MRC Secretory Control Research Group, The Physiological Laboratory, University of Liverpool, Crown Street, Liverpool L69 3BX, UK
* Author for correspondence (e-mail: o.v.gerasimenko{at}liverpool.ac.uk)
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Summary |
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Key words: cADPR, NAADP, Ins(1,4,5)P3, Ryanodine receptor, NPC
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Introduction |
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The first concerns the permeability of the nuclear pore complexes (NPCs), which span the inner and outer membranes of the NE (Bootman et al., 2000). The diameter of the nuclear pore should allow free diffusion of small ions including Ca2+ (Perez-Terzic et al., 1997
; Lee et al., 1998
). However, there are many reports about the existence of nuclear-cytosolic Ca2+ gradients. Most are based on confocal microscopy. Although discussion continues about this topic, an overwhelming body of evidence supports the view that the NPCs are highly Ca2+ permeable (Lipp and Niggli, 1994
), and most likely the reported cytoplasmic-nuclear Ca2+ gradients are due to differences in the behaviour of the fluorescent dyes in different subcellular compartments (Al-Mohanna et al., 1994
; O'Malley et al., 1999
).
The second controversial area concerns the nature of the nuclear Ca2+ release. So far, there is no consensus on the location of the Ins(1,4,5)P3 receptors [(Ins(1,4,5)P3Rs] and ryanodine receptor (RyR) Ca2+ channels that release Ca2+ in the nucleus. The nuclear Ca2+ store can release Ca2+ into the nucleoplasm as well as outside (Gerasimenko et al., 1995). Indirect functional evidence indicates that Ins(1,4,5)P3Rs and RyRs reside on the inner surface of the NE (Gerasimenko et al., 1995
; Gerasimenko et al., 1996a
; Petersen et al., 1998
). This hypothesis is supported by several studies (Humbert et al., 1996
; Santella and Carafoli, 1997
; Adebanjo et al., 1999
; Adebanjo et al., 2000
), but the role of intranuclear receptors in normal intracellular responses has been disputed (Lipp et al., 1997
; Bootman et al., 2000
).
The third area of dispute is the role of NAADP. Genazzani et al. (Genazzani and Galione, 1996) have suggested that NAADP releases Ca2+ from stores either in lysosome-like organelles or in related granules that are separate from the ER. This would appear to exclude the possibility of NAADP-induced Ca2+ signalling in the nucleus. Nevertheless, recent data (Gerasimenko et al., 2003
) indicate that NAADP can indeed release Ca2+ from the NE and thereby generate nucleoplasmic Ca2+ signals.
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Nuclear-cytoplasmic Ca2+ gradients? |
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An example of a transient nuclear-cytoplasmic gradient is shown in Fig. 1. Localized Ca2+ spikes in the secretory region of acinar cells do not propagate into the nucleus or the basal area of the cell (Gerasimenko et al., 1996b). There is a reason for the transiently different Ca2+ concentrations in the nucleus and the cytosol. Perigranular and perinuclear mitochondria are able to restrict local Ca2+ spikes elicited by small doses of agonists to the secretory granule area (Johnson et al., 2003
; Tinel et al., 1999
). Therefore, the transient difference in Ca2+ concentration is quite understandable, since nuclei in many cell types are normally surrounded by mitochondria sequestering Ca2+ during physiological responses (Duchen, 1999
; Robb-Gaspers et al., 1998
). Strong stimulation can induce large Ca2+ waves that can overcome this mitochondrial barrier (Fig. 1C) and therefore quickly penetrate the nucleus. In this case, the difference between the Ca2+ concentration in the cytosol and the nucleus is marginal (Al-Mohanna et al., 1994
; Lipp and Niggli, 1994
).
|
Accurate measurements of the nuclear Ca2+ concentration are extremely difficult and require separate calibration of the nuclear dye owing to many possible artefacts, such as increased brightness of most of the fluorescent indicators in the nucleoplasm (Al-Mohanna et al., 1994; Bootman et al., 2000
; Perez-Terzic et al., 1997
). In addition to exhibiting differences in dissociation constant and dynamic range, the indicators can also be bound inside the nucleoplasm and sequestered in Ca2+ stores (Al-Mohanna et al., 1994
; Burnier et al., 1994
; Ikeda et al., 1996
; Ronde and Nichols, 1997
). These problems effectively invalidate the majority of the observations of nuclear-cytoplasmic Ca2+ gradients. There is thus probably no persistent nuclear-cytoplasmic gradient (Badminton et al., 1996
; Badminton et al., 1998
; Brown et al., 1997
; Bootman et al., 2000
; Bootman et al., 2002
; Tovey et al., 1998). Indeed, this is convincingly shown by luminescence measurements of targeted aequorin (Brini et al., 1993
).
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The Ca2+ permeability of NPCs |
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The NPC is a supramolecular assembly that has a molecular weight of 125,000 kDa (Greber and Gerace, 1995
) and a large aqueous channel with a diameter of
9 nm. Normally, molecules <40 kDa pass through such a channel without the need for a nuclear localization signal. Some studies suggest that free diffusion of such molecules could be inhibited by the depletion of the nuclear Ca2+ store (Greber and Gerace, 1995
; Lee et al., 1998
; Lyman and Gerace, 2001
; Perez-Terzic et al., 1999
). The mechanism might involve binding of intra-ER Ca2+ to the NPC protein gp210 (Greber and Gerace, 1995
). However, we and others have not observed this (Strubing and Clapham, 1999
; Stehno-Bittel et al., 1995
; Perez-Terzic et al., 1996
; Wei et al., 2003
; Gerasimenko et al., 2003
). Very convincing data in favour of free diffusion through NPCs have been obtained recently using fluorescence recovery after photobleaching (FRAP) of 27 kDa enhanced green fluorescence protein (EGFP) in intact cells (Wei et al., 2003
). These recent studies employed a transfection technique that does not affect nuclear transport; by contrast, microinjection, which was used previously, can disrupt the cytoskeleton (Swaminathan et al., 1997
).
Our own results indicate that, after depletion of the NE Ca2+ stores with Ins(1,4,5)P3 or NAADP, subsequent external application of a high Ca2+ concentration followed by the Ca2+ chelator EGTA induces a large rise and thereafter a fast decrease in the nucleoplasmic Ca2+ concentration (Gerasimenko et al., 2003). These measurements demonstrate rapid movement of Ca2+ across the NE, most likely through the NPCs. On the basis of all these data, we favour the argument that the NPCs are permeable to Ca2+ even after depletion of the NE Ca2+ stores.
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Ins(1,4,5)P3Rs in the nuclear membranes |
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Interesting data in favour of such a system (Clubb et al., 1998; Fricker et al., 1997) show that the NE has invaginations into the nucleoplasm in many cell types and could explain Ca2+ release sites inside the nucleoplasm. Recent data by Echevarria et al. confirm these suggestions and show that local Ca2+ release from the nucleoplasmic reticulum occurs through Ins(1,4,5)P3Rs and induces translocation of protein kinase C (PKC) to the NE membrane (Echevarria et al., 2003
). These new data argue for an independent intranuclear Ca2+ signalling system.
Unfortunately, because accurate measurement of the Ca2+ concentration in the nucleoplasm of intact cells is difficult (as discussed above), there are no reliable Ca2+ measurements that unequivocally show independent activation of an intranuclear Ca2+ signalling system with a physiological agonist.
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RyRs in nuclear membranes |
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NAADP-induced Ca2+ release |
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We found recently that NAADP can release Ca2+ into the nucleoplasm in isolated pancreatic nuclei, a preparation that only contains an ER-type Ca2+ store and does not contain lysosomes or other acidic organelles (Gerasimenko et al., 2003). The NAADP-sensitive nuclear store is ATP dependent and thapsigargin sensitive, and is distinct from any acidic, endocytic or Golgi-type Ca2+ store (Gerasimenko et al., 1996c
; Gerasimenko et al., 1998
; Pinton et al., 1998
). Remarkably, the Ca2+ release normally induced by NAADP [but not by Ins(1,4,5)P3] is completely blocked by inhibitors of RyRs (e.g. high ryanodine concentration or Ruthenium Red). These findings indicate that, in pancreatic nuclei, NAADP releases Ca2+ from the same thapsigargin-sensitive store as Ins(1,4,5)P3 and cADPR. These findings also cast doubt on the idea that NAADP releases Ca2+ only from a distinct pool.
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Conclusions |
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In the intact pancreatic acinar cells, the Ca2+ store in the NE is part of one lumenally continuous ER store (Petersen et al., 2001); however, it is highly specialized in different parts of the cell (Gerasimenko et al., 2002
). The data on isolated nuclei (Gerasimenko et al., 2003
), as compared with the studies on local Ca2+ spiking in the secretory pole in intact cells (Cancela et al., 2000
; Cancela et al., 2002
; Osipchuk et al., 1990
; Park et al., 2001
; Petersen et al., 1991
; Petersen et al., 1994
), reveal that local control of Ca2+ release can operate differently in different parts of the cell. All three messengers can induce Ca2+ release at both sites. The local Ca2+ spiking in the secretory region of pancreatic acinar cells [as well as the global Ca2+-induced Ca2+ waves (Ashby and Tepikin, 2002
; Ashby et al., 2003
; Thorn et al., 1993
; Thorn et al., 1994
)] are highly dependent on cooperative interaction of Ins(1,4,5)P3Rs and RyRs (Ashby et al., 2002
; Boittin et al., 1998
; Cancela et al., 2000
; Kidd et al., 1999
; Koizumi et al., 1999
; Lipp et al., 2000
). By contrast, there is little cooperativity of Ins(1,4,5)P3Rs and RyRs in the nucleus; in fact, the receptors can function independently, inducing similar release of Ca2+ into the nucleoplasm (Gerasimenko et al., 2003
).
The difference between the NAADP effects in the nucleus and the secretory granule area are even more striking: whereas there is a mutually potentiating interaction of Ins(1,4,5)P3, cADPR and NAADP in the secretory granule area (Cancela et al., 2002), there is no such potentiation in the nucleus (Gerasimenko et al., 2003
). These differences could be explained in two different ways. Three separate channels (receptors) could interact. Such a model would depend on the presence of so-far-uncharacterized NAADPR Ca2+ channels. A much simpler hypothesis (Fig. 4) is that there are only two types of Ca2+ release channels Ins(1,4,5)P3Rs and RyRs in a single store. Ca2+ can enter the nucleoplasm through Ins(1,4,5)P3Rs or RyRs in the inner nuclear membrane, although we cannot exclude Ca2+ release from the Ins(1,4,5)P3Rs or RyRs in the outer nuclear membrane and subsequent entry through NPCs. All three Ca2+-releasing messengers, Ins(1,4,5)P3, cADPR and NAADP, can be produced inside the NE, although they can also enter the nucleoplasm through the NPCs. Ca2+ is pumped into the NE by SERCA on the outer nuclear membrane. Potentiating or non-potentiating interactions of Ins(1,4,5)P3Rs and RyRs (see discussion above) in this simpler model would depend on the degree of closeness of the two types of Ca2+ release channel and of the cADPR and NAADP receptors. This exciting area of research will definitely attract more attention in the future.
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Acknowledgments |
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References |
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