Assembling the Presynaptic Active Zone

Zhai, R. Grace; Vardinon-Friedman, Hagit; Cases-Langhoff, C; Becker, Birgit; Gundelfinger, Eckart D.; Ziv, Noam; Garner, Craig C.

doi:10.1016/s0896-6273(01)00185-4

Cited by 380 publications

(158 citation statements)

References 46 publications

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“…The question arises whether the ubiquitous and active zone-specific functions of ERCs are connected. Such a connection is supported by the assembly of active zone components from precursor vesicles (34,35) that may be generated in the Golgi complex by a Rab6-dependent process, which in turn could require ERC binding to Rab6. Furthermore, at least in neurons Rab6 may participate in a post-Golgi trafficking function (36), which could involve an interaction with ERCs.…”

Section: Discussionmentioning

confidence: 99%

A family of RIM-binding proteins regulated by alternative splicing: Implications for the genesis of synaptic active zones

Wang

Liu

Biederer

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

233

276

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RIMs are presynaptic active zone proteins that regulate neurotransmitter release. We describe two related genes that encode proteins with identical C-terminal sequences that bind to the conserved PDZ domain of RIMs via an unusual PDZ-binding motif. These proteins were previously reported separately as ELKS, Rab6-interacting protein 2, and CAST, leading us to refer to them by the acronym ERC. Alternative splicing of the C terminus of ERC1 generates a longer ERC1a variant that does not bind to RIMs and a shorter ERC1b variant that binds to RIMs, whereas the C terminus of ERC2 is synthesized only in a single RIM-binding variant. ERC1a is expressed ubiquitously as a cytosolic protein outside of brain; ERC1b is detectable only in brain, where it is both a cytosolic protein and an insoluble active zone component; and ERC2 is brain-specific but exclusively localized to active zones. Only brainspecific ERCs bind to RIMs, but both ubiquitous and brain-specific ERCs bind to Rab6, a GTP-binding protein involved in membrane traffic at the Golgi complex. ERC1a and ERC1b͞2 likely perform similar functions at distinct localizations, indicating unexpected connections between nonneuronal membrane traffic at the Golgi complex executed via Rab6 and neuronal membrane traffic at the active zone executed via RIMs. R IM1␣ and -2␣ are multidomain adaptor proteins that were discovered as putative effectors for Rab3, a synaptic vesicle protein that binds GTP and regulates neurotransmitter release (1-4). RIMs are composed of an N-terminal Zn 2ϩ -finger domain, a central PDZ domain, and C-terminal C 2 A and C 2 B domains (3, 4). The binding of RIMs to Rab3 and the localization of RIM1␣ to presynaptic active zones suggested a function in neurotransmitter release, which was confirmed by genetic experiments in Caenorhabditis elegans and mice (5-7). Deletion of RIM1␣ in mice caused distinct phenotypes in different types of synapses. In excitatory synapses capable of N-methyl-Daspartate (NMDA)-dependent long-term potentiation (e.g., Schaffer collateral͞commissural fiber synapses in the CA1 region of the hippocampus) and in inhibitory synapses, deletion of RIM1␣ decreased the neurotransmitter release probability in response to Ca 2ϩ influx, leading to a decline in synaptic transmission and changes in short-term synaptic plasticity (6). In excitatory synapses that lack NMDA-dependent long-term potentiations but experience protein kinase A-dependent longterm potentiation (e.g., mossy fiber synapses in the CA3 region of the hippocampus), deletion of RIM1␣ had no detectable effect on acute neurotransmitter release but prevented protein kinase A-dependent potentiation (7). Although these results confirmed an important role for RIM1␣ and, by extension, RIM2␣, in presynaptic function, the spectrum of mutant phenotypes suggests that this role is incompletely understood.It is likely that RIMs regulate release by interacting with other proteins. Several binding partners were identified. The Nterminal Zn 2ϩ -finger domain of RIM1␣ directly binds to Rab3 [w...

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Section: Discussionmentioning

confidence: 99%

A family of RIM-binding proteins regulated by alternative splicing: Implications for the genesis of synaptic active zones

Wang

Liu

Biederer

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

233

276

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“…S ynapse formation involves stabilization of initial sites of contact between axons and dendrites, followed by recruitment of specific protein complexes to newly formed presynaptic and postsynaptic structures (1)(2)(3)(4). Neuronal contact formation is spatially and temporally controlled by changes in protein content and shape at areas of contact (5,6).…”

mentioning

confidence: 99%

A balance between excitatory and inhibitory synapses is controlled by PSD-95 and neuroligin

Prange

Wong

Gerrow

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

336

342

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Factors that control differentiation of presynaptic and postsynaptic elements into excitatory or inhibitory synapses are poorly defined. Here we show that the postsynaptic density (PSD) proteins PSD-95 and neuroligin-1 (NLG) are critical for dictating the ratio of excitatory-to-inhibitory synaptic contacts. Exogenous NLG increased both excitatory and inhibitory presynaptic contacts and the frequency of miniature excitatory and inhibitory synaptic currents. In contrast, PSD-95 overexpression enhanced excitatory synapse size and miniature frequency, but reduced the number of inhibitory synaptic contacts. Introduction of PSD-95 with NLG augmented synaptic clustering of NLG and abolished NLG effects on inhibitory synapses. Interfering with endogenous PSD-95 expression alone was sufficient to reduce the ratio of excitatory-to-inhibitory synapses. These findings elucidate a mechanism by which the amounts of specific elements critical for synapse formation control the ratio of excitatory-to-inhibitory synaptic input.S ynapse formation involves stabilization of initial sites of contact between axons and dendrites, followed by recruitment of specific protein complexes to newly formed presynaptic and postsynaptic structures (1-4). Neuronal contact formation is spatially and temporally controlled by changes in protein content and shape at areas of contact (5, 6). The total number of synapses formed and ratio of excitatory-to-inhibitory synaptic inputs a neuron receives are factors critical for determining neuronal excitability. Appropriate synthesis and recruitment of specific factors important for building synaptic contacts are thought to power this process. However, the identity of molecules that dictate the balance between excitatory and inhibitory synaptic contacts remains elusive. Several lines of evidence indicate that the scaffolding postsynaptic density (PSD) protein, PSD-95, is involved in orchestrating excitatory synapse maturation and specificity (7). PSD-95 is exclusively localized to glutamatergic synapses (8). Moreover, PSD-95 expression correlates with the period of excitatory synapse maturation (7, 9-11). Augmentation of excitatory synapse activity and ion channel clustering is driven by PSD-95 but not by related proteins, including synapse-associated protein (SAP)-102 and , and PSD-95 regulates clustering and activity of the ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors through a direct interaction with stargazin (7,(13)(14)(15)(16)(17)(18)(19)(20). However, it is unknown how PSD-95 effects are translated into changes in apposing presynaptic terminals. A candidate molecule for mediating PSD-95 effects on presynaptic maturation is the cell adhesion molecule neuroligin (NLG). NLG is present at excitatory postsynaptic sites and associates with the third PSD-95͞Dlg͞ZO-1 homology (PDZ) domain of PSD-95 through its C-terminal PDZ-binding site (2,21,22).The postsynaptic PDZ protein S-SCAM, another known binding partner of NLG, is also possibly involved in modulating NLG effects on ...

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“…These include dense-core granulated vesicles transporting the presynaptic active zone components Piccolo and Bassoon to nascent synapses (8) and retrograde signaling endosomes (9 -11). The observation that both endosomal markers Rab5 (10) and Rab7 (11) contribute to retrograde axonal transport of neurotrophins indicates that both early and late endosomes regulate neurotrophin signaling.…”

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confidence: 99%

Sunday Driver Interacts with Two Distinct Classes of Axonal Organelles

Abe

Almenar-Queralt

Lillo

et al. 2009

Journal of Biological Chemistry

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The extreme polarized morphology of neurons poses a challenging problem for intracellular trafficking pathways. The distant synaptic terminals must communicate via axonal transport with the cell soma for neuronal survival, function, and repair. Multiple classes of organelles transported along axons may establish and maintain the polarized morphology of neurons, as well as control signaling and neuronal responses to extracellular cues such as neurotrophic or stress factors. We reported previously that the motorbinding protein Sunday Driver (syd), also known as JIP3 or JSAP1, links vesicular axonal transport to injury signaling. To better understand syd function in axonal transport and in the response of neurons to injury, we developed a purification strategy based on anti-syd antibodies conjugated to magnetic beads to identify sydassociated axonal vesicles. Electron microscopy analyses revealed two classes of syd-associated vesicles of distinct morphology. To identify the molecular anatomy of syd vesicles, we determined their protein composition by mass spectrometry. Gene Ontology analyses of each vesicle protein content revealed their unique identity and indicated that one class of syd vesicles belongs to the endocytic pathway, whereas another may belong to an anterogradely transported vesicle pool. To validate these findings, we examined the transport and localization of components of syd vesicles within axons of mouse sciatic nerve. Together, our results lead us to propose that endocytic syd vesicles function in part to carry injury signals back to the cell body, whereas anterograde syd vesicles may play a role in axonal outgrowth and guidance.

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Assembling the Presynaptic Active Zone

Cited by 380 publications

References 46 publications

A family of RIM-binding proteins regulated by alternative splicing: Implications for the genesis of synaptic active zones

A family of RIM-binding proteins regulated by alternative splicing: Implications for the genesis of synaptic active zones

A balance between excitatory and inhibitory synapses is controlled by PSD-95 and neuroligin

Sunday Driver Interacts with Two Distinct Classes of Axonal Organelles

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