UNC-11, a<i>Caenorhabditis elegans</i>AP180 Homologue, Regulates the Size and Protein Composition of Synaptic Vesicles

Nonet, Michael L.; Holgado, Andrea; Brewer, Faraha; Serpe, Craig J.; Norbeck, Betty A.; Holleran, Julianne L.; Wei, Liping; Hartwieg, Erika; Jørgensen, Erik M.; Alfonso, Aixa

doi:10.1091/mbc.10.7.2343

Cited by 250 publications

(234 citation statements)

References 72 publications

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“…If this is true, then mutations in the endosomal machinery involved in early steps of endocytosis and trafficking should suppress the mutant phenotypes of rab-10 and/or lin-10. Previously, UNC-11 (a clathrin adaptin protein AP180 orthologue that mediates endocytosis) was identified as a regulator of the synaptic abundance of AMPARs (Nonet et al, 1999;Burbea et al, 2002). Indeed, mutations in unc-11 result in an ϳ50% increase in the size of postsynaptic GLR-1 clusters (Figure 4, A and D) (Burbea et al, 2002).…”

Section: Unc-11 and Itsn-1 Function Upstream Of Lin-10 But Not Rab-10mentioning

confidence: 95%

RAB-10 Regulates Glutamate Receptor Recycling in a Cholesterol-dependent Endocytosis Pathway

Glodowski

Chen

Schaefer

et al. 2007

MBoC

104

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Regulated endocytosis of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) is critical for synaptic plasticity. However, the specific combination of clathrin-dependent and -independent mechanisms that mediate AMPAR trafficking in vivo have not been fully characterized. Here, we examine the trafficking of the AMPAR subunit GLR-1 in Caenorhabditis elegans. GLR-1 is localized on synaptic membranes, where it regulates reversals of locomotion in a simple behavioral circuit. Animals lacking RAB-10, a small GTPase required for endocytic recycling of intestinal cargo, are similar in phenotype to animals lacking LIN-10, a postsynaptic density 95/disc-large/zona occludensdomain containing protein: GLR-1 accumulates in large accretions and animals display a decreased frequency of reversals. Mutations in unc-11 (AP180) or itsn-1 (Intersectin 1), which reduce clathrin-dependent endocytosis, suppress the lin-10 but not rab-10 mutant phenotype, suggesting that LIN-10 functions after clathrin-mediated endocytosis. By contrast, cholesterol depletion, which impairs lipid raft formation and clathrin-independent endocytosis, suppresses the rab-10 but not the lin-10 phenotype, suggesting that RAB-10 functions after clathrin-independent endocytosis. Animals lacking both genes display additive GLR-1 trafficking defects. We propose that RAB-10 and LIN-10 recycle AMPARs from intracellular endosomal compartments to synapses along distinct pathways, each with distinct sensitivities to cholesterol and the clathrin-mediated endocytosis machinery. INTRODUCTIONContinuous movement of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) into and out of synaptic membranes is a key mechanism for the regulation of excitatory synaptic strength. Previous work has shown that insertion of AMPARs into the plasma membrane strengthens synapses and that it is required to convert silent synapses into active synapses (Bredt and Nicoll, 2003;Malenka, 2003;Malinow, 2003;Sheng and Hyoung Lee, 2003;Gerges et al., 2005). Furthermore, it has recently been shown that recycling of AMPARs from internal endosomal compartments back to the plasma membrane is important for long-term potentiation (Park et al., 2004). By contrast, endocytosis of AMPARs at sites adjacent to the postsynaptic density is important for long-term depression (Carroll et al., 2001;Racz et al., 2004). Thus, molecular machinery required for endocytosis, as well as intracellular membrane trafficking processes, ultimately regulates the character of signal transmitted at each synapse.Multiple endocytosis trafficking pathways have been observed in cells. Clathrin-dependent endocytosis occurs at clathrin-coated pits, where transmembrane protein cargo and adaptor molecules recruit soluble clathrin (Le Roy and Wrana, 2005). Vesicles coated with a clathrin lattice are then pinched off from the membrane. Members of the Rab family of small guanosine triphosphate (GTP)ases mediate the intracellular membrane trafficking of endocytose...

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Section: Unc-11 and Itsn-1 Function Upstream Of Lin-10 But Not Rab-10mentioning

confidence: 95%

RAB-10 Regulates Glutamate Receptor Recycling in a Cholesterol-dependent Endocytosis Pathway

Glodowski

Chen

Schaefer

et al. 2007

MBoC

104

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“…The carboxy-terminal half of the molecules contains a clathrin-binding segment and motifs that bind the AP2 appendages. Many lower organisms have a single AP180/ CALM ortholog, and deletion of these in Drosophila and Caenorhabditis elegans leads to an increase in the size of synaptic vesicles but to a decrease in their number and in transmitter release, causing unregulated movement (Nonet et al 1999;Bao et al 2005). Although overexpression of CALM inhibits clathrin-mediated endocytosis (Tebar et al 1999), knockdown by RNAi in HeLa cells leads to formation of aberrant coated structures: very large "coated pits" with some attached tubular structures, rather than the 1000 Å budding vesicles seen in control cells (Meyerholz et al 2005).…”

Section: Other Adaptorsmentioning

confidence: 99%

Molecular Structure, Function, and Dynamics of Clathrin-Mediated Membrane Traffic

Kirchhausen

Owen

Harrison

2014

Cold Spring Harbor Perspectives in Biology

434

442

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Clathrin is a molecular scaffold for vesicular uptake of cargo at the plasma membrane, where its assembly into cage-like lattices underlies the clathrin-coated pits of classical endocytosis. This review describes the structures of clathrin, major cargo adaptors, and other proteins that participate in forming a clathrin-coated pit, loading its contents, pinching off the membrane as a lattice-enclosed vesicle, and recycling the components. It integrates as much of the structural information as possible at the time of writing into a sketch of the principal steps in coated-pit and coated-vesicle formation.

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“…syd-9(ju49) mutants displayed specific genetic interactions with snt-1, unc-26, unc-57, and unc-11, all genes that participate in endocytosis (13,14,19,21,60). In fact, the morphological defects of syd-9 (specifically, the thin body and lack of sinusoidal wave) are reminiscent of these mutants.…”

Section: Syd-9 Mutants Show Genetic Interactions With Endocytotic Mutmentioning

confidence: 99%

“…We performed electron microscopy analysis to examine whether syd-9 mutants display ultrastructural features consistent with a defect in endocytosis. Several characteristic ultrastructural defects have been observed in C. elegans endocytosis mutants (13,14,19,21,60). These defects include a reduction in the total synapse vesicle number, reflecting the defective replenishment of synaptic vesicles, and an altered distribution pattern of synaptic vesicles, with more membrane-contacting vesicles present away from active zones.…”

Section: Syd-9 Mutants Show Genetic Interactions With Endocytotic Mutmentioning

confidence: 99%

The C2H2 zinc-finger protein SYD-9 is a putative posttranscriptional regulator for synaptic transmission

Wang

Gracheva

Richmond

et al. 2006

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

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Communication between neurons is largely achieved through chemical synapses, where neurotransmitters are released from synaptic vesicles at presynaptic terminals to activate postsynaptic cells. Exo-and endocytosis are coordinated to replenish the synaptic vesicle pool for sustained neuronal activity. We identified syd-9 (syd, synapse defective), a gene that encodes multiple C2H2 zinc-finger domain-containing proteins specifically required for synaptic function in Caenorhabditis elegans. syd-9 loss-of-function mutants exhibit locomotory defects, a diffuse distribution of synaptic proteins, and decreased synaptic transmission with unaffected neurodevelopment. syd-9 mutants share phenotypic and ultrastructural characteristics with mutants that lack synaptic proteins that are required for endocytosis. syd-9 mutants also display genetic interactions with these endocytotic mutants, suggesting that SYD-9 regulates endocytosis. SYD-9 proteins are enriched in the nuclei of both neuron and muscle cells, but their neuronal expression plays a major role in locomotion. SYD-9 isoforms display a speckle-like expression pattern that is typical of RNAbinding proteins that regulate premRNA splicing. Furthermore, syd-9 functions in parallel with unc-75 (unc, uncoordinated), the C. elegans homologue of the CELF͞BrunoL family protein that regulates mRNA alternative splicing and processing, and is also required specifically for synaptic transmission. We propose that neuronal SYD-9 proteins are previously uncharacterized and specific posttranscriptional regulators of synaptic vesicle endocytosis.BrunoL͞UNC-75 ͉ Caenorhabditis elegans ͉ endocytosis ͉ synaptic function C hemical synapses mediate neuronal communication through the regulated release of neurotransmitters from synaptic vesicles. Extensive studies have focused on the molecular machinery that mediates and regulates exocytosis, the process in which membrane fusion between synaptic vesicles and the plasma membrane leads to neurotransmitter release and endocytosis, the process that recovers synaptic vesicles from the plasma membrane (1, 2).The release of neurotransmitters is stimulated by the influx of Ca 2ϩ at the presynaptic active zones. Protein components of the vesicle membranes (synaptobrevin, SNB) and plasma membranes [syntaxin and SNAP-25 (synaptosome-associated protein of 25 kDa)] form a SNARE complex that functions as a minimal fusion machine to drive vesicle fusion (3-5). The formation and conformational change of the SNARE complex requires modulation by other proteins (6-9). Synaptotagmin (SNT) is a vesicle membrane protein that binds to Ca 2ϩ and forms complexes with phospholipids and SNARE complexes. It is a proposed Ca 2ϩ sensor for Ca 2ϩ -dependent exocytosis (10-12). SNT-1 knockout mice display selective loss of Ca 2ϩ -triggered fast exocytosis, and loss of SNT function in Caenorhabditis elegans and Drosophila leads to a large reduction of exocytosis (13,14). Disrupting the function of UNC13͞mUNC13 and UNC-18͞mUNC18 (UNC, uncoordinated) also leads to a reduction...

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UNC-11, aCaenorhabditis elegansAP180 Homologue, Regulates the Size and Protein Composition of Synaptic Vesicles

Cited by 250 publications

References 72 publications

RAB-10 Regulates Glutamate Receptor Recycling in a Cholesterol-dependent Endocytosis Pathway

RAB-10 Regulates Glutamate Receptor Recycling in a Cholesterol-dependent Endocytosis Pathway

Molecular Structure, Function, and Dynamics of Clathrin-Mediated Membrane Traffic

The C2H2 zinc-finger protein SYD-9 is a putative posttranscriptional regulator for synaptic transmission

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