1 Department of Anesthesiology, Mayo Clinic and Foundation, Rochester, Minnesota 55905; and 2 Department of Internal Medicine, University of Miami, Jackson Memorial Medical Center, Miami, Florida 33136
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ABSTRACT |
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Nicotinic acid adenine dinucleotide phosphate (NAADP) is one of the most potent stimulators of intracellular Ca2+ release known to date. The role of the NAADP system in physiological processes is being extensively investigated at the present time. Exciting new discoveries in the last 5 years suggest that the NAADP-regulated system may have a significant role in intracellular Ca2+ signaling. The NAADP receptor and its associated Ca2+ pool have been hypothesized to be important in several physiological processes including fertilization, T cell activation, and pancreatic secretion. However, whether NAADP is a new second messenger or a tool for the discovery of a new Ca2+ channel is still an unanswered question.
calcium; endoplasmic reticulum; fertilization; sea urchin eggs; cyclic adenosine 5'-diphosphate-ribose
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INTRODUCTION |
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THE DISCOVERY of intracellular second messengers represented a major step in understanding how extracellular signals are capable of regulating cellular behavior. In this regard, the release of intracellular calcium ions (Ca2+) plays a fundamental role in cell signaling. Release of Ca2+ from intracellular stores, such as the endoplasmic and sarcoplasmic reticulum, is a key component in several intracellular signaling pathways. Ca2+ fluxes display complex spatial and temporal signatures, enabling more information to be encoded by Ca2+ signals. To meet the demands of this complexity, cells rely on precise regulation of Ca2+ channel activity (7). Understanding of the regulation of intracellular Ca2+ release and its relationship to extracellular stimuli was greatly enhanced by the discovery of the inositol 1,4,5-trisphosphate (IP3) signaling pathway (7). In addition to IP3-induced Ca2+ release, cells contain other mechanisms for intracellular Ca2+ release (7, 23, 25, 27, 33, 35).
One of these Ca2+-releasing pathways is regulated by the newly discovered nucleotide cyclic ADP-ribose (cADPR). cADPR was discovered in 1987 by H. C. Lee and collaborators (23), who observed that incubation of sea urchin egg homogenates with nicotinamide adenine dinucleotide (NAD+) resulted in Ca2+ release from microsomal stores (23, 33). Subsequent studies revealed that the Ca2+ release activity of NAD+ was actually due to conversion of NAD+ to an active metabolite, later identified as a cyclic compound derived from the ADP-ribose moiety of NAD+ and named cADPR (39). In 1991, it was concluded that cADPR mobilizes Ca2+ by activation or sensitization of the so-called ryanodine receptor/channel (RyR) (26).
The Ca2+-releasing properties of cADPR suggested a signaling role for this molecule. Since the discovery of cADPR, much interest has been raised about the possible role of other nucleotides as second messengers involved in control of intracellular Ca2+. In fact, it was discovered that another nucleotide, nicotinic acid adenine dinucleotide phosphate (NAADP), is a potent activator of intracellular Ca2+ release (13, 36). This nucleotide activates an intracellular Ca2+ release mechanism that differs in many ways from that modulated by both IP3 and cADPR (1, 7-13, 16-18, 20-23, 25-31, 33-38). In contrast to IP3 and cADPR, the research on NAADP is only in its infancy, and further experimentation is needed to determine the precise role of this Ca2+-releasing pathway in cell signaling. In this review we discuss several aspects of NAADP research and the potential role of NAADP in cellular signal transduction. NAADP has been the subject of recent descriptive reviews by other authors (27, 37, 39, 44). While briefly describing the major findings in the field, this review is devoted to a critical appraisal of several key issues that need to be resolved to determine whether NAADP is a new second messenger or a tool for the discovery of a new class of Ca2+ channels. In any case, studies of the NAADP Ca2+ release system will provide exciting new information about the complex mechanism of intracellular Ca2+ mobilization.
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STRUCTURE AND DISCOVERY OF NAADP |
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In 1987 it was discovered that incubation of NADP in alkaline pH
generated a Ca2+-releasing metabolite (23).
However, it was not until 1995 that it was described for the first time
that a nicotinic acid derivative of NADP was a potent mobilizer of
intracellular Ca2+ in sea urchin egg homogenates, an
experimental system in which IP3-induced Ca2+
release and Ca2+-induced Ca2+ release (CICR)
can be measured easily in real time (13, 36). Our
laboratory analyzed the products of alkali-treated -NADP, and, using
several physicochemical methods, we (13) found that the
Ca2+ releasing activity was mediated by a nucleotide with a
molecular mass only 1 Da larger than
-NADP (Fig.
1). We concluded that the substance with
Ca2+-releasing properties was a NADP-related compound that
has a nicotinic acid instead of a nicotinamide in the molecule. We
(13) then described this molecule as NAADP. In fact, the
only difference between NAADP and NADP is the change of an
NH2 of the amide in NADP to OH of the carboxyl group in
NAADP. This substitution accounts for a difference of 1 Da between the
compounds (Fig. 1).
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The structural requirements of NAADP-induced Ca2+ release system appear to be very stringent, because several structural analogs of NAADP have no effect on intracellular Ca2+ release (13, 35). Of particular interest, the phosphate in position 2' is crucial for the biological activity of NAADP, because NAAD has no Ca2+-mobilizing property (13, 35). However, changing the position of the third phosphate from 2' to 3' has no effect on the Ca2+-releasing properties of the molecule (13, 35). In fact, whether the third phosphate is in position 2' or 3' or whether it is cyclic on positions 2' and 3' does not change the Ca2+-mobilizing properties of this nucleotide (13, 35). Recently, a fluorescent analog of NAADP, 1,N6-etheno-NAADP, with Ca2+-mobilizing properties was synthesized (37). This compound may be a useful tool for the identification of the NAADP receptor.
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UNIQUE MECHANISM OF INTRACELLULAR CA2+ RELEASE |
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The mechanism of Ca2+ release elicited by NAADP was
initially characterized in sea urchin eggs (13, 26-31, 36,
46). In initial studies, the most striking feature of NAADP was
its ability to induce Ca2+ release even after
IP3 and ryanodine channels had previously been desensitized
(13, 36). This behavior suggested that another Ca2+ release mechanism, possibly a new Ca2+
channel, was involved in NAADP-mediated Ca2+ release. Other
lines of evidence supported this notion, including findings that
1) antagonists of ryanodine and IP3
channels were ineffective in blocking NAADP-mediated Ca2+
release (13); 2) known modulators of ryanodine
and IP3 channels, such as Ca2+,
Mg2+, caffeine, ryanodine, ruthenium red, and procaine as
well as pH, did not influence NAADP-mediated Ca2+ release
(Table 1; Refs. 11-13,
16-18, 25, 27-31,
33, 35, 36); and 3)
L-type Ca2+ channel antagonists could inhibit NAADP-induced
Ca2+ release but not IP3-induced
Ca2+ release or CICR (28-31). Together,
these findings revealed a distinct pharmacological behavior
of the NAADP Ca2+ release system of sea urchin eggs,
further strengthening the hypothesis that NAADP is an activator of a
novel Ca2+ release system.
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A remarkable distinct property of the NAADP Ca2+ release system is the self-inactivation mechanism elicited by "low" doses of NAADP: sea urchin egg homogenates preexposed to a subthreshold concentration of NAADP that does not elicit Ca2+ release per se become unresponsive to further challenges of maximal doses of NAADP (1, 28, 33). This self-inactivation mechanism is time and dose dependent, suggesting that a specific NAADP binding site is required. This behavior is also suggestive of irreversible binding of NAADP to the receptor, possibly locking the Ca2+ channel in a closed state, but this remains to be demonstrated. The inactivation mechanism might permit the NAADP Ca2+ release system to be activated in cells only once, or not at all if a low concentration of NAADP inactivates the receptor first. These characteristics suggest that the mechanism of Ca2+ release induced by NAADP may be highly tuned to detect sudden increases in NAADP concentration. Moreover, if the self-inactivation mechanism of the NAADP Ca2+ release system indeed occurs in vivo, it raises the intriguing question of whether it could represent a simple form of cell memory (22), such as that required in one-time events like egg fertilization or lymphocyte activation. All these characteristics make NAADP a rather unique trigger of intracellular Ca2+ release.
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CELLS RESPONSIVE TO NAADP |
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Invertebrate cells. Ca2+ release induced by NAADP was first described in sea urchin egg homogenates and in intact sea urchin eggs (13, 36, 46). These preparations provide an easy system to measure Ca2+ release from microsomal stores with fluorescent Ca2+-sensitive molecular probes. In addition, both IP3-responsive channels and RyR are present in the same preparation. In this experimental system, NAADP induced a robust Ca2+ release from both thapsigargin (tg)-sensitive and -insensitive stores (29). As discussed previously, NAADP-induced Ca2+ release remarkably differs in many ways from the Ca2+ release elicited by IP3 and cADPR (13, 36): 1) Ca2+ release induced by NAADP is not cross-desensitized by cADPR or IP3; 2) NAADP-induced Ca2+ release is not inhibited by antagonists of RyR and IP3 channels; and 3) NAADP-induced Ca2+ release is inhibited by L-type Ca2+ channel blockers whereas the cADPR and IP3 channels are not.
The precise role of NAADP-mediated Ca2+ release in sea urchin egg fertilization is not known. However, preliminary evidence indicates that NAADP-sensitive Ca2+ stores are activated during fertilization (46). In fact, we (46) showed that fertilization of the sea urchin egg leads to a complete inactivation of the NAADP-induced Ca2+ release. These data indicate that the Ca2+ pool regulated by NAADP may have an important role during sea urchin egg fertilization. NAADP-induced Ca2+ release has also been demonstrated in intact starfish and ascidian oocytes (47).Plant cells. Recently, NAADP-induced Ca2+ release was described in cauliflower and red beet microsomes (42). However, the physiological role of this compound in plants remains unknown.
Mammalian cells.
Until recently, research on NAADP-induced Ca2+
release was largely limited to invertebrate cells, in part because of
the advantages of measuring Ca2+ fluxes in sea urchin
preparations. More recently, NAADP-induced Ca2+ release has
been shown to be widespread in mammalian cells and tissues (Table
2), including rat brain, T lymphocytes,
vascular smooth muscle cells, cardiac myocytes, fibroblasts, and HL-60 cells (3-5, 20, 50).
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NAADP RECEPTOR |
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The molecular identity of the NAADP receptor is still obscure. Nevertheless, specific binding of radioactive NAADP has been described in sea urchin eggs (8, 43) and in rat brain with autoradiographic techniques (45). A single and saturable binding site was more thoroughly characterized in sea urchin eggs (8, 43). In microsomes, the dissociation constant (Kd) was 280 pM, consistent with a high-affinity binding receptor (8). NADP and NAADPH appear to compete for binding (8, 43), but it is unclear whether this is due to NAADP present as a contaminant in NADP and NAADPH solutions used in these studies. Ca2+ and pH did not affect NAADP binding, which probably explains why Ca2+ and pH do not influence NAADP-induced Ca2+ release in sea urchin eggs. More importantly, NAADP binding seemed to be irreversible (8, 44), suggesting an explanation for the molecular basis of the inactivation phenomenon observed with subthreshold concentrations of NAADP.
Furthermore, NAADP binding has also been described in brain microsomes (45), and with autoradiographic techniques those authors described that NAADP binding sites are diffusely distributed in rat brain tissues.
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SYNTHESIS AND DEGRADATION OF NAADP |
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We (15, 19, 20, 41, 50) previously described
synthesis of NAADP in several tissues including brain, liver, spleen, heart, and kidney glomeruli. Synthesis of NAADP can be
catalyzed in vitro by a NAD(P)ase, analog to the lymphocyte antigen
CD38 (2, 19), in a reaction called the base-exchange
reaction (Fig. 2; Ref. 6).
The enzyme catalyzes the exchange of nicotinamide for nicotinic acid on
the molecule of NADP+, generating NAADP (Fig. 2; Refs.
6, 13, 16, 19).
Whether NAADP can be generated via the base-exchange reaction in vivo is still an open question. Under the present experimental conditions used for synthesis of NAADP, the concentrations of substrate needed, namely nicotinic acid, are several times higher than would be expected
to be present in intact cells (6, 13, 19). Furthermore, the optimal pH for this reaction is out of the physiological range (2, 20). However, compartmentalization of nicotinic acid and NADP into an acid environment could theoretically provide a
possible milieu for the synthesis of NAADP in vivo. Another theoretical
problem is the fact that in mammalian cells, the base-exchange reaction
seems to be catalyzed by CD38, which is an ectoenzyme. This therefore
raises the question of how substrates would be available to the CD38
catalytic site and, once NAADP is generated, how it would be made
available in the cytosol to induce Ca2+ release.
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For these reasons, it is important to consider other theoretical pathways for the synthesis of NAADP in vivo (Fig. 2). Conceivably, NAADP might be generated by deamination of NADP+ (Fig. 2) or phosphorylation of NAAD+. The latter is a particularly attractive hypothetical route because NAAD+ is a compound present in cells and NAADP might be then catalyzed by NAD+ kinase with ATP as a 2'-phosphate donor (Fig. 2). These alternative synthetic pathways ought to be explored in future studies. Notably, Lerner et al. (40) characterized a human NAD+ kinase in vitro and found no evidence that it could synthesize NAADP by phosphorylation of NAAD+. Nevertheless, these data do not completely exclude the possibility that NAAD+ phosphorylation might perhaps occur in vivo, if intracellular cofactors or other putative physiological conditions are required to modify the enzyme and enable the reaction. They also do not exclude the possibility that other isoforms might catalyze the reaction. Therefore, the postulated NAAD+ phosphorylation pathway seems unlikely at this point but cannot be completely discarded yet.
Despite the limitations discussed, the base-exchange reaction is the only pathway currently described for the synthesis of NAADP in biological systems (2, 4, 6, 13, 19, 20, 42, 50). In this regard, an important observation is that enzymes with ADP-ribosyl cyclase activity (capacity for synthesis of cyclic ADP-ribose) are also able to catalyze the synthesis of NAADP through the base-exchange reaction (2, 14, 19, 24). In fact, the mammalian version of the ADP-ribosyl cyclase (CD38) is capable of generating both NAADP and cADPR (2, 14). This observation led to the proposal of a cross talk between these two possible signaling pathways (34). However, as discussed above, whether the base-exchange reaction occurs under physiological conditions is still an open question. Using CD38 knockout mice, we (13a) determined that CD38 is the major enzyme responsible for the base-exchange reaction in mouse tissues. However, in one study (50) the capacity for synthesis of NAADP by the base-exchange reaction in cells did not correlate with the presence of NAADP-induced Ca2+ release in the same cells. As result, this discrepancy raises doubts about the role of the base-exchange reaction as the physiological route for the synthesis of NAADP.
Far less is known about the pathways of NAADP degradation. NAADP hydrolysis has been described in several mammalian tissues including kidney, heart, spleen, liver, and brain (15). This activity appears to be mediated by the tissue alkaline phosphatase, and, in fact, isolated alkaline phosphatase is capable of NAADP hydrolysis (13).
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REGULATION OF NAADP SYNTHESIS |
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To be considered a second messenger, the intracellular concentration of NAADP would be expected to change in response to physiological stimuli. In fact, because low concentrations of NAADP inactivate the NAADP receptor, one would expect that NAADP levels have to rise rapidly in the cytosol to activate Ca2+ release. Such a rapid rise in NAADP synthesis would demand a fast activation of enzymes involved in NAADP synthesis. Very little is known, however, about how enzymes involved in NAADP metabolism are regulated. One study in sea urchin eggs demonstrated that both cAMP and cGMP could enhance synthesis of NAADP by a membrane-bound enzyme (49). However, cGMP did not affect NAADP synthesis in another study (32). These important points need to be addressed in future studies.
Regulation of NAADP synthesis might theoretically also be upregulated by hormones or agents that increase expression of enzymes capable of catalyzing the base-exchange reaction, such as ADP-ribosyl cyclases and CD38 (14, 24, 48). For example, we (20, 24) demonstrated that retinoic acid enhances the activity of ADP-ribosyl cyclase in rat smooth muscle and mesangial cells. Likewise, when cultured rat mesangial cells were incubated with 9-cis-retinoic acid, increased synthesis of NAADP was observed (20). The exact role of this and other examples of convergence of the cADPR and NAADP synthetic pathways still remains largely unexplored.
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ROLE OF NAADP IN INTRACELLULAR CA2+ HOMEOSTASIS |
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The unique Ca2+-releasing properties of NAADP make it an exciting candidate for an intracellular messenger. The data obtained in sea urchin egg homogenates, in which the normal architecture of intracellular Ca2+ stores is lost, indicate that NAADP-induced Ca2+ release is completely distinct and independent of the other intracellular Ca2+-releasing systems regulated by cADPR and IP3 (13, 36). As discussed above, in sea urchin egg homogenates the NAADP-regulated Ca2+ system is not inhibited by inhibitors of the cADPR and IP3 systems. However, in intact cells the NAADP system appears to interact actively with other intracellular Ca2+ systems (9, 10, 21, 47). In fact, it has been proposed, for example, that in pancreatic acinar cells NAADP would be the trigger of Ca2+ oscillations induced by cholecystokinin (CCK) (9, 10) and that Ca2+ released by NAADP, in response to CCK, would activate the CICR mediated by cADPR and IP3. These interactions between Ca2+ systems will lead to amplification of the Ca2+ signaling and generation of the Ca2+ oscillation (9, 10). In fact, self-inactivation of the NAADP receptor in intact pancreatic acinar cells attenuates the Ca2+ signal in response to CCK (9, 10).
A similar role for NAADP has been proposed for the mobilization of Ca2+ in intact starfish oocyte and sea urchin eggs (21, 47). In these cells, microinjection or release of caged NAADP leads to a robust Ca2+ release followed by oscillations (21, 47). It appears that in these intact invertebrate cells NAADP-induced Ca2+ release can further promote Ca2+ mobilization by activation or sensitization of the ryanodine and IP3 receptors (21, 47). In fact, in both intact sea urchin eggs and starfish oocytes the NAADP-induced Ca2+ oscillations can be inhibited by dual block of the cADPR and IP3 systems with 8-amino-cADPR (a cADPR antagonist) and heparin (an IP3 inhibitor). In contrast, NAADP-induced Ca2+ oscillations in these intact cells are insensitive to either heparin or 8-amino-cADPR alone (21, 47).
In fact, the Ca2+ released from the NAADP pool can modulate
the intracellular Ca2+ release by at least two different
mechanisms: 1) a mode of priming the intracellular
Ca2+ pools as described by Churchill and Galione
(21); and 2) direct sensitization of the CICR
(Fig. 3). In the first case, it was demonstrated that the Ca2+ released from the NAADP pool
will increase the amount of Ca2+ in tg-dependent stores
(21). These stores correspond to the cADPR- and
IP3-regulated pools (21). In this model, NAADP
promotes Ca2+ oscillation by releasing Ca2+
from its tg-independent store and then the Ca2+ released is
taken by CICR stores. The Ca2+ priming of the CICR stores
leads to a cycle of Ca2+ overload, release, and reuptake
that corresponds to the Ca2+ oscillations
(21).
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In the second case, the Ca2+ released by NAADP could affect the apparent affinity of the RyR (9, 10). In this case, Ca2+ released by NAADP sensitizes the RyR to its agonists by a mechanism similar to the so-called CICR (Fig. 3B).
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NAADP CA2+ POOL |
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The NAADP-regulated Ca 2+ store in sea urchin eggs is physically distinct from the cADPR and IP3 pools. In fact, two different mechanisms of intracellular Ca2+ uptake are observed in sea urchin egg homogenates. Sea urchin egg homogenates have both tg-sensitive and -insensitive Ca2+ uptake systems. These data indicate that egg homogenates have both a sarco(endo) plasmic reticulum Ca2+-ATPase (SERCA)-like pool and also a second different mechanism of Ca2+ uptake that is not mediated by a SERCA-like enzyme. Genazzani and Galione (29) demonstrated that cADPR and IP3 promoted Ca2+ release only through the tg-sensitive pools. In contrast, NAADP is able to induce Ca2+ release from both tg-sensitive and -insensitive pools, indicating that, in sea urchin egg homogenates, the NAADP and cADPR Ca2+ pools are at least to some extent independent (29). More recently, it was demonstrated that the NAADP and cADPR pools can be segregated to opposite poles of intact sea urchin eggs by centrifugation (38). In addition, it was demonstrated that the NAADP-regulated Ca2+ pool in sea urchin eggs is distinct from the endoplasmic reticulum and mitochondria. This new, yet unidentified, Ca2+ pool provides exciting possibilities in NAADP research, and its identification may lead to the discovery of a new type of intracellular organelle involved in Ca2+ homeostasis.
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CONCLUSION![]() |
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Over the last decade, intensive research on mechanisms of intracellular calcium regulation has led to the discovery of potential new second messengers and a novel Ca2+ release system. The role of the NAADP system in physiological processes is being extensively investigated at the present time, and the title of this review may imply that we can provide an answer for this question. However, although NAADP displays many characteristics of a signal transduction molecule, in our opinion, we are far from answering whether NAADP is indeed an intracellular messenger.
Several requirements must be fulfilled before NAADP can be considered an intracellular messenger. 1) NAADP levels must be determined in cells. 2) The physiological pathways for the synthesis of NAADP must be defined. 3) The concentration of intracellular NAADP must be regulated by external or internal stimuli. 4) A correlation between stimulated intracellular NAADP levels and Ca2+ release must be established.
To date, none of these requirements has been completely fulfilled, and it would be premature to promote NAADP to the status of second messenger at this point. In fact, it is possible that NAADP may not be an intracellular messenger, and, in analogy to ryanodine, NAADP may be a pharmacological, rather than physiological, agonist of a new intracellular Ca2+ channel. However, even if NAADP turns out not to be a physiological agonist, it will lead to the discovery of a new class of intracellular Ca2+ channels with unique properties relevant to cell physiology. As discussed in this review, several pieces of the NAADP puzzle await clarification through more research investigation. Certainly, the future holds new and exciting discoveries in this field.
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ACKNOWLEDGEMENTS |
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We acknowledge the excellent secretarial assistance provided by Lea Dacy.
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FOOTNOTES |
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Mayo Foundation and the American Heart Association supported this research.
Address for reprint requests and other correspondence: E. N. Chini, Dept. of Anesthesiology, Mayo Clinic and Foundation, 200 First St., Rochester, MN 55905 (E-mail: chini.eduardo{at}mayo.edu).
10.1152/ajpcell.00475.2001
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