Articles |
the Department of Medicine (Y.I.), Brigham & Women's Hospital, Harvard Medical School, Boston, Mass, and COR Therapeutics Inc (C.J.H.), San Francisco, Calif.
Correspondence to Yoshihiro Ishikawa, MD, PhD, Brigham & Women's Hospital, 221 Longwood Ave, Boston, MA 02115, or Charles J. Homcy, MD, COR Therapeutics Inc, 256 E Grand Ave, South San Francisco, CA 94080.
Key Words: adenylyl cyclase heart regulation transmembrane signaling
| cAMP Generation in the Heart |
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subunit from Gß
. GTP-bound Gs
then binds to and stimulates adenylyl cyclase. Adenylyl cyclase is a membrane-bound enzyme that catalyzes the conversion of ATP to cAMP.1 cAMP, an intracellular second messenger, activates protein kinase A by dissociating its regulatory subunit from the catalytic subunit.2 The free catalytic subunit thereupon initiates a series of enzymatic reactions leading to a phosphorylation cascade, activating multiple proteins that regulate both the rate and force of cardiac contraction. Phosphorylation of the L-type calcium channel, for example, enhances calcium entry into cardiocytes, leading to increased contractility.3 On phosphorylation of phospholamban, the inhibition exerted by the nonphosphorylated form of phospholamban on the sarcoplasmic reticulum calcium pump is removed, and its rate of calcium uptake is increased, thereby leading to a more rapid decrease of the cytosolic calcium concentration during diastole.4 Dissociation of the troponin Ccalcium complex is also enhanced when troponin I is phosphorylated, which leads to an accelerated relaxation rate. These latter events underlie the lusitropic effects of ßAR stimulation.5 Thus, a series of reactions occurs within cardiocytes that is initiated at the level of the cell surface ßAR. The integrated effect is an enhancement in cardiac output. This process rapidly reverses when agonist occupancy of the receptor ceases, ie, at the removal of norepinephrine from the synaptic cleft. cAMP is eventually degraded to 5' AMP by phosphodiesterase.6 Protein kinase A is then inactivated by reassociation of the catalytic subunit with the regulatory subunit.2 Phosphorylated proteins are rapidly dephosphorylated by specific phosphatases, returning their conformation to a less active form. These changes are rapid, occurring in the millisecond-to-second time frame.
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In various pathophysiological conditions, such as heart failure, major changes develop within the catecholamine signaling pathway.7 Using various animal models and cardiac tissues obtained from failing human hearts, investigators have demonstrated that "malfunction" of multiple components within the cAMP signaling pathway occurs. Changes in the content and function of the receptor, G proteins, and adenylyl cyclase may thus constitute fundamental defects underlying certain cardiac diseases. Thus, it is important to understand the properties of each component of the ßARGsadenylyl cyclase signaling pathway. We will focus this review article on adenylyl cyclase in particular, which has been characterized for many years biochemically but cloned only recently.
| The Structure of Adenylyl Cyclase |
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, the latter all derived from a single gene product. Except for the ß3AR, whose expression is generally restricted to adipose tissue, these components are all expressed rather ubiquitously, and their coupling to adenylyl cyclase shows no major differences.
Among the three major components of the ßARGsadenylyl cyclase signaling pathway, the last was cloned most recently. It is interesting to note, however, that a cAMP-synthesizing activity was identified within the membrane fraction of cells more than three decades ago. In the 1970s, adenylyl cyclase was successfully solubilized with nonionic detergents and partially purified, and its molecular mass (>100 kD) was calculated on the basis of its hydrodynamic properties.9 Biochemical characterization of the enzyme obtained from various tissues demonstrated that there were two distinct subtypes: calmodulin-sensitive and -insensitive isoforms.10 However, the cloning of the first adenylyl cyclase cDNA, followed by the identification of multiple other isoforms, was not achieved until the 1990s. This delay was due to the fact that adenylyl cyclase is a rare component of the cell membrane, constituting only
0.001% of the total membrane protein. Furthermore, its enzymatic activity is fragile; incubation at 37°C for 0.5 hour readily inactivates the enzyme when it is uncoupled from Gs
.11
The first adenylyl cyclase isoform was cloned from the brain.12 The amino acid sequence deduced from the cDNA clone showed several interesting characteristics. It was known that adenylyl cyclase was a membrane-bound enzyme. However, the predicted structure from the brain isoform was unexpected: hydropathy analysis predicted a molecule consisting of a module of six transmembrane spans linked to a large cytoplasmic domain that was tandemly repeated (Fig 2
). The amino acid sequence within the transmembrane domains (M1 and M2) did not show sequence homology to any other proteins. However, the sequences within the two cytoplasmic domains (C1a and C2a) showed significant homology to each other and to the sequences within both bacterial and yeast adenylyl cyclases and even within guanylyl cyclase. Because of highly conserved amino acid sequence homology, the two domains (C1a and C2a) are considered to be catalytic domains. These findings also suggest that both eukaryotic and prokaryotic adenylyl cyclases, as well as guanylyl cyclase, share the same ancestral origin.
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The complex structure of adenylyl cyclase is not typical for a membrane-bound enzyme; it is rather similar to that of transporters or ion channels.13 In particular, membrane transporters, such as P-glycoprotein, share the same membrane topology, ie, two modules of six transmembrane-spanning regions followed by a large cytoplasmic domain. The adenylyl cyclases may seem to be related to this larger family of membrane transporters, which are also referred to as the ABC (ATP-binding cassette) family of proteins. However, the adenylyl cyclases do not possess an ATP-binding or "Walker" motif. Whether a mammalian adenylyl cyclase might also possess transporter-like activity has also not been demonstrated, although an adenylyl cyclase from Paramecium possesses potassium channel activity.14
Why did the adenylyl cyclases evolve with such an intricate design? It seems unlikely that this exists simply to concentrate the catalyst in a membrane-delimited manner near the G protein so as to ensure rapid amplification of the agonist-triggered signal. As discussed below, the two cytoplasmic domains of adenylyl cyclase likely interact to initiate efficient catalytic activity. The enzyme's configuration might promote a proper interaction of the two catalytic domains upon its activation. Nevertheless, it remains unclear as to why such a complex membrane tethering evolved to support this enzyme's activity.
| Diversity in Adenylyl Cyclase Isoforms |
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subunits, and in their tissue distribution may explain the conflicting findings of earlier studies in which membranes prepared from a variety of different tissues were used.
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Types I and VIII form the neuronal subgroup, which is expressed only in the brain. They are both stimulated by calmodulin. Sequence homology between these two isoforms is the least conserved among all the subgroups. Gß
subunits inhibit the catalytic activity of type I. There are at least three splice variants of the type VIII isoform that differ in calmodulin sensitivity25 ; in contrast, two potential splice variants of the type I isoform do not show any functional differences.26
Types II, IV, and VII form the ubiquitous subgroup, which is expressed in multiple tissues, including the heart. They are insensitive to calmodulin. In contrast to the neuronal isoforms, the ubiquitous isoforms are stimulated by Gß
subunits. The type IV and VII isoforms can be detected in most tissues, although one variant of type VII is expressed only in the retina.27 The ubiquitous isoforms are potently stimulated by protein kinase C,28 29 30 although other isoforms can also be stimulated by this kinase.31 The type II isoform seems to be the major isoform in the lung; this isoform is expressed in airway smooth muscle cells32 and in vascular endothelial cells from a variety of tissues.33 Since this isoform responds to a variety of signals emanating from different receptors and G proteins,34 including chemotactic35 and growth factor receptors, its output represents an integrated response to multiple extracellular stimuli, placing it at a key position to modulate airway resistance.32 Whether changes in the expression of this isoform occur under pathophysiological conditions has not been examined.
Originally isolated from olfactory tissue, the type III isoform is calmodulin sensitive.15 36 Although its expression is highest in olfactory tissue, its mRNA can also be detected in other tissues, such as the atria and brown fat.37
Types V and VI are the most closely related isoforms within the mammalian adenylyl cyclase family. Although these isoforms were cloned from several tissue sources, including the heart,18 19 liver,20 and neuronal cells,21 these represent the major adenylyl cyclase isoforms in the heart, as described below in detail, and constitute the cardiac subgroup. There are also splice variants of these isoforms.38 39
Type IX is the newest member of the mammalian adenylyl cyclase family. This isoform, isolated from a pituitary tumor cell line, shows a unique interaction with calcineurin,24 40 a calcium-sensitive serine-threonine phosphatase widely expressed in mammalian cells. This isoform can be stimulated by FK506, a calcineurin inhibitor, suggesting that the activity of this isoform is maintained through phosphorylation.
The distribution of the various isoforms within the brain is heterogeneous, suggesting that each isoform is involved in a distinct aspect of neuronal signaling.41 For example, the type V isoform is restricted to the striatum, implicating its involvement in motor regulation.39 The hippocampus is rich in the type I isoform, and since this isoform is activated by calcium-calmodulin, it has been speculated that it plays a role in long-term potentiation mediated by the glutamate receptor. Indeed, knockout mice lacking the type I isoform show an impaired learning capacity.42 The involvement of a particular isoform in the neuronal control of blood pressure or the circulation has not been investigated.
Each of the various isoforms has a unique chromosomal distribution. Unlike G-protein subtypes,43 all the adenylyl cyclase isoforms are found on different chromosomes, even within the same subgroup,44 45 indicating that the adenylyl cyclase gene family expanded by chromosomal duplication rather than by gene duplication. Since distinct promoter/enhancer elements control the transcription of these different adenylyl cyclase genes, their unique patterns of developmental- and tissue-specific expression would be predicted.
Thus, there is significant heterogeneity in the distribution and biochemical properties of the various adenylyl cyclase isoforms. It is also apparent that a single tissue or cell expresses multiple adenylyl cyclase isoforms; no cell type has been found thus far that expresses only one isoform of adenylyl cyclase. Each tissue and cell type, however, likely possesses a unique "mixture" of adenylyl cyclase isoforms. The heterogeneity among adenylyl cyclase isoforms distinguishes this enzyme family from the other components of the ßAR signaling pathway, specifically, the ßAR itself and Gs
, which lack this diversity either in the number of isoforms expressed or in their pattern of tissue-specific expression.
| Mechanisms of Catalytic Activation |
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and ß, which are distinct gene products, must be coexpressed to catalyze cGMP synthesis.46 An analogous situation appears to exist for the adenylyl cyclases. For the type I, II, and V isoforms,47 48 expression of either the
half (M1/C1) or ß half (M2/C2) of the molecule alone is insufficient to generate enzymatic activity. The type V isoform is particularly intriguing in that the single type V adenylyl cyclase gene can generate, in addition to its full-length product, an
-half molecule (M1/C1a) containing a single catalytic domain through the use of an alternative polyadenylation signal located within an intron in the middle of the gene.48 When either half of the molecule,
(M1C1) or ß (M2C2), is expressed alone, the product is inactive. Catalytic activity is rescued when the two halves are coexpressed. Additional evidence supporting this mechanism comes from the finding that a 20amino acid residue peptide, whose sequence was taken from a highly conserved region in the first cytoplasmic domain of type V adenylyl cyclase, can directly inhibit the catalytic activity of all isoforms against which it was tested.49 It is hypothesized that this region of C1a directly contacts C2a and that the peptide, by way of competition, blocks the interaction and thereby inhibits catalytic activity. Interestingly, the two catalytic domains (or halves) need not originate from the same isoform; a chimeric molecule termed I-
/II-ß containing the front half (M1C1) of type I and the back half (M2C2) of type II is also active. However, active chimeric molecules cannot be randomly assembled from different isoform "halves." The rules that determine a successful mating have not been worked out.50
More recent studies have demonstrated that the two cytosolic domains alone (C1/C2), in the absence of their transmembrane regions, can generate enzymatic activity. A type I-C1/II-C2 chimera, consisting of only the cytoplasmic catalytic domain of each isoform connected by a short linker and devoid of the transmembrane spans, shows a high level of enzymatic activity. This soluble enzyme was produced using a bacterial expression system.51 52 53 The purified product could be stimulated by Gs
and forskolin as well as inhibited by Gß
and P-site inhibitors (adenosine and its analogues), indicating that the cytoplasmic domains alone can recapitulate the major biochemical properties of the wild-type enzyme. Other studies have shown that noncatalytic domains, such as the amino-terminal region, contribute to the catalytic activity of one isoform (type I)47 but not of another (type V),20 54 suggesting that certain regions may modify enzymatic activity but in an isoform-dependent manner. Unexpected properties may also exist within other noncatalytic domains, such as a voltage-sensing activity in the transmembrane regions.55 Depolarization of cultured neuronal cells with KCl was synergistic with a ßAR agonist in stimulating adenylyl cyclase activity. The concept that the transmembrane spans of adenylyl cyclase, like those of voltage-gated ion channels, can detect changes in membrane potential and thereby signal a conformational change in the enzyme is intriguing. This mechanism has particular implications for excitable cells such as neurons and cardiocytes, where, if it were operational, adenylyl cyclase itself might play a primary role in both sensing and modulating the cell's overall response to stimuli that otherwise could not directly activate a G proteinlinked signaling pathway. Although the two catalytic domains (C1/C2) are necessary to generate enzymatic activity, the above studies suggest that other domains contribute to the complete biochemical and regulatory profile of the intact molecule.
Regions important for the interaction with various regulatory components of adenylyl cyclase have been demonstrated using synthetic peptides. A 27amino acid residue peptide whose sequence was taken from the C2a region of type II adenylyl cyclase blocked Gß
stimulation of this isoform.56 This peptide also inhibited other enzymes that are known to be stimulated by Gß
, such as phospholipase ß, certain potassium channels, and ß-adrenergic receptor kinase. Interestingly, this peptide contained a motif QXXER that is shared by these Gß
-regulated enzymes, suggesting that this motif is important for Gß
interaction and that the region containing this motif within type II adenylyl cyclase is a binding domain for Gß
. A region important for calmodulin interaction has also been identified. A 28amino acid residue peptide whose sequence was taken from the C1b region of type I adenylyl cyclase inhibited the calmodulin-stimulated activity of adenylyl cyclase purified from brain.57 Another study showed that the mutation, F503 to R503, in type I adenylyl cyclase within the region corresponding to this peptide abolished calmodulin stimulation of type I adenylyl cyclase,58 suggesting that this is the calmodulin binding domain of the type I isoform.
| Diversity in Regulation by G-Protein Subunits |
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inhibits type I adenylyl cyclase while it stimulates type II adenylyl cyclase. The stimulation of type II adenylyl cyclase is augmented in the presence of Gs
stimulation of this isoform.61 62 Type IV adenylyl cyclase, an isoform closely related to type II, is also stimulated by Gß
. In contrast, type V and VI adenylyl cyclase isoforms are not directly responsive to Gß
. Inhibition of catalytic activity by Gi
is also not universal among the isoforms, and variable degrees of inhibition have been reported.61 63 In studies using membranes prepared from insect cells expressing a particular adenylyl cyclase isoform, all Gi
subtypes (Gi
1 to Gi
3) elicited a similar degree of inhibition of the type V and VI isoforms. Type I adenylyl cyclase was inhibited, but weakly, compared with types V and VI.61 Protein kinase C influences the Gi
-mediated inhibition of adenylyl cyclase.64 In studies using COS cell membranes coexpressing the type II adenylyl cyclase isoform and a constitutively active Gi
, inhibition of type II adenylyl cyclase by Gi
was abolished upon treatment of the cells with phorbol ester. These data suggest that Gi
inhibits adenylyl cyclase in an isoform-dependent manner and that this inhibition is influenced by other factors, such as the phosphorylation state of the enzyme. Inhibition by other G
subunits also occurs in an isoform-specific way. Go
inhibits type I adenylyl cyclase while minimally affecting type VI. G
12 does not affect a variety of adenylyl cyclase isoforms, whereas Gz
inhibits type I and V adenylyl cyclase.65 Finally, although all isoforms are stimulated by Gs
, the extent of this effect varies among the isoforms and is influenced by other factors as well.66 The outcome of these findings is that the combination of G-protein subtypes and adenylyl cyclase isoforms expressed by a cell is important in determining cAMP production in response to external stimuli. In certain cases, the same stimulus may result in the opposite effect on cAMP production within different cell types, such as stimulation of adenylyl cyclase through an inhibitory G proteinlinked receptor. Stimulation of the
2-adrenergic receptor, which is coupled in an inhibitory manner to adenylyl cyclase through Gi, usually leads to decreased cAMP production. However, coexpression of this receptor with the type II adenylyl cyclase isoform results in increased cAMP production, probably through the stimulation of the enzyme by Gß
subunits.67 These results underscore the two major determinants of cAMP production within a cell: which adenylyl cyclase isoforms are expressed and what are their relative amounts? These factors, in addition to the repertoire of G proteinlinked receptor subtypes expressed by the cell, are important in determining the direction and degree of cAMP signaling (Fig 3
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| Calcium Sensitivity of Adenylyl Cyclase Isoforms |
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subunits. However, these isoforms have been shown to be directly inhibited by submicromolar concentrations of calcium.21 NCB-20 cells, which express mostly the type VI isoform, increase intracellular calcium concentration in response to bradykinin. This results from an initial release of calcium from inositol 1,4,5-tris-phosphatesensitive stores, which, in turn, inhibits adenylyl cyclase catalytic activity.68 Interestingly, more generalized elevations of intracellular calcium produced by calcium ionophores do not necessarily inhibit cAMP production in these same cells; this suggests that calcium-sensitive adenylyl cyclase isoforms may be functionally colocalized with certain calcium entry channels.69
The type III isoform is stimulated by calcium/calmodulin in vitro when concomitantly stimulated with Gs
.36 However, when this isoform is hormonally stimulated in intact cells, it is inhibited by an increase in intracellular calcium. Since this inhibition is blocked by a calmodulin kinase inhibitor, it has been proposed that calmodulin kinase directly inhibits the type III isoform in vivo.70 Therefore, this calmodulin-sensitive isoform appears to be under dual regulation: stimulation by calcium/calmodulin and inhibition by calmodulin kinase.
The most recently proposed mechanism by which calcium can regulate adenylyl cyclase activity is through calcineurin, a calcium-sensitive phosphatase. The type IX isoform is activated by FK506, an inhibitor of this particular phosphatase, suggesting that calcium-dependent dephosphorylation (not phosphorylation) is a potentially important mechanism regulating the activity of this isoform.24
Thus, a variety of mechanisms involving calcium can impinge on the activity of various adenylyl cyclase isoforms; similarly, cAMP-triggered mechanisms can directly gate the strength and duration of the calcium signal. For example, ßAR-mediated activation of adenylyl cyclase and, thereby, protein kinase A leads to increased intracellular calcium concentrations by enhancing external calcium entry and the release of internal stores. This, in return, can regulate various adenylyl cyclases, either directly or indirectly, through the activation of various calcium-dependent kinases and phosphatases. Thus, cAMP and calcium concentrations may oscillate, providing both temporal and spatial information to the cell. Although dynamic interplay between these two second messenger pathways has been demonstrated,71 its significance for excitable cell types, such as the cardiocyte, has not been defined.
| Adenylyl Cyclase Isoforms in the Heart |
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An interesting question arises: why does the heart express two isoforms that are quite similar in their biochemical properties? Type V appears to be an adult isoform, whereas type VI is more highly expressed in the neonate.74 75 Expression of the type VI isoform is most abundant in the fetus, gradually declines with age, and reaches its lowest level in mature adults. The expression of type V follows an opposite pattern. The expression is lowest in the fetus, gradually increases with age, and reaches a maximum in the mature adult. Thus, two major isoforms in the heart appear to be developmentally regulated in an opposite manner, a pattern analogous to the expression of the
- and ß-myosin heavy chains.76 Nevertheless, by mRNA analysis, these two isoforms are the most abundant in the heart at each stage of development.
It has been suggested that a decreased capacity to generate cAMP may be a fundamental defect in cardiac disease, particularly heart failure.77 The expression of the cardiac adenylyl cyclase isoforms V and VI is significantly decreased in the dog after the development of heart failure generated by ventricular overdrive pacing. After 4 weeks of pacing, left ventricular end-diastolic pressure and heart rate increase significantly, coincident with the appearance of the signs and symptoms of heart failure, ie, edema, ascites, and exercise intolerance. Basal and forskolin-stimulated adenylyl cyclase activities decrease significantly. These changes are accompanied by a reduction in the steady state mRNA levels of both the type V and VI isoforms. These findings suggest that decreased adenylyl cyclase mRNA levels underlie the downregulation of catalytic activity. Whether this plays a causal role in the contractile dysfunction of heart failure remains unclear. Changes in adenylyl cyclase expression in other forms of cardiac disease have not been extensively investigated. In cardiac hypertrophy, for example, it would be interesting to determine whether the expression of the neonatal type VI isoform is increased.
Cardiac adenylyl cyclase may be regulated by protein kinase C under ischemic conditions and thereby play a role in maintaining cardiac contractility.78 79 Protein kinase C, which has classically been defined as a calcium-activated serine-threonine kinase, actually comprises at least 11 isozymes. These can be divided into three classes according to their cofactor requirements for activation: classic (
, ßI, ßII, and
, which are sensitive to both calcium and diacyl glycerol), novel (
,
,
,
, and µ, which are insensitive to calcium and sensitive to diacyl glycerol), and atypical (
and
, which are insensitive to both calcium and diacyl glycerol).80 The heart expresses at least the
, ß,
, and
isozymes.81 The
and
isozymes directly phosphorylate and activate the type V cardiac adenylyl cyclase isoform in vitro60 ; the
isozyme activates type V adenylyl cyclase in a calcium-independent manner, and the
isozyme requires calcium, affording yet another mechanism for calcium-mediated regulation of adenylyl cyclase activity.
It is also known that growth factors, including insulin, can regulate cardiac cAMP production and contractility. Insulin receptor stimulation activates phosphatidylinositol-3-OH kinase, leading to the formation of specific lipid products, such as phosphatidylinositol-3,4,5 triphosphate,82 that activate protein kinase C
.83 In cells overexpressing the type V isoform, insulin augments cAMP production; this augmentation can be further enhanced by coexpressing the protein kinase C
isozyme.84 These data imply that growth factors regulate cAMP signaling via an atypical protein kinase C, such as protein kinase C
, although further studies are required to confirm this mechanism in vivo. Such regulation may occur in an isoform-specific manner; epidermal growth factormediated augmentation of cAMP production is also observed with the type V isoform, but not with other isoforms.85 More recent data, however, suggest that this stimulation is due, at least in part, to epidermal growth factorstimulated phosphorylation of Gs
.86
In contrast to the enhancement of type V activity by protein kinase Cmediated phosphorylation, phosphorylation by protein kinase A directly inhibits its activity, by decreasing the Vmax of the enzyme without changing its Km for the substrate ATP.87 The phosphorylation and inhibition of type V adenylyl cyclase by protein kinase A suggest the presence of a negative-feedback loop at the level of adenylyl cyclase itself as well as a mechanism for heterologous desensitization of the cAMP signaling pathway.
| Other Adenylyl Cyclases |
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| Future Studies |
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In addition to the known isoforms, an additional cardiac adenylyl cyclase isoform may also exist. Although a calmodulin-sensitive adenylyl cyclase activity in the heart has been reported,89 no known calmodulin-sensitive isoforms are expressed in the heart, except for type III, which is found in the atria37 but not in the ventricle. Future cloning studies may isolate a new isoform(s) and further expand the repertoire of cardiac adenylyl cyclases.
| Acknowledgments |
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| Footnotes |
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Received September 18, 1996; accepted November 8, 1996.
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