Howard Hughes Medical Institute, Department of Medicine and Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710
HEPTAHELICAL receptors, so called because of their
conserved structure featuring seven During the past few years, however, several reports
have appeared in the literature describing various physiological consequences of heptahelical receptor stimulation
that, surprisingly, do not seem to be mediated by G protein activation. Concurrently, novel techniques for detecting protein-protein interactions such as yeast two-hybrid,
phage display, and fusion protein overlays have revealed
associations of heptahelical receptors with a variety of intracellular partners other than G proteins. This convergence of unexplained physiology and provocative protein-
protein interactions has led increasingly to the realization
that the mechanisms of heptahelical receptor signaling are
more diverse than previously thought. This mini-review
summarizes recent work on the subject of intracellular signaling by heptahelical receptors through means other than
classical G protein pathways.
Arrestins and G Protein-coupled Receptor Kinases
Activated heptahelical receptors are phosphorylated by a
family of G protein-coupled receptor kinases (GRKs).1
Following phosphorylation, the receptors bind to another
family of proteins called arrestins (Lefkowitz, 1998 It was proposed recently, for example, that GRKs may also be signaling intermediates for heptahelical receptors rather than just proteins involved in receptor desensitization. Recently, it was found that GRK2 can
associate with and phosphorylate tubulin (Carman et al.,
1998 SH2 Domain-containing Signaling Proteins
Several subtypes of heptahelical receptors have been proposed to organize SH2 domain-based signaling complexes
in a manner analogous to that seen for receptor tyrosine
kinases. The heptahelical angiotensin AT1 receptor, for
example, activates the Jak2 tyrosine kinase following stimulation with angiotensin II (Marrero et al., 1995 The Small GTP-binding Proteins
Heptahelical receptor-mediated regulation of small GTP-binding proteins, such as Ras, Rab, Rho, and ARF, has
been studied for years but has typically been viewed as a
downstream consequence of heterotrimeric G protein activation (Buhl et al., 1995 PDZ Domain-containing Proteins
The heptahelical receptor-binding proteins discussed so
far (heterotrimeric G proteins, arrestins, GRKs, SH2 proteins, and small GTP-binding proteins) all bind to either
the receptor third intracellular loop or the portion of the
receptor tail nearest the plasma membrane. Many heptahelical receptors, however, have quite long intracellular
carboxyl-terminal tails, suggesting that the distal portions
of some receptor tails may also be capable of mediating
association with various intracellular signaling proteins.
Moreover, the carboxyl-terminal tails of some heptahelical receptors terminate in variants of the T/S-x-V motif required for binding to PDZ domain-containing proteins
such as PSD-95 (Kornau et al., 1995 One example of a heptahelical receptor with a long intracellular tail is the Rhodopsin is another heptahelical receptor that has
been found to associate with a PDZ domain-containing
protein in a functionally relevant manner. Rhodopsin
binds to InaD (Chevesich et al., 1997 The interactions of PDZ domains with the carboxyl termini of their target proteins are quite specific (Songyang
et al., 1997 Polyproline-binding Proteins
Several heptahelical receptors exhibit polyproline regions
on either their third intracellular loops or carboxyl-terminal tails. Polyproline regions are known to mediate binding to a variety of conserved protein domains such as SH3
domains, WW domains, and EVH domains (Pawson and
Scott, 1997 Another heptahelical receptor that can bind signaling
proteins through a polyproline region is the dopamine D4
receptor, which contains a stretch of prolines in its third intracellular loop. This polyproline region in the D4 receptor can mediate in vitro binding to a number of SH3 domain-containing proteins, including Grb2 and Nck, as
assessed by yeast two-hybrid and protein pull-down assays
(Oldenhof et al., 1998 Unsolved Heptahelical Receptor Mysteries
Several heptahelical receptor binding partners have been
identified for which no clear roles in downstream signaling
have yet been demonstrated. Examples include the interaction of Grb2 with the While such lines of research are describing novel mechanisms by which heptahelical receptors may generate intracellular signals, other lines of research are describing physiological effects mediated by heptahelical receptors for
which the molecular mechanisms are unknown. Genetic
studies in invertebrates, in particular, have yielded a number of examples of heptahelical receptors mediating physiological actions through pathways that are apparently independent of G proteins. For instance, the cyclic AMP
receptors of the slime mold Dictyostelium discoideum are
heptahelical receptors that induce chemotaxis of undifferentiated Dictyostelium cells into an aggregated fruiting
body. These chemotactic effects of Dictyostelium cyclic
AMP receptor stimulation are known to be mediated
through G protein activation (Devreotes, 1994 More genetic evidence for signaling by heptahelical receptors through means other than traditional G protein
pathways comes from the study of a family of receptors
known as frizzled. In many species, ranging from C. elegans to Drosophila to mammals, tissue polarity during development is regulated by the Wnt family of secreted proteins, which exert their effects on developing cells by
binding to members of the frizzled family (Bhanot et al.,
1996 Dishevelled is the most proximal frizzled signaling intermediate identified. It is not known if the interaction between frizzled and dishevelled is direct, but it is interesting
to note that dishevelled contains a PDZ domain and many
frizzled family members possess carboxyl-terminal motifs
appropriate for PDZ domain association. Therefore, it is
possible that members of the frizzled family may signal
through direct coupling to PDZ domain-containing proteins like dishevelled in a manner analogous to the PDZ
domain-mediated interaction of the Another genetically identified heptahelical receptor
that signals via unknown mechanisms is smoothened. This
receptor is a relative of the frizzled family of receptors,
and is a key mediator of hedgehog signaling (Alcedo et al.,
1996 Beyond the G Protein Paradigm
Over the past several years, evidence has emerged that
heptahelical receptors can signal through associations with
intracellular partners other than G proteins. In some
cases, these partners are known receptor-interacting proteins, such as arrestins and GRKs, which were thought
previously to be involved only in receptor desensitization.
In other cases, they are novel partners such as NHERF or
Homer, which were not known previously to interact with
heptahelical receptors. For heptahelical receptors that
seem to mediate physiological effects via unknown G protein-independent pathways, such as frizzled and smoothened, it might be useful to consider analogies with other
heptahelical receptors for which the early steps of various
G protein-independent signaling mechanisms have been
elucidated. Some of these mechanisms are likely to be quite general: for example, arrestins and GRKs can bind
to many heptahelical receptors, and arrestin- and GRK-mediated formation of signaling complexes may therefore
be a feature common to many heptahelical receptors.
Other mechanisms, such as the activation of small GTP-binding proteins or the formation of SH2-based signaling complexes organized around tyrosine-phosphorylated residues, may be relevant to a small number of heptahelical
receptors but not to the majority. Still other mechanisms
are likely to be highly receptor-specific: the binding of
NHERF to the There are >1,000 heptahelical receptors but only ~20
different heterotrimeric G proteins. Such an arrangement
would seem to place limitations on the specificity of heptahelical receptor signal transduction, if G proteins were the
only mediators of heptahelical receptor-initiated signaling. However, it now seems likely that each heptahelical
receptor may activate its own relatively specific set of intracellular signaling pathways, including both G protein-
dependent and G protein-independent mechanisms (Fig. 1). The net physiological effect of stimulation of a particular heptahelical receptor will thus reflect the sum of the
various intracellular pathways it can activate, with some of
the pathways being quite general, others being fairly specific, and some being unique to the individual receptor.
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References
-helical
transmembrane spans, mediate physiological responses to a remarkably diverse array of stimuli. These include hormones, neurotransmitters, small peptides, proteins, lipids and ions, as well as sensory stimuli such as
odorants, pheromones, bitter and sweet tastants, and photons. This superfamily of receptors contains >1,000 members, making it the largest class of cell surface molecules in
the mammalian genome. Moreover, it was found recently
that heptahelical receptors account for >5% of the total
genes in the Caenorhabditus elegans genome (Bargmann, 1998
), testifying to the importance of this family and demonstrating that the structure of these receptors has been
highly conserved throughout evolution. For many years,
this family of receptors has been referred to as G protein-
coupled, a term based on the well documented paradigm
that such receptors interact with and signal through heterotrimeric G proteins. Simply stated, this repeatedly validated paradigm is that when heptahelical receptors are
stimulated with ligand, their intracellular regions undergo conformational changes, allowing the receptors to interact
with G proteins. This association in turn causes conformational changes in the G proteins that facilitate GDP release and GTP binding, leading to dissociation of G
and
G
subunits. The activated G protein subunits then bind
to and regulate various intracellular effectors.
). The
regions of the receptors that arrestins bind to, generally
the third intracellular loop and the portion of the carboxyl-terminal tail closest to the membrane, are also primary determinants for G protein interaction. Arrestin
binding to receptors thus results in desensitization of G
protein-mediated signaling by preventing interaction of
receptors with G proteins. An emerging view, however, is
that the binding of arrestins to heptahelical receptors also
initiates a new set of signaling pathways in addition to
blocking those mediated by G protein activation.
-arrestin
can act as an adaptor protein to recruit the tyrosine kinase
Src into a signaling complex organized around the
2-adrenergic receptor (Luttrell et al., 1999
). It is well known
that stimulation of many heptahelical receptors can lead to
the activation of MAP kinases, but the mechanisms involved have been difficult to define. While G protein activation is clearly necessary, activation of tyrosine kinases of
the Src family is required in many cases as well (Luttrell et
al., 1996
). The most recent findings reveal that Src associates in cells with agonist-activated
2-adrenergic receptors,
as assessed by immunofluorescence and coimmunoprecipitation. The recruitment of cellular Src to
2-adrenergic receptors is potentiated by overexpression of
-arrestin, and
in vitro pull-down studies reveal a direct high-affinity association between Src and
-arrestin.
-Arrestin-mediated
association of Src with
2-adrenergic receptors is a key
step in mitogenic signaling by these receptors, since inhibition of the binding of
-arrestin to either the
2-adrenergic receptor or Src attenuates
2-adrenergic activation of
MAP kinase. These results indicate that the association of
arrestins with heptahelical receptors does not simply uncouple receptors from G protein pathways, but rather induces a switch in receptor signaling from classical second
messenger-generating G protein-mediated pathways to
other pathways such as those involving Src and leading to
the activation of MAP kinase. Moreover, arrestins have
also been found to interact with a number of cellular proteins involved in endocytosis such as clathrin heavy chain
(Goodman et al., 1996
), the clathrin adaptor AP-2 (Laporte et al., 1999
), and NSF (N-ethylmaleimide sensitive
fusion protein) (McDonald et al., 1999
). These interactions represent potential mechanisms by which heptahelical receptors might directly regulate the cellular endocytic
machinery. Thus, arrestins may well represent multifunctional adaptor proteins that mediate a number of aspects
of heptahelical receptor signaling.
; Haga et al., 1998
; Pitcher et al., 1998
). GRKs have
also been shown to associate with actin (Freeman et al.,
1998
) and a novel ARF GTPase-activating protein (ARF
GAP) called GIT1 (Premont et al., 1998
). These findings
illustrate at least two ways in which the recruitment of
GRKs to activated heptahelical receptors may lead directly to cytoskeletal regulation or to modulation of other
intracellular processes: (a) allosteric activation of GRKs
by ligand-occupied receptors (Palczewski et al., 1991
;
Chen et al., 1993
; Premont et al., 1994
) may catalyze the
phosphorylation of key nonreceptor substrates such as tubulin; and (b) GRKs may act as noncatalytic adaptors to
recruit key signaling intermediates (e.g., an ARF GAP)
into complex with the receptors at the plasma membrane.
). The
mechanism underlying this effect involves Src-mediated tyrosine phosphorylation of the AT1 receptor itself (Venema et al., 1998
). It is interesting to speculate that this
phosphorylation might result from
-arrestin-mediated
recruitment of Src to the receptor, but at present this idea
has not been tested. When Tyr319 on the AT1 receptor
carboxyl-terminal tail is phosphorylated, Jak2 coimmunoprecipitates with the AT1 receptor in an agonist-dependent fashion; mutation of Tyr319 to Phe blocks coimmunoprecipitation of Jak2 with AT1 receptors and also
attenuates Jak2 activation mediated by angiotensin II
stimulation (Ali et al., 1997
). Originally, it was thought
that Jak2 interaction with the AT1 receptor was direct.
Jak2 does not have an SH2 domain, however, so it was not clear how it could bind to the AT1 receptor tail in a phosphotyrosine-dependent manner. Subsequent studies revealed that the Jak2/AT1 receptor tail interaction can be
blocked by antibodies to the SHP family of SH2 domain-
containing tyrosine phosphatases (Marrero et al., 1998
),
indicating that SHP proteins probably act as adaptors to facilitate the association of Jak2 with the AT1 receptor. It
has also been shown that another SH2 domain-containing
protein, phospholipase C
1, can be coimmunoprecipitated
with the tyrosine-phosphorylated AT1 receptor (Venema
et al., 1998
), although the significance of this interaction
for downstream signaling by the receptor has not yet been clarified.
2-adrenergic receptor is phosphorylated on tyrosine by the insulin receptor tyrosine kinase (Hadcock et al.,
1992
; Karoor et al., 1995
; Valiquette et al., 1995
; Baltensperger et al., 1996
). Several tyrosines in the
2-adrenergic receptor have been shown to be phosphorylated, and
it has also been reported that the SH2 domain-containing
adaptor protein Grb2 can associate with
2-adrenergic receptors following phosphorylation of Tyr350/354 on the
receptor (Karoor et al., 1998
). It is not yet known, however, if this association mediates any downstream signaling
by the
2-adrenergic receptor. Nonetheless, given these
provocative findings with the AT1 and
2-adrenergic receptors, a significant point of future interest will be to see
if other heptahelical receptors may be tyrosine-phosphorylated and thus capable of hosting SH2 or PTB domain-based signaling complexes.
; Kozasa et al., 1998
). Recently,
however, it has been shown that activation of phospholipase D by certain heptahelical receptors, including M3
muscarinic acetylcholine receptors and H1 histamine receptors, is not blocked by inhibitors of heterotrimeric G
protein pathways, such as pertussis toxin or phospholipase
C inhibitors, but is sensitive to the ARF inhibitor brefeldin
A and the Rho inhibitor C3 botulinum toxin (Mitchell et
al., 1998
). ARF and Rho can also be immunoprecipitated
in an agonist-dependent fashion in association with M3
muscarinic receptors and AT1 angiotensin receptors. The receptors capable of binding ARF and Rho exhibit a conserved motif (N-P-x-x-Y) in their seventh transmembrane
span. Mutation of this motif prevents association of the receptors with ARF and Rho and also alters receptor signaling to phospholipase D. While it is not clear at present if
the association of ARF and Rho with the heptahelical receptors is direct, it is clear that these small GTP-binding
proteins can form a complex with some heptahelical receptors and that formation of this complex can mediate
signaling of these receptors to phospholipase D.
).
2-adrenergic receptor. Overlay studies demonstrated that the tail of this receptor binds with
very high affinity to a single protein in tissue extracts; subsequent purification and sequencing revealed this binding
partner to be a PDZ domain-containing protein, the Na+/
H+ exchanger regulatory factor (NHERF) (Hall et al.,
1998a
). NHERF binds not only to the
2-adrenergic receptor tail in vitro, but also to the full-length
2-adrenergic receptor in cells in an agonist-dependent fashion as assessed
by immunofluorescence studies.
2-Adrenergic regulation of renal Na+/H+ exchange has
long been known to be opposite of what would be expected from a Gs-coupled receptor. Activation of Gs-coupled receptors such as parathyroid hormone receptors increases cellular cyclic AMP, which in a PKA-dependent fashion facilitates the association of NHERF with renal
Na+/H+ exchangers and thus leads to inhibition of Na+/H+
exchange (Weinman and Shenolikar, 1993
). Activation of
2-adrenergic receptors also increases cellular cyclic AMP,
yet paradoxically leads to stimulation of renal Na+/H+ exchange (Bello-Reuss, 1980
; Weinman et al., 1982
). A point
mutant of the
2-adrenergic receptor with the final residue
of the receptor changed from leucine to alanine, which
cannot bind NHERF but which exhibits normal G protein
coupling, inhibits the activity of the renal Na+/H+ exchanger in cells rather than stimulating it like the wild-type receptor (Hall et al., 1998a
). These findings suggest
that the ability of the
2-adrenergic receptor to bind
NHERF is critical for
2-adrenergic regulation of renal
Na+/H+ exchange in vivo.
; Xu et al., 1998
), a
multi-PDZ domain scaffolding protein that also associates
with a number of signaling intermediates involved in
rhodopsin-initiated pathways, such as phospholipase C
,
protein kinase C, and the TRP ion channel (Huber et al.,
1996
; Shieh and Zhu, 1996; Chevesich et al., 1997
; Tsunoda
et al., 1997
; Xu et al., 1998
). Mutations in InaD profoundly
distort photon-induced rhodopsin signaling (Scott and
Zuker, 1998
). The physical association of rhodopsin and
InaD has been demonstrated by coimmunoprecipitation and by in vitro fusion protein pull-down experiments
(Chevesich et al., 1997
; Xu et al., 1998
), but it is not known
at present if the association of InaD and rhodopsin in cells
occurs constitutively or if instead it is promoted by photoactivation of rhodopsin. In any case, it seems that rhodopsin can facilitate the assembly of intracellular protein complexes involved in phototransduction via its interaction
with InaD.
). As demonstrated by the
2-adrenergic receptor point mutant, a change of a single amino acid can be
enough to completely disrupt an otherwise high-affinity
association. Only a small number of heptahelical receptors terminate in the carboxyl-terminal motif (S/T-x-L)
required for high-affinity NHERF binding (Hall et al., 1998b
). However, since the >50 known PDZ domain-containing proteins recognize diverse target motifs, it is probable that some of these proteins associate with specific
heptahelical receptors in a functionally relevant manner.
Signaling through PDZ domain-mediated associations may therefore be a feature common to many heptahelical receptors.
). Recently, several subtypes of heptahelical
metabotropic glutamate receptor (mGluR) were shown to
bind members of the Homer family of EVH domain-containing proteins through a polyproline region found in the
mGluR tail region (Brakeman et al., 1997
; Tu et al., 1998
;
Xiao et al., 1998
). This binding has been shown in yeast
two-hybrid studies, fusion protein pull-downs, and coimmunoprecipitation studies. Some members of the Homer
family can dimerize, and are thus capable of linking
mGluRs to other proteins with appropriate polyproline
motifs. For example, Homer proteins can facilitate a functional interaction between mGluRs and endoplasmic reticulum-based inositol trisphosphate (IP3) receptors, which
control intracellular calcium release. When the mGluR/
Homer association is blocked, the ability of mGluRs to
mobilize intracellular calcium is attenuated (Tu et al.,
1998
). These findings suggest that Homer is a key intermediate in mGluR regulation of intracellular calcium levels,
and thus shed light on the puzzling observation made
shortly after the cloning of the mGluRs that alternative splicing of the mGluR1 carboxyl-terminal tail results in
profound differences in the ability of this receptor to mobilize intracellular calcium (Pin et al., 1992
; Joly et al.,
1995
).
). It is not clear at present, however, which polyproline-binding proteins are the relevant cellular partners for D4 receptors or for other polyproline-containing heptahelical receptors such as
1-adrenergic receptors and M4 muscarinic receptors. Further work in this
area should reveal which polyproline-binding proteins
couple to which receptors in cells, as well as what the consequences of these interactions are for receptor signaling.
2-adrenergic receptor and
dopamine D4 receptor, as described above, as well as
the interaction of the
2-adrenergic receptor and some
-adrenergic receptor subtypes with the
subunit of the
eukaryotic initiation factor 2B (Klein et al., 1997
), and the
interaction of the bradykinin B2 receptor with endothelial nitric oxide synthase (Ju et al., 1998
). The recent proliferation of techniques for detecting protein-protein interactions is likely to lead to an increase in the number of
known binding partners for various heptahelical receptors.
Each of these interactions will represent a new potential
mechanism of heptahelical receptor signaling, although
the true physiological significance of each interaction may
not be immediately obvious.
). However,
aggregated Dictyostelium cells undergo a number of cyclic
AMP receptor-mediated transcriptional changes that are
independent of G protein activation, since cells with G
protein subunits deleted still exhibit these changes following stimulation by cyclic AMP (Milne et al., 1995
; Schnitzler et al., 1995
; Maeda et al., 1996
; Jin et al., 1998
). The
mechanisms by which this class of heptahelical receptors
might mediate G protein-independent effects, however,
are completely unknown.
; Yang-Snyder et al., 1996
; He et al., 1997
). Activation of some frizzled family heptahelical receptors results in increases in cellular calcium that can be inhibited by modulators of G protein function such as pertussis toxin and
GDP-
-S (Slusarski et al., 1997
). Thus, it seems that frizzled receptors can couple to G proteins. However, genetic
studies have identified a number of signaling intermediates downstream of frizzled, such as dishevelled, glycogen
synthase kinase-3,
-catenin, and the product of the adenomatous polyopsis coli (APC) gene (Dale, 1998
), and
none of these proteins resemble known components of
classical G protein signaling pathways.
2-adrenergic receptor with NHERF. Some components of frizzled signaling
pathways have been identified as oncogenes in mammalian tissues (Kinzler and Vogelstein, 1996
), emphasizing the importance of understanding frizzled signaling.
; van den Heuvel and Ingham, 1996). Hedgehog, a soluble protein first identified as a regulator of patterning
during Drosophila development, binds to a cell surface receptor known as patched (Chen and Struhl, 1996
; Stone
et al., 1996
), which leads to regulation of the activity of
smoothened to exert control over cell proliferation and differentiation. Since smoothened is a heptahelical receptor,
much attention has been focused on the possibility that it
might couple to heterotrimeric G proteins, but at present
there is no conclusive evidence for such coupling. Indeed,
genetic studies have identified several key proteins, such
as the serine/threonine kinase fused and the putative transcriptional factor cubitus interruptus, as intermediates in
the smoothened signaling pathway; none of these proteins
resemble known components of G protein signaling pathways (Ingham, 1998
). Activating mutations in the mammalian homologue of smoothened have been identified
recently as underlying causes of sporadic basal-cell carcinoma (Xie et al., 1998
), revealing that smoothened, like
frizzled, may be involved in carcinogenesis. The intracellular signaling mechanisms used by both frizzled and smoothened are thus of interest not just as novel examples of heptahelical receptor signaling, but also as potential points of
clinical intervention in the treatment of some cancers.
2-adrenergic receptor and the binding of
Homer to metabotropic glutamate receptors, for example,
depend on the presence of precise motifs that are likely to
be found in few other heptahelical receptors, although other receptors are likely to contain slightly modified motifs that mediate binding to other specific PDZ or polyproline-binding domains.
View larger version (34K):
[in a new window]
Fig. 1.
Schematic diagram of heptahelical receptor signaling.
(A) The G protein paradigm. Following agonist binding, heptahelical receptors activate heterotrimeric G proteins (G), which
then regulate the activity of specific cellular effectors. (B) Beyond the G protein paradigm. Following agonist binding, heptahelical receptors can associate with members of diverse families
of intracellular proteins, including heterotrimeric G proteins (G),
polyproline-binding proteins such as those containing SH3 domains (SH3), arrestins (Arr), G protein-coupled receptor kinases (GRK), small GTP-binding proteins (g), SH2 domain-containing proteins (SH2) and PDZ domain-containing proteins
(PDZ). These interactions allow heptahelical receptors to initiate
multiple intracellular signaling pathways, with each subtype of
receptor likely coupled to a relatively unique set of effectors.
The near future is likely to yield a number of new examples of heptahelical receptor signaling through means other than classical G protein pathways. Some of these new receptor-initiated signaling pathways may be variations on a theme already seen in other heptahelical receptors, while others are likely to be completely novel. In any case, the old view of heptahelical receptors as simple G protein activators is currently being replaced by a new view of these receptors as complicated signal-transducing machines capable of directly coupling to a host of intracellular signaling pathways.
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Footnotes |
---|
Address correspondence to Robert J. Lefkowitz, Howard Hughes Medical Institute, Box 3821, Duke University Medical Center, Durham, NC 27710. Tel.: (919) 684-2974. Fax: (919) 684-8875. E-mail: lefko001{at}mc.duke.edu
Received for publication 9 April 1999 and in revised form 26 April 1999.
R.J. Lefkowitz is an investigator of the Howard Hughes Medical Institute.
The authors would like to thank Audrey Claing, Stéphane Laporte, and Lou Luttrell for helpful comments on this manuscript.
![]() |
Abbreviations used in this paper |
---|
GAP, GTPase-activating protein; GRK, G protein-coupled receptor kinase; mGluR, metabotropic glutamate receptor; NHERF, Na+/H+ exchanger regulatory factor.
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