, like calreticulin, is also predominant in the cell cortex where it is found in a peculiar trilaminar arrangement (Fig. 2). The differential distribution of these proteins may reflect their functional differences. Calnexin is a chaperone, calsequestrin is a Ca2+ storage protein, whereas calreticulin carries out both functions. Thus, certain regions of the endoplasmic reticulum may be involved in intensive protein processing required for oocyte maturation and embryo development, whereas other regions may be involved in Ca2+ homeostasis. In conclusion, the spatial heterogeneity of the endoplasmic reticulum may be established early on in development, and this warrants further investigation. Deciphering the organization of Ca2+-handling proteins in the endoplasmic reticulum may hold a clue to our understanding of the generation of the multifunctionality of this membrane system.
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Footnotes |
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Acknowledgments |
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Submitted: 24 July 2002
Revised: 14 January 2003
Accepted: 15 January 2003
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References |
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