Abstract
The paradigm for soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) function in mammalian cells has been built on advancements in our understanding of structural and biochemical aspects of synaptic vesicle exocytosis, involving specifically synaptobrevin, syntaxin 1 and SNAP25. Interestingly, a good number of SNAREs which are not directly involved in neurotransmitter exocytosis, are either brain-enriched or have distinct neuron-specific functions. Syntaxins 12/13 regulates glutamate receptor recycling via its interaction with neuron-enriched endosomal protein of 21 kDa (NEEP21). TI-VAMP/VAMP7 is essential for neuronal morphogenesis and mediates the vesicular transport processes underlying neurite outgrowth. Ykt6 is highly enriched in the cerebral cortex and hippocampus and is targeted to a novel compartment in neurons. Syntaxin 16 has a moderate expression level in many tissues, but is rather enriched in the brain. Here, we review and discuss the neuron-specific physiology and possible pathology of these and other (such as SNAP-29 and Vti1a-β) members of the SNARE family.
Introduction
Soluble N-ethylmaleimide sensitive factor (NSF) attachment protein (SNAP) receptor (SNARE)-mediated membrane fusion mechanisms are evolutionarily conserved in both the exocytic and endocytic pathways of eukaryotes Citation[1], Citation[2] (see also Citation[3], Citation[4] for a more recent overview). SNAREs that are first biochemically characterized as membrane “receptors” for SNAP are those found at neuronal synapses, and which mediate synaptic vesicle fusion with the presynaptic plasma membrane Citation[5], Citation[6]. This SNARE complex responsible for synaptic vesicle exocytosis is also the first mammalian SNARE complex whose structure was revealed by X-ray crystallography Citation[7–9]. SNAREs form functional complexes in trans (i.e., between vesicle and target membranes), and the core of this structure is a four-helical bundle consisting of coiled-coil SNARE domains Citation[10] contributed by each participating SNARE from the two membranes.
The mechanism of SNARE actions during synaptic vesicle fusion is perhaps the best characterized amongst the many SNARE-mediated fusion steps in the mammalian cell. Studies of these SNAREs had been aided by the availability of proteolytic reagents, in the form of bacterial neurotoxins, which very specifically cleave synaptic SNAREs Citation[11], Citation[12]. In the final steps of synaptic vesicle exocytosis, trans-pairing occurs between synaptobrevin/VAMP 1 or 2 on synaptic vesicles and syntaxin-SNAP25 on presynaptic membrane. Completion of the trans SNARE complex formation, triggered by a Ca2 + signal, is akin to a “zippering” process that physically forces the synaptic vesicle membrane and the presynaptic membrane into contact. Interestingly, this contact need not result in complete fusion. Hemifusions and fusions that are apparently reversible could occur, with neurotransmitter molecules nonetheless released via a “kiss and run” mode Citation[13], Citation[14]. The mechanistic and regulatory aspects of synaptic vesicle exocytosis had been the subject of recent excellent, authoritative reviews Citation[15–17], and will not be elaborated at length here.
Many SNAREs mediate cellular transport processes that are essential for cell survival, and are expressed in all cell types. However, some SNAREs may have non-essential, or redundant, functions. Mice with targeted gene disruption of cellubrevin/VAMP3 Citation[18], for example, are viable and fertile. Mice with their Vti1b knockout mice are likewise viable, except for some minor abnormalities with low penetrance Citation[19]. This is in stark contrast to the embryonic lethality exhibited by syntaxin 4 knockouts Citation[20]. Still other SNAREs may have tissue/organ specific functions. An illustration of this is that targeted deletion of endobrevin/VAMP8 resulted in viable mice with pancreatic defects, and impaired exocytosis in pancreatic acinar cells Citation[21]. Mice with a homozygous synaptobrevin 2/VAMP2 deletion die immediately after birth, with their embryonic hippocampal neurons exhibiting 100 fold less Ca2 + -triggered synaptic vesicle fusion events compared to wild type mice Citation[22]. Interestingly, other than the three SNAREs directly involved in neurotransmitter exocytosis, a number of other members of the SNARE family are also enriched in brain neurons. Some of these SNAREs have recognized neuronal specific roles other than their regular cellular functions in non-neuronal cells. We discuss below recent advances in the elucidation of the neuronal roles of SNAREs such as syntaxin 12/13 and VAMP7/TI-VAMP, as well as other SNAREs (listed in ) that have been implicated to have specific localization or function in neurons.
Table I. Brain-enriched SNAREs and their known functions.
Other SNAREs implicated in the synaptic vesicle cycle
There is no doubt that isoforms of syntaxin 1A/B, VAMP 1/2 and SNAP25 are essential for synaptic vesicle fusion to the presynaptic plasma membrane per se. However, other members of the SNARE family may modulate this fusion process. Furthermore, the steps of the synaptic vesicle cycle other than fusion with the presynaptic plasma membrane may also involve SNAREs. One SNARE molecule that has been shown to participate in an indirect manner in synaptic vesicle exocytosis is SNAP29, a member of the SNAP23/25/29 subfamily which has a rather ubiquitous expression pattern and appears to bind promiscuously to several syntaxins Citation[23]. SNAP29 can be found in the presynaptic compartment, associated with synaptic vesicles and could be co-immunoprecipitated with syntaxin 1. Microinjection of recombinant SNAP29 protein into the presynaptic compartment of superior cervical ganglion neurons in culture inhibited synaptic transmission in an activity-dependent manner Citation[24]. This mode of inhibition is interesting because inhibition of synaptic transmission in the same system by SNAP25 peptides is activity-independent, which suggests that SNAP29 does not function as a direct competitor with SNAP25 for SNARE complex assembly. Exogenous over-expression of EGFP-tagged SNAP29 perturbed neither the density of synapse or basal synaptic transmission, but significantly decreased the efficiency of synaptic transmission (as indicated by post-synaptic current amplitudes) generated by low and moderate frequency (0.1–1 Hz) stimulations Citation[25]. Neurotransmitter release was unaffected by SNAP29 over-expression during intensive stimulation, but recovery after synaptic depression was attenuated. Knockdown of endogenous SNAP29 expression in neurons by small interfering RNA (siRNA) increased the efficiency of synaptic transmission during repetitive firing. SNAP29 may therefore act as a negative modulator for neurotransmitter release, perhaps not directly affecting trans-SNARE complex formation, but probably by slowing down the recycling of the SNAREs in some way after fusion and synaptic vesicle turnover.
The Golgi-localized Vti1a/Vti1-rp2 Citation[26], Citation[27] has been proposed to function in intra-Golgi traffic in mammalian cells Citation[28]. There exists a brain-specific splice isoform of Vti1a, designated Vti1a-β, which has an extra stretch of seven amino acid residues found next to the putative SNARE domain. Vti1a-β is enriched in synaptic vesicles and clathrin-coated vesicles isolated from nerve termini, and is part of an NSF and α-SNAP containing SNARE complex at synapses Citation[26]. However, it is not found in the same SNARE complex as the exocytic SNAREs, and does not coimmunoprecipitate syntaxin 1 or SNAP-25. Vti1a-β may therefore have no direct function in exocytosis, but might act (in a separate SNARE complex) in a membrane fusion step during recycling or biogenesis of synaptic vesicles.
Syntaxin 12/13, NEEP21 and glutamate receptor recycling
Syntaxin 12/13 are orthologues of the same gene (syntaxin 12 – rat; syntaxin 13 – human) whose product is localized to the endosomes Citation[29–31]. It is the first SNARE demonstrated to interact directly with a tethering factor (the early endosome autoantigen 1, EEA1) in an endosomal fusion complex that contains Rab5 effectors Citation[32]. Syntaxin 12/13 is enriched in the brain, and endogenous neuronal syntaxin 12/13 localizes to transferrin receptor-containing, brefeldin A-sensitive, tubulovesicular organelles that are present in both somatodendritic and axonal domains Citation[33]. Live cell imaging with a syntaxin 13-GFP fusion protein transiently expressed in hippocampal neurons revealed the existence of distinct stationary structures and highly mobile tubulovesicular structures. The mobile structures appear to fuse with and bud from the stationary endosomes, and the latter travels in both directions along microtubules in dendrites and axons. The expression of syntaxin 12/13 in the rodent CNS is developmentally regulated Citation[34], Citation[35]. Interestingly, its over-expression enhanced neurite outgrowth in NGF-stimulated PC12 cells, but had no effect on regulated secretion Citation[34].
Syntaxin 12/13's presence in the recycling endosomes of the neuron suggests that, other than mediating endosomal recycling of molecules such as the transferrin receptor, it may also have a role in modulating the dynamics of neurotransmitter receptors. Indeed, Hirling's laboratory had shown that syntaxin 12/13 interacts with an endosomal protein known simply as neuron-enriched endosomal protein of 21 kDa (NEEP21) Citation[36]. NEEP21 over-expression accelerates transferrin internalization and recycling, and its down-regulation by an anti-sense construct delays transferrin recycling. In primary hippocampal neurons, NEEP21 is localized to the somatodendritic compartment, and its colocalization with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor subunit GluR2 could be modulated by glutamate receptor agonists. Importantly, down-regulation of NEEP21 by an anti-sense construct appears to retard recycling of both AMPA receptor subunits GluR1 and GluR2 to the plasma membrane upon agonist stimulations, albeit with different kinetics of retardation.
In another study, NEEP21 suppression, or the expression of a dominant-negative NEEP21 fragment, reduced spontaneous and evoked AMPA receptor-mediated synaptic currents – an effect that appears to have specifically resulted from a reduction of currents mediated by AMPA, and not the N-methyl-D-Aspartate (NMDA) receptors. The induction of long-term potentiation (LTP) was also abolished in NEEP21-depleted cells or cells expressing the dominant-negative fragment. Citation[37]. A recent report by Hirling and colleagues had revealed by co-immunoprecipitation analysis that syntaxin 12/13-NEEP21 is associated with both GluR2 and the Glutamate Receptor Interacting Protein 1 (GRIP1) Citation[38]. The latter is known to play important roles in trafficking, synaptic targeting, and recycling of AMPA receptors as well as in the plasticity of glutamatergic synapses Citation[39], Citation[40]. The interaction between NEEP21 and GRIP1 is regulated by neuronal activity. Over-expression of a NEEP21 fragment containing the GRIP1-binding site decreases cell surface GluR2 levels, and delays recycling of internalized GluR2. Furthermore, infusion of a peptide corresponding to this fragment into hippocampal slices induces inward rectification of AMPA receptor-mediated excitatory postsynaptic current (EPSC). This EPSC feature is characteristic of AMPA receptors (which could either be homomeric or heteromeric complexes) lacking the GluR2 subunit. Syntaxin12/13-NEEP21-GRIP1 binding is therefore apparently important for GluR2 sorting through endosomes and also its appearance at the plasma membrane.
TI-VAMP and neuronal morphogenesis
Tetanus neurotoxin (TeNT)-insensitive VAMP (TI-VAMP, or VAMP7), was first identified within a SNARE complex (which also include syntaxin 3 and SNAP23) at the apical plasma membrane of epithelial cells Citation[41]. TI-VAMP is one of three evolutionarily conserved R-SNAREs (the other two being Sec22 and Ykt6 (which is discussed below)) with a N-terminal profilin-like motif known as the longin domain Citation[42]. As membrane trafficking associated with neurite outgrowth is analogous to polarized epithelial surface transport, and is also tetanus toxin insensitive, it follows that TI-VAMP may have a role in mediating neurite outgrowth in the developing brain. Galli's laboratory first showed that TI-VAMP is expressed widely in the adult rat brain, but its localization differs from that of synaptic SNAREs Citation[43]. It is not enriched in either synaptic vesicles or large dense-core granules, but is found in vesicles and tubules in neurites and is particularly concentrated at the leading edge of the neuronal growth cone. In matured neurons, TI-VAMP/VAMP7 is found predominantly in the somatodendritic domain. Subsequent work with another specific antibody against TI-VAMP have however revealed its presence in a subset of presynaptic termini, colocalizing with synaptophysin and labeling synaptic vesicles of neurons such as the hippocampal mossy fibres Citation[44].
Functional evidence for a direct role for TI-VAMP in neurite outgrowth was obtained when it was shown that the N-terminal longin domain of the SNARE molecule functions as a dominant negative reagent that inhibits neuritogenesis of PC12 cells in culture. Conversely, a mutant TI-VAMP with the longin domain deleted enhanced neurite outgrowth Citation[45]. Furthermore, both the dominant negative and dominant positive mutants have similar neurite outgrowth modulating actions on the axon and dendrites of primary hippocampal neurons Citation[46]. siRNA-mediated knockdown of TI-VAMP in both PC12 and hippocampal neurons also impaired neurite outgrowth.
The cargoes transported in TI-VAMP containing vesicles are not exhaustively known. Interestingly, one of these turns out to be the neuronal cell adhesion molecule L1 Citation[47], which had long been implicated in neurite outgrowth Citation[48]. L1 and TI-VAMP have overlapping expression patterns in the growing axon tracks of embryonic rodent brain, and colocalized in intracellular membranous structures in cultured neurons. siRNA-mediated knockdown of TI-VAMP expression resulted in reduced expression of L1 at the neuronal plasma membrane, and also led to impaired L1-mediated, but not N-cadherin-mediated cell adhesion. It was shown that TI-VAMP-mediated intracellular trafficking is essential for L1-dependent adhesive contacts, while L1-dependent adhesive contacts induced clustering of TI-VAMP-positive vesicles in neuronal growth cones. Neuronal growth cone morphology is modulated by dynamic changes in the actin cytoskeleton, and TI-VAMP-positive vesicles are found concentrated in the peripheral region of cultured hippocampal neurons growth cones that are enriched in F-actin Citation[49]. L1 stimulation of actin remodeling induces a site-directed and actin-dependent recruitment of TI-VAMP-positive structures. A dominant-positive mutant of Cdc42, one of the small GTPase of the Rho family which modulates cellular actin dynamics Citation[50], could stimulate the formation of TI-VAMP-enriched filopodia structures outside the growth cone. These findings illustrate important cross talks between several fundamental processes in neuronal development and axonal pathfinding, namely TI-VAMP mediated membrane trafficking, actin cytoskeleton remodeling and cell-cell adhesion.
The exact SNAREs which are required for membrane trafficking in neurite outgrowth is not clear. The exocytotic SNAREs themselves have been implicated in mediating neurite outgrowth, but results are not particularly consistent and analyses were limited to PC12 cells Citation[51–53]. TI-VAMP is capable of co-immunoprecipitating a plethora of other SNAREs (including syntaxins 1, 3, 4, 6, 7, 8 10, SNAP23, SNAP25, SNAP29 as well as Vti1b), although it is unclear which formed the in vivo TI-VAMP-containing SNARE complex that is specifically needed for mediating neurite outgrowth. Some of these are undoubtedly associated with the late-endosome-lysosome function, rather than the neurite outgrowth role, of TI-VAMP. An in vivo assay system, for example, hippocampal neurons prepared from mice with a EGFP-tagged TI-VAMP transgene, may be useful in resolving exactly which of these function in tandem with TI-VAMP in mediating neurite outgrowth. It would allow imaging of TI-VAMP-mediated transport, coupled to retrovirally transduced siRNA-mediated knockdown of individual cognate SNARE partners. The extent of TI-VAMP function in mature neurons is not particularly clear. If it has a role in constitutive transport to neuronal surfaces, TI-VAMP containing vesicle movements would presumably utilize microtubule associated motors and adaptors. A linker molecule known as syntabulin functions to attach syntaxin1-containing cargo vesicles to kinesin I, thus enabling axonal transport of syntaxin-1 Citation[54]. Identification of similar linker and motor transport mechanism for TI-VAMP would be of great interest.
Where and what is Ykt6 doing in the neuron?
Ykt6 is a multifunctional, evolutionarily conserved SNARE that was first implicated as an essential gene in yeast ER-Golgi transport Citation[55]. It was subsequently shown to be present in two mammalian Golgi-associated SNARE complexes Citation[56], Citation[57], an important component for yeast vacuole homotypic fusion Citation[58], as well as having a trans-Golgi network function in Arabidopsis Citation[59]. Ykt6 is structurally distinct from other R-SNAREs in that it lacks a C-terminal hydrophobic anchor, but has instead a prenylation motif at the C-terminus. The molecule can be both farnesylated as well as palmitoylated. Membrane association of Ykt6 in non-neuronal cells like HeLa is apparently mediated by both farnesylation and palmitoylation Citation[60]. Interestingly, Ykt6 appears to have a role in mediating the palmitoylation of other proteins Citation[61] as well as itself, the latter by what appears to be an autocatalytic activity associated with the N-terminus of Ykt6 Citation[62].
Another critical determinant of the conformation and cellular localization of Ykt6 is its N-terminal longin domain Citation[63]. The longin domain of Ykt6 could fold back and interact with its SNARE domain. Such a “closed” conformation is the functionally inactive form of Ykt6 in HeLa cells, and is cytosolic. A surprising fact about Ykt6 is that it is highly enriched in brain neurons, with only low levels of expression in other tissues. In NRK cells, immunofluorescence microscopy indicated that Ykt6 is localized to the Golgi apparatus Citation[56]. However, in neuronal and neuroendocrine cell lines such as PC12, membrane-associated Ykt6 is found in punctate and rather symmetrically distributed vesicular structures that are not cytoskeleton-associated, and presumably membranous. This Ykt6 staining pattern did not colocalize significantly with any conventional markers of the secretory and endocytic pathway, and has only very minor overlaps with lysosomes and dense-core secretory granules (although density gradient centrifugation indicated that these have a buoyant density close to that of lysosomes). Prenylation of Ykt6 is apparently required for membrane anchorage in neuronal cells, but even soluble forms of neuronal Ykt6 partition into Triton X 114, and these are therefore likely to be prenylated.
The longin domain of Ykt6 is both necessary and sufficient to confer association with these unidentified neuronal structures, and association occurs even for prenylation-deficient mutants. More detailed analyses revealed that the overall tertiary structure of the longin domain is important for targeting to the Ykt6-positive punctate structures Citation[64]. The longin domain is capable of intramolecular interactions with both the SNARE domain and the lipid moiety, and both protein-protein and protein-lipid interactions are required for a tightly closed conformation and correct targeting into the morphologically unique neuronal compartment. The intramolecular interactions of Ykt6 therefore result in a compact, closed conformation that prevents promiscuous targeting and insertion into membranes.
Both the nature and composition of the Ykt6 positive structures in neuronal cells are currently unclear. The discrepancy between the Golgi staining observed in NRK cells Citation[56] and the punctate staining in neuronal cells Citation[63] could be due to different epitope specificities of the respective antibodies to different pools of Ykt6 in the cell, where different SNARE partner associations may have resulted in the differential epitope exposure. One support for the above notion is the fact that the latter antibody does not appear to stain the Golgi or the ER-Golgi boundary of neurons, which is where Ykt6 is known to function in other cell types. Alternatively, the punctate structures are indeed neuronal specific compartments, although it is unclear at the moment what their functions are. Ultrastructural analysis and biochemical characterization of these structures immunopurified using Ykt6 antibodies should reveal more about this compartment in due course.
SNAREs and CNS pathology
Some of the neuronal-enriched SNAREs discussed above have been implicated directly and indirectly in neuropathological disorders. Promoter region polymorphism of SNAP29 has been associated with Schizophrenia Citation[65], Citation[66]. More recently, the mutant gene associated with a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (the CEDNIK syndrome) has been localized to chromosome 22q11.2. In all patients, a single nucleotide deletion in the SNAP29 gene has been identified Citation[67]. The gene encoding TI-VAMP, identified previously as SYBL1, a pseudoautosomal region gene in chromosome X that could undergo X-inactivation Citation[68], have been associated by linkage analysis with bipolar disorders Citation[69], Citation[70].
No SNARE mutation that confers susceptibility to or early onset of neurodegenerative disorders has been identified. However, it is clear that symptoms of several neurodegenerative disorders such as Huntington's disease and amyotrophic lateral sclerosis (ALS) could be direct consequences of impaired neuronal trafficking of particular proteins. Some indirect links between SNAREs and neurodegenerative diseases had recently emerged. α-synuclein, whose dominant negative mutations causes juvenile onset Parkinsonism Citation[71], appears to cooperate in some manner with another presynaptic protein, the cysteine-string protein-α (CSPα), in chaperoning the folding and refolding of synaptic SNAREs Citation[72]. Impaired synaptic SNARE function may therefore underlie neurological symptoms associated with α-synucleinopathies. Syntaxin 5, a SNARE important in ER-Golgi transport and also implicated in TGN function, appears to interact with the presenilin holoprotein and could modulate amyloid precursor protein processing and amyloid-β secretion Citation[73], Citation[74].
Concluding remarks
Neurons have an immensely large and complex polarized plasma membrane. The enormous complexity and the distances between the synaptic termini and the cell body necessitate specific structural and functional adaptation of the neuronal exocytic and endocytic apparatus Citation[75–77]. The Golgi apparatus found in the dendritic network of a neuron (numbering up to tens of thousands), for example, appear to be discrete compartments that are discontinuous with the somatic Golgi at the cell body. In view of this complexity, it is therefore not surprising that certain SNAREs, or neuronal specific isoforms of ubiquitously distributed ones, are specifically enriched in the brain and perform functions during and post-development. Other than those directly involved in the central mechanism of neurotransmitter release at chemical synapses, the function of some other brain-enriched SNAREs are gradually coming to light. What is currently known is described above. However, much remains to be explored. The reason for brain-enrichment of the TGN SNARE syntaxin 16 Citation[78], Citation[79], for example, is completely unclear at the moment, although it might be conveniently speculated that it has a role in the dendritic Golgi outposts. The ability to specifically knockdown SNARE expression with RNA interference has greatly complemented cellular studies based on the older approach of over-expressing dominant-negative SNARE domains or soluble forms of SNAREs. With the development of high-speed live imaging techniques and abilities for spatially and temporally regulated functional ablation of genes in neurons, the coming years hold good promise in furthering our understanding of neuronal protein traffic.
Work on SNAREs in BLT's laboratory is supported by a grant (R-183-000-106-112) from the Academic Staff Research Fund, National University of Singapore.
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