Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112-0840, USA
* Author for correspondence (e-mail: jorgensen{at}biology.utah.edu)
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Introduction |
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The synaptic vesicle cycle is driven by members of protein families required for general membrane trafficking, including SNAREs, UNC-18, Rab3 and vacuolar H+ ATPases (V-ATPases), and unique proteins, such as synaptotagmin, which regulate aspects of exocytosis unique to synapses. Although extensively studied, the precise roles of these proteins remain controversial. Here we survey current models proposed for their function in synaptic vesicle cycling.
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SNAREs |
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Docking
SNARE complex formation was originally thought to dock synaptic vesicles to
the plasma membrane (Sollner et al.,
1993b). SNAREs localize to distinct subcellular compartments,
representing unique molecular tags. Thus, formation of complexes between
pathway-specific SNAREs might ensure that vesicles are targeted to the correct
compartment. However, subsequent biochemical and genetic studies have failed
to support such a role. In Drosophila, SNAREs can be promiscuous, the
non-synaptic t-SNARE SNAP-24 can interact with syntaxin and synaptobrevin to
form SNARE complexes in vitro (Niemeyer
and Schwarz, 2000
) and substitute for SNAP-25 in vivo
(Vilinsky et al., 2002
); SNARE
interactions alone thus seem incapable of providing specificity for membrane
targeting. Furthermore, perturbations of the SNAREs in squid and
Drosophila fail to block the docking of synaptic vesicles
(Hunt et al., 1994
;
Broadie et al., 1995
).
Priming
Structural data indicate that SNARE complex formation in trans would bring
the synaptic vesicle membrane into close proximity to the plasma membrane
(Baumert et al., 1989;
Bennett et al., 1992
;
Hanson et al., 1997
;
Lin and Scheller, 1997
;
Sutton et al., 1998
), which
might be essential for their fusion. Consistent with this notion, the size of
the readily releasable pool (presumably primed vesicles) correlates with the
level of SNARE complex assembly in vivo
(Lonart and Sudhof, 2000
).
Fusion
The current dogma is that SNARE complex formation is sufficient for the
fusion step. Specifically, zippering together of the SNARE complex in trans
provides the energy needed to drive membrane fusion. Consistent with this
model, purified membranes containing only cognate SNARE proteins undergo
membrane fusion (Weber et al.,
1998; McNew et al.,
1999
; McNew et al.,
2000
). However, the rates observed are low
(Weber et al., 1998
),
suggesting that other components may be required in vivo to support the rapid
fusion rates observed at the synapse.
![]() |
UNC-18 |
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Docking
In the absence of Munc18-1, dense-core vesicles in chromaffin cells fail to
dock with the plasma membrane (Voets et
al., 2001). UNC-18 physically interacts with the synaptic vesicle
protein Doc2 (Verhage et al.,
1997
) and, in yeast, complexes containing its homolog Vps33p
interact with the Rab3 homolog Ypt7p (Haas
et al., 1995
; Rieder and Emr,
1997
; Ungermann et al.,
1998
; Eitzen et al.,
2000
; Price et al.,
2000
; Seals et al.,
2000
). Thus, UNC-18 may anchor synaptic vesicles to the plasma
membrane by binding Doc2 or Rab3 on the vesicle and syntaxin on the plasma
membrane. However, perturbation studies have not revealed a role for syntaxin
in docking (see above). Alternatively, UNC-18 could facilitate docking through
interactions with other membrane-associated proteins, such as the
Mint-Cask-Neurexin complex (Okamoto and
Sudhof, 1997
; Biederer and
Sudhof, 2000
).
Priming
Although syntaxin must interact with synaptobrevin to prime vesicles for
release, in solution syntaxin adopts a closed conformation; its N-terminus
folds over and occludes the SNARE-binding domain
(Calakos et al., 1994;
Dulubova et al., 1999
). Thus,
syntaxin needs to be `opened' for priming to occur. UNC-18 binds specifically
to the closed configuration of syntaxin
(Dulubova et al., 1999
;
Misura et al., 2000
;
Yang et al., 2000
). Perhaps
UNC-18 promotes exocytosis by opening syntaxin. Consistent with this model,
expression of a truncated form of the syntaxin homolog in yeast, Tlg2p,
partially suppresses mutations in the UNC-18 homolog Vps45p
(Bryant and James, 2001
).
Fusion
UNC-18 could also function in fusion. First, UNC-18 binds to syntaxin, a
putative fusion mediator. Second, in Munc18-1-null mice, fusion events are
undetectable at central synapses (Verhage
et al., 2000). Third, overexpression of altered Munc18-1 protein
in chromaffin cells alters the dynamics of the fusion pore in single-granule
exocytosis (Fisher et al.,
2001
); however, overexpression of wild-type Munc18-1 had no effect
on fusion. How UNC-18 might regulate fusion remains elusive (see below).
SNARE recycling
Overexpression of UNC-18 in Drosophila inhibits neurotransmitter
release in a syntaxin-dependent manner
(Schulze et al., 1994;
Wu et al., 1998
;
Wu et al., 2001
), which
suggests that UNC-18-syntaxin interactions inhibit rather than promote
exocytosis. Although originally proposed to regulate the priming step, a
possible role for the UNC-18 inhibitory activity is to retain syntaxin in the
plasma membrane during recycling of vesicle components. Upon fusion,
trans-SNARE complexes are converted into cis-SNARE complexes, which are
disassembled by the ATPase NSF
(N-ethylmaleimide-sensitive factor)
(Wilson et al., 1992
;
Sollner et al., 1993a
;
Littleton et al., 1998
). After
disassembly, UNC-18 binding to `closed' syntaxin might inhibit errant
cis-SNARE complex formation before synaptobrevin is removed from the plasma
membrane. Consistent with this hypothesis, UNC-18 is capable of inhibiting
SNARE complex formation in vitro (Pevsner
et al., 1994a
) and syntaxin levels are reduced in Munc18-1-null
mice (Voets et al., 2001
),
which might be due to degradation of aberrant cis-SNARE complexes.
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Rab3 |
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Docking
Synaptic vesicles fail to cluster near release sites in C. elegans
and mouse Rab3 mutants (Nonet et al.,
1997; Leenders et al.,
2001
), and overexpression of Rab3 in PC12 cells increases the
number of docked granules (Martelli et
al., 2000
). The yeast Rab3 homolog Ypt7p interacts with a complex
containing the UNC-18 homolog Vps33p, and another yeast Rab3 homolog, Ypt1p,
interacts genetically with the UNC-18 homolog Sly1p (certain Sly1 mutations
bypass loss of Ypt1p) (Ossig et al.,
1991
). Thus, Rab3 might act via UNC-18 to promote docking.
Priming
Rab3 interacts with several synaptic proteins, including the active zone
protein Rim (Rab3-interacting molecule)
(Wang et al., 1997), which in
turn interacts with UNC-13 (Betz et al.,
2001
) - a syntaxin-binding protein
(Betz et al., 1997
). Both Rim
and UNC-13 are required for the priming of synaptic vesicles for exocytosis in
mice (Brose et al., 2000
;
Schoch et al., 2002
;
Varoqueaux et al., 2002
),
Drosophila (Aravamudan et al.,
1999
) and C. elegans
(Koushika et al., 2001
;
Richmond et al., 1999
).
Moreover, UNC-13 and Rim appear to function at the priming step to promote or
stabilize the open state of syntaxin
(Koushika et al., 2001
;
Richmond et al., 2001
). Rab3
may play a role in this priming pathway by signaling the arrival of a docked
synaptic vesicle to the Rim-UNC-13 priming complex.
Fusion
Rab3A-null mice exhibit high levels of neurotransmitter release during
neuronal excitation even though the size of the readily releasable pool of
vesicles and the calcium-dependence of release is unaffected
(Geppert et al., 1994a). Rab3A
may thus act as an inhibitor of fusion, perhaps to coordinate release.
Consistent with such a role, overexpression of Rab3A in PC12 cells causes
constitutive fusion of secretory vesicles
(Schluter et al., 2002
).
However, the molecular mechanism by which Rab3 may regulate fusion is obscure.
Perhaps, as the yeast genetic data suggest, Rab3 acts via UNC-18. Such an
interaction could link Rab3 signaling to the fusion machinery, specifically
syntaxin.
Nothing at all
An ugly fact confronting those trying to develop models for Rab3 function
is that elimination of Rab3 has an extremely mild phenotype in both mice and
worms (Geppert et al., 1994a;
Nonet et al., 1997
). We might
have to confront the possibility that the important functions supplied by Rab
proteins in other fusion events have been appropriated by other proteins in
synaptic vesicle fusion. Rab3 may be a vestigial component of the synaptic
vesicle cycle.
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V-ATPase |
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Loading
Neurotransmitters are concentrated into synaptic vesicles by transporters
that use the electrochemical gradient between the vesicle lumen and the
cytoplasm to drive neurotransmitter loading (reviewed by
Schuldiner et al., 1995).
Inhibition of V-ATPase activity in vitro blocks neurotransmitter transport
into vesicles (Anderson et al.,
1982
; Hell et al.,
1990
; Moriyama et al.,
1990
). Thus, V-ATPase activity is probably required in vivo to
generate the driving force for vesicle loading.
Docking/priming
Neurotransmitter release is quantal: the amount of neurotransmitter
released in every fusion event is constant. Thus, there might be a mechanism
to prevent the fusion of partially filled vesicles. In yeast, V-ATPase
activity is required for the formation of trans-SNARE complexes and thus
membrane fusion (Ungermann et al.,
1999). A similar requirement at the synapse might provide a
checkpoint to ensure that only vesicles fully loaded with neurotransmitter are
docked or primed. However, blocking of the V-ATPase by bafilomycin does not
block synaptic vesicle release suggesting that such a checkpoint may not exist
(Zhou et al., 2000
).
Fusion
Recent data suggest that vesicle acidification may not be the only function
for the V-ATPase in synaptic vesicle exocytosis. Specifically, trans-V0
complexes assemble in a SNARE-dependent manner between yeast vacuolar
membranes destined to fuse, which suggests a late role for the V0 complex in
membrane fusion (Peters et al.,
2001). Such a complex could catalyze lipid mixing during fusion or
act as an aqueous pore for the release of neurotransmitter without the
complete mixing of vesicular and plasma membranes.
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Synaptotagmin |
---|
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Docking
Synapses in Drosophila lacking synaptotagmin contain fewer
morphologically docked synaptic vesicles per release site
(Reist et al., 1998), which
suggests that synaptotagmin promotes vesicle docking. Synaptotagmin binds
syntaxin (Chapman et al.,
1995
), SNAP-25 (Schiavo et
al., 1997
), calcium channels
(Kim and Catterall, 1997
;
Sheng et al., 1997
) and lipids
(Brose et al., 1992
;
Davletov and Sudhof, 1993
;
Zhang et al., 1998
); perhaps
these interactions link vesicles to the plasma membrane during docking.
Alternatively, the reduced number of docked vesicles in Drosophila
synaptotagmin mutants could be a secondary phenotype due to a requirement for
synaptotagmin in vesicle recycling (see below).
Calcium sensing
Synaptotagmin binds calcium via its C2 domains with an affinity that
corresponds to the calcium threshold for synaptic vesicle exocytosis
(Brose et al., 1992;
Heidelberger et al., 1994
;
Davis et al., 1999
).
Synaptotagmin might therefore function as the calcium sensor. Consistent with
this hypothesis, synaptotagimin-I-knockout mice lack the fast
calcium-dependent phase of neurotransmitter release even though wild-type
levels of vesicles are docked at the membrane
(Geppert et al., 1994b
).
Calcium binding to synaptotagmin might affect the SNARE complex, either
positively or negatively, since synaptotagmin binds the SNARE complexes near
the transmembrane domains of syntaxin and synaptobrevin
(Brose et al., 1992
;
Ernst and Brunger, 2003
;
Kee and Scheller, 1996
;
Pevsner et al., 1994a
;
Schiavo et al., 1997
;
Wu et al., 1999
).
Alternatively, recent data suggest that synaptotagmin functions as a calcium
sensor independently of SNARE complex interactions
(Shin et al., 2003
). Because
synaptotagmin binds to lipids in a calcium-dependent manner
(Brose et al., 1992
;
Davletov and Sudhof, 1993
;
Zhang et al., 1998
), it might
directly promote vesicle fusion.
Recycling
Synaptotagmin also seems to be required for the recycling of synaptic
vesicle components. Ultrastructural analysis of synaptotagmin-null mutants in
Drosophila and C. elegans indicate that their synaptic
varicosities are depleted of synaptic vesicles
(Jorgensen et al., 1995;
Reist et al., 1998
;
Littleton et al., 2001
) - a
phenotype characteristic of a defect in endocytosis. In addition,
synaptotagmin is known to bind proteins involved in clathrin-mediated
endocytosis, specifically the
and µ subunits of the clathrin
adaptor complex AP-2 (Zhang et al.,
1994
; Haucke and De Camilli,
1999
; Haucke et al.,
2000
). Thus, synaptotagmin may play dual roles to both promote
synaptic vesicle exocytosis and endocytosis.
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Future directions |
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Acknowledgments |
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