Lateral organization of endocytic machinery in dendritic spines

Rácz, Bence; Blanpied, Thomas A.; Ehlers, Michael; Weinberg, Richard J.

doi:10.1038/nn1303

Cited by 196 publications

(200 citation statements)

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“…Interestingly, recent studies of mammalian AMPARs indicate that these receptors move laterally and undergo endocytosis in membrane regions that are adjacent to the postsynaptic density (Racz et al, 2004). Thus, one possible explanation for KEL-8 localization adjacent to GLR-1 clusters is that KEL-8 is localized to tangential sites of endocytosis for GLR-1 receptors, similar to what has been observed for mammalian receptors.…”

Section: Kel-8 Is Localized Adjacent To Glr-1mentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

“…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, and proteolysis of AMPARs (Ehlers, 2000;Osten et al, 2000;Burbea et al, 2002;Esteban et al, 2003). AMPARs targeted for destruction are endocytosed in lateral regions adjacent to postsynaptic elements, although the machinery that degrades these membrane-bound proteins is less well understood (Racz et al, 2004).To investigate these questions in a genetic system, we examined the GLR-1 AMPAR subunit in C. elegans. GLR-1 is expressed in interneurons, where it functions to mediate nose-touch mechanosensation and regulate the frequency of spontaneous reversals in locomotion (Hart et al, 1995;Maricq et al, 1995;Brockie et al, 2001).…”

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confidence: 99%

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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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Section: Kel-8 Is Localized Adjacent To Glr-1mentioning

confidence: 52%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…DA receptors, like most GPCRs, internalize via the dynamin-dependent, clathrin-mediated endocytic pathway [43] (Figure 1B). Endocytosis occurs frequently in dendritic shafts, and core endocytic proteins, including adaptor protein 2 (AP-2), clathrin, and dynamin-3, are present in the spine heads [49]. These proteins are systematically arrayed near, but not at, the PSD, to form stable endocytic zones near the PSD in the spine head [30].…”

Section: Local Da Receptor Trafficking In Spinesmentioning

confidence: 99%

Dopaminergic signaling in dendritic spines

Yao

Spealman

Zhang

2008

Biochemical Pharmacology

108

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Dopamine regulates movement, motivation, reward, and learning and is implicated in numerous neuropsychiatric and neurological disorders. The action of dopamine is mediated by a family of seven-transmembrane G protein-coupled receptors encoded by at least five dopamine receptor genes (D1, D2, D3, D4, and D5), some of which are major molecular targets for diverse neuropsychiatric medications. Dopamine receptors are present throughout the soma and dendrites of the neuron, but accumulating ultrastructural and biochemical evidence indicates that they are concentrated in dendritic spines, where most of the glutamatergic synapses are established. By modulating local channels, receptors, and signaling modules in spines, this unique population of postsynaptic receptors is strategically positioned to control the excitability and synaptic properties of spines and mediate both the tonic and phasic aspects of dopaminergic signaling with remarkable precision and versatility. The molecular mechanisms that underlie the trafficking, targeting, anchorage, and signaling of dopamine receptors in spines are, however, largely unknown. The present commentary focuses on this important subpopulation of postsynaptic dopamine receptors with emphases on recent molecular, biochemical, pharmacological, ultrastructural, and physiological studies that provide new insights about their regulatory mechanisms and unique roles in dopamine signaling. The Central Dopaminergic Systems: An OverviewDopamine (DA) is a prototypical slow neurotransmitter that plays pivotal roles in a variety of cognitive, motivational, neuroendocrine, and motor functions [1][2]. Two major groups of DAcontaining neurons in the mammalian brain reside in the substantia nigra pars compacta (SN) and the ventral tegmental area (VTA) [3]. SN neurons form the nigrostriatal pathway, which projects mainly to the dorsal part of striatum where they control postural reflexes and initiation of movements. VTA neurons give rise to two pathways: the mesolimbic pathway, which projects to the subcortical and limbic nuclei, and the mesocortical pathway, which projects mainly to the cingulate, entorhinal and medial prefrontal cortices. Dysfunction of dopaminergic transmission in these major pathways has been implicated in an array of neurological and neuropsychiatric disorders, including Parkinson's disease, Huntington's diseases, schizophrenia, attention-deficit hyperactivity disorder (ADHD), and drug addiction [1][2]. Drugs targeting dopaminergic mechanisms are widely used to manage these and other conditions.The action of DA is mediated by a family of seven-transmembrane G protein-coupled receptors (GPCRs) encoded by at least five DA receptor genes (D1, D2, D3, D4, and D5) in the mammalian brain [4]. These receptors are classified into two subfamilies, the D1-class and Corresponding author: Wei-Dong Yao, Ph.D., Department of Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical Center, New England Primate Research Center, One Pine Hill Drive, P.O. Box 9102, Southborough,...

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“…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.…”

Section: Introductionmentioning

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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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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Lateral organization of endocytic machinery in dendritic spines

Cited by 196 publications

References 15 publications

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

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

Dopaminergic signaling in dendritic spines

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

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