The Anaphase-Promoting Complex Regulates the Abundance of GLR-1 Glutamate Receptors in the Ventral Nerve Cord of C. elegans

Juo, Peter; Kaplan, Joshua M.

doi:10.1016/j.cub.2004.11.010

Cited by 155 publications

(166 citation statements)

References 38 publications

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“…If mutations in rab-10 or lin-10 result in the accumulation of GLR-1 at an internal membrane trafficking compartment, then these mutations should result in corresponding GLR-1-mediated behavioral phenotypes (Burbea et al, 2002;Juo and Kaplan, 2004;Shim et al, 2004;Umemura et al, 2005;Schaefer and Rongo, 2006). In C. elegans, GLR-1 signaling positively regulates spontaneous reversals during forward locomotion as animals forage for food (Mellem et al, 2002;Zheng et al, 2004).…”

Section: Mutations In Either Rab-10 or Lin-10 Results In Behavioral Phmentioning

confidence: 99%

“…18, November 2007 4389 (White et al, 1986;Kaplan and Horvitz, 1993). Mutants with reduced GLR-1 activity have a lower frequency of spontaneous reversals and are nose-touch insensitive, whereas mutants with increased GLR-1 activity (e.g., higher levels of synaptic GLR-1 at the cell surface) have a higher frequency of spontaneous reversals (Hart et al, 1995;Maricq et al, 1995;Burbea et al, 2002;Mellem et al, 2002;Juo and Kaplan, 2004;Shim et al, 2004;Zheng et al, 2004;Umemura et al, 2005;Schaefer and Rongo, 2006). We examined GLR-1-mediated behaviors in wild-type animals and in animals with mutations in lin-10 and rab-10.…”

Section: Rab-10 Regulates Glur Recyclingmentioning

confidence: 99%

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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: Mutations In Either Rab-10 or Lin-10 Results In Behavioral Phmentioning

confidence: 99%

Section: Rab-10 Regulates Glur Recyclingmentioning

confidence: 99%

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 levels of GLR-1 on the postsynaptic membrane can be monitored through changes in behavior (Burbea et al, 2002;Juo and Kaplan, 2004). C. elegans spend the majority of their time moving forward; however, this forward locomotion is occasionally halted by spontaneous reversals in the direction of movement, and GLR-1 signaling positively regulates these spontaneous reversals (Zheng et al, 1999;Mellem et al, 2002).…”

Section: Kel-8 Negatively Regulates Glr-1 Functionmentioning

confidence: 99%

“…GLR-1::GFP is postsynaptically localized to clusters in the nerve ring (a region of proximal neurites that circumscribe the pharynx) and along the ventral nerve cord (a fascicle of distal neurites that runs anterior to posterior along the ventral midline of the body) (Rongo et al, 1998;Burbea et al, 2002). The synaptic abundance of GLR-1::GFP is regulated by the ubiquitination and subsequent endocytosis of the GLR-1 subunit (Burbea et al, 2002;Juo and Kaplan, 2004).Ubiquitination is used to regulate numerous biological processes, and ubiquitin-mediated proteolysis is a critical component in protein turnover (Hegde, 2004 tion is conducted in a stepwise manner by E1 ubiquitinactivating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin ligases, which recognize target proteins and catalyze the covalent attachment of ubiquitin to these target substrates. Ubiquitinated membrane proteins are substrates for endocytosis, although the exact mechanism by which such endocytosed membrane proteins are eventually degraded is unclear (Haglund et al, 2003;Hicke and Dunn, 2003).…”

mentioning

confidence: 99%

KEL-8 Is a Substrate Receptor for CUL3-dependent Ubiquitin Ligase That Regulates Synaptic Glutamate Receptor Turnover

Schaefer

Rongo

2006

MBoC

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The regulated localization of ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors (AMPARs) to synapses is an important component of synaptic signaling and plasticity. Regulated ubiquitination and endocytosis determine the synaptic levels of AMPARs, but it is unclear which factors conduct these processes. To identify genes that regulate AMPAR synaptic abundance, we screened for mutants that accumulate high synaptic levels of the AMPAR subunit GLR-1 in Caenorhabditis elegans. GLR-1 is localized to postsynaptic clusters, and mutants for the BTB-Kelch protein KEL-8 have increased GLR-1 levels at clusters, whereas the levels and localization of other synaptic proteins seem normal. KEL-8 is a neuronal protein and is localized to sites adjacent to GLR-1 postsynaptic clusters along the ventral cord neurites. KEL-8 is required for the ubiquitin-mediated turnover of GLR-1 subunits, and kel-8 mutants show an increased frequency of spontaneous reversals in locomotion, suggesting increased levels of GLR-1 are present at synapses. KEL-8 binds to CUL-3, a Cullin 3 ubiquitin ligase subunit that we also find mediates GLR-1 turnover. Our findings indicate that KEL-8 is a substrate receptor for Cullin 3 ubiquitin ligases that is required for the proteolysis of GLR-1 receptors and suggest a novel postmitotic role in neurons for Kelch/CUL3 ubiquitin ligases. INTRODUCTIONGlutamate is the most abundant excitatory neurotransmitter in the brain, and glutamatergic synapses play a critical role in learning, memory, and developmental plasticity of the central nervous system (Meldrum, 2000). Ionotropic glutamate receptors (GluRs) receive and transduce glutamatergic signals on the postsynaptic face of synapses, where these multitransmembrane spanning proteins assemble into tetrameric glutamate-gated channels of differing subunit composition (Hollmann and Heinemann, 1994;Dingledine et al., 1999). The regulation of these receptors, the ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) type in particular, is a critical mechanism by which neurons modulate synaptic strength (Bredt and Nicoll, 2003;Malenka, 2003;Malinow, 2003;Sheng and Hyoung Lee, 2003). In addition, GluRs play a role in several diseases of the nervous system, ranging from neurodegeneration to drug addiction and schizophrenia (Tzschentke, 2002;Mattson, 2003;Moghaddam, 2003;Aarts and Tymianski, 2004). To better understand how AMPA-type GluRs (AMPARs) function in the nervous system, it is essential to determine how the synaptic level and activity of AMPARs are regulated.AMPAR synaptic levels are controlled by proteins that interact with signaling elements on the carboxy-terminal tail sequences that are exposed to the cytosol (Dong et al., 1997;Rongo et al., 1998;Song et al., 1998;Srivastava et al., 1998;Xia et al., 1999;Sans et al., 2001). Although some of the tail sequence signaling elements function to maintain high levels of AMPARs at the synapse, other signaling elements recruit factors that result in the ubiquitination, endocytosis, ...

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“…The UPS has been shown to regulate GluR synaptic abundance both directly and indirectly. In C. elegans, direct ubiquitination and proteasomal degradation of GluR1 subunits has been demonstrated (Burbea et al, 2002), but the UPS also indirectly regulates GluR1 synaptic abundance through multiple other pathways (Juo and Kaplan, 2004;Dreier et al, 2005;Schaefer and Rongo, 2006). In cultured rat hippocampal neurons, indirect regulation of AMPA receptors has been demonstrated through ubiquitination and degradation of the postsynaptic scaffolding protein PSD-95 (Colledge et al, 2003), and agonist-induced AMPA receptor internalization has been shown to be dependent on UPSmediated degradation of an undetermined synaptic protein (Patrick et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

The ubiquitin–proteasome system postsynaptically regulates glutamatergic synaptic function

Haas

Miller

Friedman

et al. 2007

Molecular and Cellular Neuroscience

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The ubiquitin proteasome system (UPS) actively controls protein dynamics and local abundance via regulated protein degradation. This study investigates UPS roles in the regulation of postsynaptic function and molecular composition in the Drosophila neuromuscular junction (NMJ) genetic system. To specifically impair UPS function postsynaptically, the UAS/GAL4 transgenic method was employed to drive postsynaptic expression of proteasome β2 and β6 subunit mutant proteins, which operate through a dominant negative mechanism to block proteasome function. When proteasome mutant subunits were constitutively expressed, excitatory junctional current (EJC) amplitudes were increased, demonstrating that postsynaptic proteasome function limits neurotransmission strength. Interestingly, the alteration in synaptic strength was calcium-dependent and miniature EJCs had significantly smaller mean amplitudes and more rapid mean decay rates. Postsynaptic levels of the Drosophila PSD-95/SAP97 homologue, discs large (DLG), and the GluRIIB-containing glutamate receptor were increased, but GluRIIA-containing receptors were unaltered. With acute postsynaptic proteasome inhibition using an inducible transgenic system, neurotransmission was similarly elevated with the same specific increase in postsynaptic GluRIIB abundance. These findings demonstrate postsynaptic proteasome regulation of glutamatergic synaptic function that is mediated through specific regulation of GluRIIB-containing glutamate receptors.

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The Anaphase-Promoting Complex Regulates the Abundance of GLR-1 Glutamate Receptors in the Ventral Nerve Cord of C. elegans

Cited by 155 publications

References 38 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

KEL-8 Is a Substrate Receptor for CUL3-dependent Ubiquitin Ligase That Regulates Synaptic Glutamate Receptor Turnover

The ubiquitin–proteasome system postsynaptically regulates glutamatergic synaptic function

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