Cytosolic tail sequences and subunit interactions are critical for synaptic localization of glutamate receptors

Chang, Howard C.; Rongo, Christopher

doi:10.1242/jcs.02320

Cited by 23 publications

(29 citation statements)

References 49 publications

(81 reference statements)

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“…This result is in agreement with the finding that the proximal 39 aa of GluR1 tail are sufficient for dendritic targeting in vertebrate neurons (51). The juxtamembrane 30 aa of GLR-1 contain a proximal, highly conserved 12 aa sequence that is present in vertebrate glutamate receptors (37). This highly conserved sequence has been found to be critical for AMPA-stimulated GluR2 endocytosis in HEK cells (53), and for endocytosis and endocytic sorting of NMDA receptors (54).…”

Section: Discussionsupporting

confidence: 88%

“…Thus, this region of glutamate receptor C termini appears crucial for various endocytic and exocytic processes, as well as interactions with the cytoskeleton. Interestingly, distal C-terminus PDZ motifs of AMPA-type glutamate receptors have been implicated in their synaptic clustering/retention in both vertebrates (58,59) and in C. elegans (26,37). Yet, these PDZ motifs are not required for glutamate receptor dendritic targeting (51, and this study), suggesting that molecular mechanisms specifying ''global targeting'' (to the dendrite) and ''local targeting'' (to the synapse) are at least partly distinct.…”

Section: Discussionmentioning

confidence: 99%

“…Given the importance of glutamate receptors for basal neurotransmission and plasticity in the vertebrate nervous system (38), we sought to identify more specific dendritic targeting motifs within the GLR-1 C terminus. Alignment with vertebrate glutamate receptors had previously revealed a highly conserved stretch of amino acids that immediately follow the last transmembrane domain (37) (Fig. 4A).…”

Section: Juxtamembrane 30 Aa Of Glr-1 Are Necessary and Sufficient Fomentioning

confidence: 95%

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Clathrin adaptor AP-1 complex excludes multiple postsynaptic receptors from axons in C. elegans

Margeta

Wang

Shen

2009

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

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Neurons are highly polarized cells with morphologically and molecularly distinct axonal and dendritic compartments. It is not well understood how postsynaptic receptors are selectively enriched in dendrites in vivo. We investigated the molecular mechanisms of dendritically polarized localization of a glutamate receptor, an acetylcholine receptor, and a ROR-type receptor tyrosine kinase in the interneuron RIA in C. elegans. We found that the clathrin adaptor AP-1 complex 1 subunit UNC-101 functions cell autonomously to maintain the correct localization of these receptors in a dynamindependent manner. In unc-101 mutants, instead of being dendritically enriched, all 3 receptors are evenly distributed in the axonal and dendritic compartments. Surprisingly, UNC-101 predominantly localizes to the axonal compartment, suggesting a possible transcytosis model for the dendritic targeting of neurotransmitter receptors.polarity ͉ trafficking ͉ glutamate receptor ͉ dendrite N eurons are polarized cells that receive, process, and transmit information. These different functions are performed by morphologically and functionally distinct subcellular compartmentsdendrites and axons-that contain proteins specialized for signal input or output. In principle, many different cellular mechanisms could contribute to molecular polarization in neurons (1, 2). Proteins destined for the axon or the dendrite could be selectively sorted into different transport vesicles at the transGolgi network (TGN) and selectively delivered to their proper subcellular compartment. Alternatively, steady-state differences in axonal and dendritic protein distribution could be achieved by selective stabilization of proteins by scaffolding proteins at certain areas of the plasma membrane, as well as by selective sorting and redistribution following endocytosis.What is currently known about sorting and trafficking of axonal and dendritic proteins to their proper compartments? Three axonally localized proteins, NgCAM, Nav1.2, and VAMP, are delivered to both axons and dendrites in neurons and achieve polarization following selective endocytosis from the dendritic plasma membrane (3-6). In contrast, dendritically localized transferrin receptor appears to be directly transported to the dendrite (3). For a number of dendritically targeted proteins, structure-function analysis has revealed C-terminal tyrosine-based or dileucine-based cytoplasmic motifs that mediate dendritic targeting (7,8).Interesting parallels have been made between dendritic sorting in neurons and basolateral sorting in epithelia (9). A number of basolaterally sorted proteins localize to the somatodendritic region in cultured hippocampal neurons and rely on the same sorting sequences in both cell types (10). One of the key players involved in basolateral sorting in polarized epithelial cells is 1B, the medium subunit of clathrin adaptor AP-1 complex (11). AP complexes are cytosolic tetramers that mediate sorting in secretory and endocytic pathways by promoting budding of clathrin-coated vesicles (...

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Juxtamembrane 30 Aa Of Glr-1 Are Necessary and Sufficient Fomentioning

confidence: 95%

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Clathrin adaptor AP-1 complex excludes multiple postsynaptic receptors from axons in C. elegans

Margeta

Wang

Shen

2009

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

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“…Early studies showed that a point mutation in this PDZ-ligand of GluR1 (GluR1T887A) blocked interactions with PDZ proteins (Cai et al 2002) and prevented longterm potentiation (LTP) and CaMKII-induced potentiation in organotypic hippocampal slices . Subsequent studies with this GluR1 (T887A) mutant in dissociated cultured neurons (Passafaro et al 2001), hippocampal slice cultures (Piccini and Malinow 2002), or Caenorhabditis elegans in vivo (Chang and Rongo 2005) also found receptor trafficking deficits. In contrast, a recent study using a mouse knock-in model showed that removal of the last seven amino acids of GluR1 (GluR1⌬7) does not affect receptor incorporation into synapses or LTP .…”

mentioning

confidence: 94%

“…PDZ domains play critical roles in protein-protein interactions for many cellular processes (Garner et al 2000;Kim and Sheng 2004). The GluR1 C-terminal PDZ-ligand domain is conserved among humans (TGL), rodents (TGL), birds (TGL), fish (SGM), and worms (TLF), suggesting that this region is important for GluR1 function (Chang and Rongo 2005). Early studies showed that a point mutation in this PDZ-ligand of GluR1 (GluR1T887A) blocked interactions with PDZ proteins (Cai et al 2002) and prevented longterm potentiation (LTP) and CaMKII-induced potentiation in organotypic hippocampal slices .…”

mentioning

confidence: 99%

Two mutations preventing PDZ–protein interactions of GluR1 have opposite effects on synaptic plasticity

Boehm¹,

Ehrlich²,

Hsieh³

et al. 2006

Learn. Mem.

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The regulated trafficking of GluR1 contributes significantly to synaptic plasticity, but studies addressing the function of the GluR1 C-terminal PDZ-ligand domain in this process have produced conflicting results. Here, we resolve this conflict by showing that apparently similar C-terminal mutations of the GluR1 PDZ-ligand domain result in opposite physiological phenotypes during activity-and CamKII-induced synaptic plasticity.The modification of synapses is a key feature underlying plasticity that occurs during development and learning. Mechanistic studies have shown that synaptic incorporation of additional AMPA-type receptors (AMPA-Rs) contributes to activity-induced enhancement at glutamatergic synapses during long-term potentiation (LTP) and plasticity in vivo (Malinow and Malenka 2002;Bredt and Nicoll 2003;Takahashi et al. 2003;Rumpel et al. 2005). However, a clear understanding of the molecular interactions that lead to stable synaptic incorporation of AMPA-Rs is missing.Here, we investigate the role played by the last seven amino acids in the GluR1 C terminus, which ends in a PDZ type I consensus sequence (S/T-X-) (Songyang et al. 1997). PDZ domains play critical roles in protein-protein interactions for many cellular processes (Garner et al. 2000;Kim and Sheng 2004). The GluR1 C-terminal PDZ-ligand domain is conserved among humans (TGL), rodents (TGL), birds (TGL), fish (SGM), and worms (TLF), suggesting that this region is important for GluR1 function (Chang and Rongo 2005). Early studies showed that a point mutation in this PDZ-ligand of GluR1 (GluR1T887A) blocked interactions with PDZ proteins (Cai et al. 2002) and prevented longterm potentiation (LTP) and CaMKII-induced potentiation in organotypic hippocampal slices . Subsequent studies with this GluR1 (T887A) mutant in dissociated cultured neurons (Passafaro et al. 2001), hippocampal slice cultures (Piccini and Malinow 2002), or Caenorhabditis elegans in vivo (Chang and Rongo 2005) also found receptor trafficking deficits. In contrast, a recent study using a mouse knock-in model showed that removal of the last seven amino acids of GluR1 (GluR1⌬7) does not affect receptor incorporation into synapses or LTP . Although both mutations, T887A and ⌬7, prevent interactions between the GluR1 cytoplasmic tail and PDZ proteins (Cai et al. 2002;Kim et al. 2005), they appear to have opposite effects on synaptic receptor incorporation and plasticity. It is unclear if these results are due to experimental approaches, or if a mechanistic difference exists between the point mutant (GluR1[T887A]) and the deletion mutant (GluR1⌬7).To resolve this discrepancy, we compared the physiological effects of GluR1(wildtype[wt]), GluR1(T887A), and GluR1⌬7 in the same experimental system, using viral overexpression (Sindbis virus, Invitrogen) of recombinant receptors in organotypic slice cultures. To visualize neurons that express receptors, we tagged GluR1 and its mutants with GFP. GFP-GluR1(wt) and GFPGluR1(T887A), with or without coexpressing tCaMKII (using an internal ribo...

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Smarter neuronal signaling complexes from existing components: How regulatory modifications were acquired during animal evolution

Thomas

Hayashi

2013

BioEssays

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Neurons of organisms with complex and flexible behavior, especially humans, must precisely control protein localization and activity to support higher brain functions such as learning and memory. In contrast, simpler organisms generally have simpler individual neurons, less complex nervous systems and display more limited behaviors. Strikingly, however, many key neuronal proteins are conserved between organisms that have very different degrees of behavioral complexity. Here we discuss a possible mechanism by which conserved neuronal proteins acquired new attributes that were crucial in the evolution of complexity of nervous system structure and function. Specifically, we hypothesize that vertebrate-specific post-translational palmitoylation sites and PDZ-binding protein-protein interaction motifs act as gain-of-function mutations, increasing the regulatory potential of conserved proteins without affecting their core functions. We further hypothesize that the additional regulation of neurotransmitter receptors and other membrane proteins made possible by these sites and motifs is critical for the function of complex nervous systems.

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Cytosolic tail sequences and subunit interactions are critical for synaptic localization of glutamate receptors

Cited by 23 publications

References 49 publications

Clathrin adaptor AP-1 complex excludes multiple postsynaptic receptors from axons in C. elegans

Clathrin adaptor AP-1 complex excludes multiple postsynaptic receptors from axons in C. elegans

Two mutations preventing PDZ–protein interactions of GluR1 have opposite effects on synaptic plasticity

Smarter neuronal signaling complexes from existing components: How regulatory modifications were acquired during animal evolution

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