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Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

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Synaptic Endosomes

1 and 1.

1 These authors contributed equally to this work.

Endosomes are important functional elements of the chemical synapse. They are used in membrane trafficking pathways controlling recycling and degradation of pre- and post-synaptic membrane proteins. Recent data indicate that they play a role in maintaining the pool of small synaptic vesicles and are involved in recycling of dense-core vesicle membrane during neurotransmitter release.

Membrane Trafficking Events at Synapses

Membrane trafficking in nerve cells appears to be more complex than in most other cell types. In addition to pathways common for nonneuronal cells, these cells utilize membrane trafficking mechanisms to release neuroactive substances into the surrounding environment.1,2 These events occur to a large extent in specialized intracellular contacts established by neurons on target cells. These junctions are referred to as chemical synapses.

Chemical synapses are specialized signaling units composed of a pre- and a post-synaptic element. The postsynaptic element contains neurotransmitter receptors and protein machineries involved in signaling and receptor trafficking (see below). The presynaptic nerve terminal, in addition, contains neurotransmitter-filled organelles (vesicles), which may fuse with the presynaptic membrane. Neurons can secrete a variety of nonpeptidergic/classical and peptidergic transmitters via at least two types of secretory organelles, the small synaptic vesicles (SSVs) and the dense-core vesicles (DCVs), also referred to as secretory granules (Figs. 1 and 2A, B). According to the current model, the classical neurotransmitters acetylcholine (ACh), noradrenaline (NA), glutamate, glycine, and GABA are released from SSVs.2 Neuropeptides, on the other hand, are stored in, and released from, DCVs,3 which are directly formed at the trans-Golgi network and transported down the axon to their release sites.

Figure 1. Membrane-trafficking pathways in synapses.

Figure 1

Membrane-trafficking pathways in synapses. Small synaptic vesicles (SSV) releasing neurotransmitter at the active zone (triangles) may be retrieved via “kiss and run” as well as via a clathrin-mediated mechanism. During intense activity, (more...)

Figure 2. Ultrastructure of endocytic intermediates.

Figure 2

Ultrastructure of endocytic intermediates. A) Electron micrograph of a chemical synapse from the cat spinal cord. An area of the terminal containing small synaptic vesicles (SSV) and dense-core vesicles (DCV) is shown in (B) at higher magnification. C) (more...)

Exocytosis of SSVs and DCVs is differentially regulated and takes place at different release sites of the nerve terminal.4,5 SSVs empty their content upon depolarization and fusion of synaptic vesicles at defined regions of the presynaptic membrane. These areas contain a high density of calcium channels and protein complexes involved in vesicle docking and fusion and are referred to as “active zones”.2 DCVs tend to fuse outside the active zone region. Following neuroexocytosis, neurotransmitter molecules bind to postsynaptic receptors leading to an electrical response of the postsynaptic neuron. In addition, neurotransmitter release may lead to an activation of presynaptic receptors, which control retrograde modulation of neurotransmitter release. Recent data clearly demonstrate that receptors located on pre- and post-synaptic membranes can be retrieved from, or exposed at the membrane surface via distinct membrane-trafficking mechanisms, which may underlie synaptic plasticity phenomena.6

Several membrane retrieval mechanisms may function in a synaptic terminal. These involve uptake of membrane components related to SSVs, DCVs (see below), as well as receptors and ion channels. The latter mechanism resembles internalization of nutrient and signaling receptors in nonneuronal cells described in other chapters of this book.

Endocytic Recycling of Presynaptic Vesicles

Three mechanisms for synaptic vesicle endocytosis have been proposed: direct reformation of vesicles via the rapid closure of a transient fusion pore (“kiss-and-run”), clathrin-mediated endocytosis,7 and bulk endocytosis.8,9 During “kiss and run”, SSVs are hypothesized to make brief contact with the plasma membrane forming a transient fusion pore through which the neurotransmitter is released.2,10,11 In contrast, clathrin-mediated endocytosis occurs after complete fusion of SSVs with the plasma membrane.2,12,13 The key components of the clathrin-dependent endocytosis machinery are: clathrin, the heterotetrameric adaptor complex (AP-2), and dynamin.2,14 These proteins are part of the coat complex from very early stages. Recruitment of AP-2 to the plasma membrane is a complex process, which involves interactions with phosphoinositides, synaptotagmin,10,15,16 and accessory proteins.16 Although synapses use basically the same clathrin-dependent endocytic mechanism as nonneuronal cells, they utilize protein isoforms, most highly expressed in neurons. These include for example: AP180, auxillin, intersectins, dynamin-I, adaptin and the splice-variants of clathrin light chains.2,14,17,18 AP180/CALM, epsins, intersectin and HIP1/HIP1R (huntingtin interacting proteins) function as cargo adaptors in addition to AP-2 (see chapter 10). While the clathrin lattice is formed, endophilin, epsin, and amphiphysin are involved in membrane invagination and clathrin rearrangements.2,14,18 The GTPase dynamin is required for fisson of endocytic membrane vesicles.17 Observation of clathrin-coated pit dynamics using total internal reflection microscopy indicates that during fission, dynamin recruitment to coated pits is rapidly followed by recruitment of actin.19 Moreover perturbation of actin disrupts the endocytic reaction with accumulation of coated pits with wide necks20 suggesting a role of actin and dynamin-interacting accessory proteins in promoting constriction of the neck. In lamprey, snake, and fly neuromuscular synapses, the invagination of the membrane into pits occurs at distinct “endocytic zones” surrounding the active zones of exocytosis. Distinct “hot-spots of endocytosis” have been also described at the post-synaptic membrane (Figs. 1 and 5; see also refs. 12, 21).

Deep plasma membrane expansions and endosome-like compartments have been observed in synaptic terminals close to active zones during high-frequency stimulation of neuromuscular junctions, retina and also in central synapses.7-9,22 They could be clearly seen in the lamprey giant synapse. The active zone in this junction is surrounded by organelle-free axoplasmic matrix. This allows following of these structures in serial ultrathin sections using electron microscopy (Fig. 2 C-I). Nonspecific membrane internalization by bulk endocytosis may prevent expansion of the cell surface under conditions in which clathrin-mediated endocytosis becomes rate limiting. Clathrin-coated buds are present not only at the plasma membrane but also on such endosome-like invaginations in synapses, consistent with the existence of the parallel pathway for clathrin-dependent synaptic vesicle formation (Figs. 1 and 2).

Presynaptic Endosomal Compartments

In analogy to nonneuronal cells endocytic vesicles presumably fuse with an endosomal compartment after detachment from the plasma membrane. Several studies performed recently support the involvement of bona fide endosomes in synaptic membrane recycling, although their role in different pathways still remains a matter of debate.2,23 In hippocampal synapses for example, the role of endosomes in SSV recycling until recently had been believed to be limited. Studies using the fluorescent membrane dye FM1-43 have demonstrated that the amount of dye per vesicle taken up by endocytosis equals the amount of dye a vesicle releases upon exocytosis. It was thus concluded that the internalized vesicles participating in endo-exo recycling do not communicate with intermediate endosomal compartments during the recycling process.24 These experiments, however, did not exclude the possibility that a remaining, “second” population of vesicles, not participating in exo-endocytic recycling, could exchange membrane with an endosome or that this organelle could be recruited upon certain activity demands. Several recent studies have provided evidence that the population of SSVs is indeed inhomogenous, consistent with the idea that different pools of vesicles may use distinct membrane-trafficking pathways during the synaptic vesicle cycle. It has been shown, that during development, vesicular release along growing axons of frog motoneurons in culture is sensitive to brefeldin A (BFA), whereas quantal release from nerve terminals is BFA-insensitive.25 It cannot be excluded that a similar mechanism may be retained in adult synapses. Studies in hippocampal synapses, for example, show that spontaneously recycling vesicles and activity-dependent recycling vesicles originate from distinct pools with limited crosstalk with each other.26

Figure 3. An endosomal compartment at the presynaptic terminal.

Figure 3

An endosomal compartment at the presynaptic terminal. A) Double labeling showing GFP-2xFYVE (green) to monitor the endosomes and Fasciclin II immunostaining to label the NMJ presynaptic terminals (FasII, red). B) GFP-2xFYVE fluorescence in an abdominal (more...)

Figure 4. Cryoimmuno-EM of the GFP-2xFYVE endosome.

Figure 4

Cryoimmuno-EM of the GFP-2xFYVE endosome. A-D) Cryoimmuno-electron micrographs showing two Drosophila presynaptic terminals (A/B and C/D), where GFP-2xFYVE is labeled by 10-nm gold particles (anti-GFP antibody). B and D) High magnifications of the boxes in (more...)

Early Endosomal Compartments

Recent studies at the Drosophila neuromuscular junction have provided direct support for the involvement of an endosomal pathway in the synaptic vesicle cycle.27 For a number of years it has been known that the small GTPase Rab5 is present on isolated SSVs.23,27-29 By recruitment of several effector molecules Rab5 promotes the formation of endosomes in nonneuronal cells.30,31 Active Rab5 recruits two phosphatidylinositol-3-kinases, PI(3)-kinases p85/p110 and VPS34/p150, which trigger a local enrichment of phosphatidylinositol- 3-phosphate, PI(3)P, in the endosomal membrane.32 PI(3)P specifically binds to the FYVE zinc-finger domain of endosomal factors such as the Rab5 effectors EEA1 and Rabenosyn-5, which ultimately mediate endocytic vesicle tethering and fusion with early endosomes.33-36 Consistently, blocking of PI(3)-kinases with antibodies or wortmannin impairs the association of FYVE domain proteins with early endosomes thereby, blocking endosomal membrane trafficking.35,37 FYVE domains binds to PI(3)P within an intact lipid bilayer38,39 and the localization of a myc-tagged tandem repeat of the FYVE domain (myc-2xFYVE) is restricted to early endosomes and the internal membrane of multivesicular bodies.40 Thus, both Rab5 and 2xFYVE can be considered as selective markers for PI(3)P-containing endosomes. Using these two GFP-tagged markers as well as antibodies, González-Gaitánand colleagues have recently demonstrated the presence of Rab5-positive, PI(3)P-containing endosomes at the presynaptic terminal of Drosophila neuromuscular junctions.27 Under conditions in which the SSV pool was depleted, endosomes were drastically reduced in size and recovered by dynamin-mediated endocytosis. Interfering with Rab5 function using a dominant-negative version of Rab5 caused a reduction in the number of released quanta during synaptic transmission, whereas elevated levels of Rab5 increased the quantal content. These data indicate that Rab5-dependent trafficking pathway plays a role in presynaptic vesicle cycling.

Support for the involvement of an early endosomal compartment in synaptic membrane trafficking also comes from studies on the endosomal membrane adaptor complex AP-3. AP-3, which exists as both ubiquitously expressed AP-3A as well as a neuron-specific AP-3B isoform, is localized to the TGN and/or endosomal compartments. It participates in trafficking to the vacuole/lysosome in yeast,41,42 flies,43-45 and mammals.46,47 AP-3B as well as ADP ribosylation factor 1 (ARF1)48,49 are required for the biogenesis of synaptic-like microvesicles budding from PC12 cell endosomes.49-52 Genetic analysis of AP-3 mutant mice has been linked to a variety of neurological defects.50,53-55 The mocha mouse, a null mutation of the δ subunit of AP-3, exhibits balance and hearing problems, is hyperactive, and is prone to seizures.50,53-55 Mice in which the neuron-specific AP-3B subunit μ3B has been genetically deleted, show specific defects related to the biogenesis of GABA-containing SSVs suggesting a particularly important function for AP-3B at inhibitory synapses.56

Another potential function for endosome-derived synaptic vesicles and AP-3 dependent pathway is in the recovery of membrane components of dense core vesicles (DCVs) that have just undergone exocytosis. Membrane retrieval of this type has been followed in PC12 cells transfected with a chimeric P-selectin.52,57,58 It had been proposed that, neuronal AP-3B may recapture protein components of DCV proteins. A recapture step could sequester selected DCV proteins from a degradative pathway and allow them to be incorporated into the synaptic vesicle cycle. The distribution of neuronal AP-3B showed some resemblance to that reported for chromogranin A, a marker of dense core granules, particularly in the stratum oriens and the molecular layer of the dentate gyrus.59 These data indirectly support a role for AP-3B in the recovery of DCV-derived membrane components.

Late Endosomal Compartments

A more acidic late endosomal compartment has been shown to form during maturation of early endosomes in nonneuronal cells.1 Whereas early endosomes tend to be tubular and are located towards the cell periphery, late endosomes are more spherical and often appear closer to the nucleus. A subset of late endosomes has a multivesicular appearance, hence named multivesicular bodies (MVBs). Late endosomes form a dynamic network together with lysosomal structures, the end point of endocytosis and site of protein degradation. As mentioned above, transport of DCV membrane constituents in neurons involves early endosomes,58 whereas multivesicular bodies may particpate in retrograde transport of DCV components towards the cell body. Such transport has been observed i.e., in the splenic nerve.60

Endosomes in Postsynaptic Receptor Trafficking

Over the past few years it has become clear that the strength of synaptic connections, in particular with respect to postsynaptic responses, is subject to plastic changes. At excitatory synapses, activation of glutamate receptors, such as AMPA-type glutamate-gated ion channels provides the primary depolarization in excitatory neurotransmission. AMPA receptor-mediated postsynaptic currents are modulated by changes in their localization and surface expression. Glutamate receptor density thus appears to be carefully regulated by fine-tuning receptor synthesis, endosomal trafficking, and degradation.6 Since most of what we know about endosomal trafficking of postsynaptic receptors has been derived from studies on excitatory glutamate receptors we will focus primarily on these, but it is expected that similar mechanisms are utilized for other receptor types as well. In agreement with this notion it has been reported that ionotropic GABAA61-63 and glycine64,65 receptors regulating inhibitory neurotransmission in the nervous system, can also be internalized into endosomal or subsynaptic compartments.

AMPA Receptors Are Internalized via Constitutive or Ligand-Induced Pathways

AMPA receptors, heterotetramers composed of related GluR1-4 subunits, undergo dynamic redistribution in and out of the postsynaptic membrane. Most excitatory synapses form on dendritic spines, that emanate from the main shaft and usually bear a single synaptic contact at their heads. AMPA receptors, concentrated at the postsynaptic density (PSD) of dendritic spines, serve to propagate the signal66 and are able to dynamically move into and out of the postsynaptic density by lateral diffusion. They may also undergo constitutive internalization.67 Stimulation of glutamatergic synapses with AMPA, NMDA, or insulin has been shown to enhance AMPA receptor internalization by clathrin-mediated endocytosis.67-71 AMPA receptor internalization along the endocytic pathway correlates physiologically with activity-dependent long-term depression (LTD). Conversely, during long-term potentiation (LTP), a cellular model for learning and memory, an increase in the number of functional, cell-surface exposed AMPA receptors at the postsynaptic membrane is observed (Fig. 1; see also refs. 6, 72). These receptors are thought to originate from an intracellular reserve pool.73,74 Endocytic removal of AMPA receptors occurs mostly from extrasynaptic sites.75 This observation is consistent with the predominant localization of endocytic proteins including clathrin, AP-2, and dynamin lateral to the postsynaptic density.76

The exact molecular mechanisms of the constitutive and regulated pathways for AMPA receptor internalization are not yet completely understood. Although all pathways are dependent on the GTPase dynamin, an accessory protein required for fission of both clathrin- and nonclathrin-coated vesicles, and its SH3 domain-containing binding partners,67 they seem to be spatially segregated and differentially influenced by protein kinases,77 phosphatases, and calcium ions.68,70

AMPA Receptors Undergo Differential Endosomal Sorting

Different stimuli differentially affect the subcellular localization of internalized receptors. AMPA receptors endocytosed via direct agonist stimulation (i.e., AMPA) colocalize with early endosomal markers such as early endosomal antigen 1 (EEA1), syntaxin 13, and endocytosed transferrin receptors. In contrast, AMPA receptors internalized via insulin- or NMDA-regulated signaling pathways although initially present in EEA1-positive early endosomes appear to segregate into distinct compartments, which may include late endosomes and lysosomes;78 but see77 for a different view). How precisely and at which stage differential endosomal sorting occurs remains unclear. Activated AMPA receptors colocalize with AP-269 and Eps1567 in clathrin-coated pits. Direct binding of the basic stretch within the cytoplasmic tail of the AMPA receptor, subunits GluR1-3, to the clathrin adaptor complex AP-2 is only required, for NMDA-induced AMPA receptor endocytosis,79 thus indicating that differential recognition modes at the cell surface may contribute to endosomal sorting. In nematodes, GluR is subject to multi-ubiquitination, which may target glutamate receptors for internalization and late endosomal/ lysosomal degradation.80 Differential sorting of receptors recognized directly by endocytic adaptors or modified by ubiquitination is seen in nonneuronal cells, i.e., in the case of internalized transferrin vs. epidermal growth factor receptors.81,82 Additionally, insulin-stimulated AMPA receptor internalization may be regulated by tyrosine phosphorylation,83 similar to what is seen for growth factor receptors.81

Receptor Determinants for Endosomal Sorting

As discussed above AMPA receptors internalized in response to direct agonist binding (i.e., AMPA) or NMDA-induced signaling cascades initially share the same early endosomal sorting pathway.78,84 During AMPA-induced internalization, homomeric GluR2 receptors appear to be retained within early recycling endosomes, whereas GluR2 endocytosed in response to NMDA is diverted to late endosomes and lysosomes for degradation.78 One important factor regulating sorting appears to be the subunit composition of heteromeric AMPA receptors. Homomeric GluR1 receptors are retained in recycling endosomes, whereas GluR3 homomers enter the late endosomal/ lysosomal pathway regardless of stimulation.78 In the context of heteromers endosomal sorting is apparently governed by GluR2, which exerts dominant effects, perhaps by recruiting adaptor proteins,85 by undergoing posttranslational modifications including tyrosine phosphorylation83 and ubiquitination80 or by binding to ubiquitinated adaptor proteins such as PSD-95.86 In nonneuronal cells, sorting of ubiquitinated cargo is achieved by ubiquitin-interacting motif (UIM) or ubiquitin-associated domain (UBA) containing accessory proteins including the phosphoinositide binding protein epsin, the EH-domain containing endocytic accessory protein Eps15, and Hrs.81,82 Both epsin and Eps15 are highly expressed in the brain and could serve functions in postsynaptic receptor sorting within the endosomal system, similar to their known roles in presynaptic vesicle recycling. In the case of the inhibitory GABAA receptor channel, it has recently been demonstrated that huntingtin-associated protein 1 (HAP1) modulates cell surface receptor number by inhibiting lysosomal GABAA receptor degradation.87 Since HAP1 can associate with the ubiquitin-binding adaptor Hrs85 it is tempting to speculate that HAP1 may act by suppressing Hrs-dependent lysosomal receptor targeting. Although HAP1 action appears to be restricted to inhibitory synapses similar regulatory principles may hold true for early endosomal trafficking of glutamate receptors.

Whereas endosomal targeting of AMPA receptors during conditions of long-term depression (LTD) is well established, much less is known about the recycling of internalized receptors to the cell surface. Recent data suggest that indeed recycling endosomes rather than trans-Golgi network (TGN)-derived vesicles supply AMPA receptors for long-term potentiation (LTP). Blocking exit from recycling endosomes by expression of dominant-negative mutants of either Rab11a or the EH-domain containing accessory protein EHD1/ Rme1 trapped internalized AMPA receptors in recycling endosomes (Fig. 5) and prevented expression of LTP in hippocampal slices.84

Figure 5. Recycling endosomes supply AMPA receptors for long-term potentiation (LTP).

Figure 5

Recycling endosomes supply AMPA receptors for long-term potentiation (LTP). Overexpressing a mutant version of the Eps15-homology domain protein EHD1/ Rme1 (Rme1-G429R) traps internalized AMPA receptor GluR1 (green) in recycling endosomes where it colocalizes (more...)

Thus, early recycling endosomes appear to play crucial roles in synaptic plasticity by regulating the internalization, recycling, degradation, and thus cell surface number of glutamate and possibly other ionotropic receptors at synapses.

References

1.
Le RoyC, Wrana JL. Clathrin- and nonclathrin-mediated endocytic regulation of cell signalling. Nat Rev Mol Cell Biol. 2005;6(2):112–126. [PubMed: 15687999]
2.
Murthy VN, De Camilli P. Cell biology of the presynaptic terminal. Annu Rev Neurosci. 2003;26:701–728. [PubMed: 14527272]
3.
Torrealba F, Carrasco MA. A review on electron microscopy and neurotransmitter systems. Brain Res Brain Res Rev. 2004;47(1-3):5–17. [PubMed: 15572159]
4.
Bruns D, Jahn R. Real-time measurement of transmitter release from single synaptic vesicles. Nature. 1995;377(6544):62–65. [PubMed: 7659162]
5.
Lundberg JM, FrancoCereceda A, Lou YP. et al. Differential release of classical transmitters and peptides. Adv Second Messenger Phosphoprotein Res. 1994;29:223–234. [PubMed: 7848713]
6.
Bredt DS, Nicoll RA. AMPA receptor trafficking at excitatory synapses. Neuron. 2003;40(2):361–379. [PubMed: 14556714]
7.
Heuser JE, Reese TS. Evidence for recycling of synaptic vesicle membrane during transmitter release at the frog neuromuscular junction. J Cell Biol. 1973;57(2):315–344. [PMC free article: PMC2108984] [PubMed: 4348786]
8.
Gad H, Low P, Zotova E. et al. Dissociation between Ca2+-triggered synaptic vesicle exocytosis and clathrin-mediated endocytosis at a central synapse. Neuron. 1998;21(3):607–616. [PubMed: 9768846]
9.
Takei K, Mundigl O, Daniell L. et al. The synaptic vesicle cycle: A single vesicle budding step involving clathrin and dynamin. J Cell Biol. 1996;133(6):1237–1250. [PMC free article: PMC2120898] [PubMed: 8682861]
10.
Galli T, Haucke V. Cycling of synaptic vesicles: How far? How fast! Sci STKE. 2004;2004(264):re19. [PubMed: 15613688]
11.
Valtorta F, Meldolesi J, Fesce R. Synaptic vesicles: Is kissing a matter of competence? Trends Cell Biol. 2001;11(8):324–328. [PubMed: 11489637]
12.
Jarousse N, Kelly RB. Endocytotic mechanisms in synapses. Curr Opin Cell Biol. 2001;13(4):461–469. [PubMed: 11454453]
13.
Wenk MR, De Camilli P. Protein-lipid interactions and phosphoinositide metabolism in membrane traffic: Insights from vesicle recycling in nerve terminals. Proc Natl Acad Sci USA. 2004;101(22):8262–8269. [PMC free article: PMC420382] [PubMed: 15146067]
14.
Szymkiewicz I, Shupliakov O, Dikic I. Cargo- and compartment-selective endocytic scaffold proteins. Biochem J. 2004;383(Pt 1):1–11. [PMC free article: PMC1134037] [PubMed: 15219178]
15.
Craxton M. Synaptotagmin gene content of the sequenced genomes. BMC Genomics. 2004;5(1):43. [PMC free article: PMC471550] [PubMed: 15238157]
16.
Takei K, Haucke V. Clathrin-mediated endocytosis: Membrane factors pull the trigger. Trends Cell Biol. 2001;11(9):385–391. [PubMed: 11514193]
17.
Hinshaw JE. Dynamin and its role in membrane fission. Annu Rev Cell Dev Biol. 2000;16:483–519. [PMC free article: PMC4781412] [PubMed: 11031245]
18.
McMahon HT, Mills IG. COP and clathrin-coated vesicle budding: Different pathways, common approaches. Curr Opin Cell Biol. 2004;16(4):379–391. [PubMed: 15261670]
19.
Merrifield CJ. Seeing is believing: Imaging actin dynamics at single sites of endocytosis. Trends Cell Biol. 2004;14(7):352–358. [PubMed: 15246428]
20.
Shupliakov O, Bloom O, Gustafsson JS. et al. Impaired recycling of synaptic vesicles after acute perturbation of the presynaptic actin cytoskeleton. Proc Natl Acad Sci USA. 2002;99(22):14476–14481. [PMC free article: PMC137908] [PubMed: 12381791]
21.
Blanpied TA, Scott DB, Ehlers MD. Dynamics and regulation of clathrin coats at specialized endocytic zones of dendrites and spines. Neuron. 2002;36(3):435–449. [PubMed: 12408846]
22.
Paillart C, Li J, Matthews G. et al. Endocytosis and vesicle recycling at a ribbon synapse. J Neurosci. 2003;23(10):4092–4099. [PubMed: 12764096]
23.
de Hoop MJ, Huber LA, Stenmark H. et al. The involvement of the small GTP-binding protein Rab5a in neuronal endocytosis. Neuron. 1994;13(1):11–22. [PubMed: 8043272]
24.
Murthy VN, Stevens CF. Synaptic vesicles retain their identity through the endocytic cycle. Nature. 1998;392(6675):497–501. [PubMed: 9548254]
25.
Zakharenko S, Chang S, O'Donoghue M. et al. Neurotransmitter secretion along growing nerve processes: Comparison with synaptic vesicle exocytosis. J Cell Biol. 1999;144(3):507–518. [PMC free article: PMC2132923] [PubMed: 9971745]
26.
Sara Y, Virmani T, Deak F. et al. An isolated pool of vesicles recycles at rest and drives spontaneous neurotransmission. Neuron. 2005;45(4):563–573. [PubMed: 15721242]
27.
Wucherpfennig T, Wilsch-Brauninger M, Gonzalez-Gaitan M. Role of Drosophila Rab5 during endosomal trafficking at the synapse and evoked neurotransmitter release. J Cell Biol. 2003;161(3):609–624. [PMC free article: PMC2172938] [PubMed: 12743108]
28.
Fischer von Mollard G, Stahl B, Walch-Solimena C. et al. Localization of Rab5 to synaptic vesicles identifies endosomal intermediate in synaptic vesicle recycling pathway. Eur J Cell Biol. 1994;65(2):319–326. [PubMed: 7720727]
29.
Shimizu H, Kawamura S, Ozaki K. An essential role of Rab5 in uniformity of synaptic vesicle size. J Cell Sci. 2003;116(Pt 17):3583–3590. [PubMed: 12876219]
30.
de Renzis S, Sonnichsen B, Zerial M. Divalent Rab effectors regulate the sub-compartmental organization and sorting of early endosomes. Nat Cell Biol. 2002;4(2):124–133. [PubMed: 11788822]
31.
Sonnichsen B, De Renzis S, Nielsen E. et al. Distinct membrane domains on endosomes in the recycling pathway visualized by multicolor imaging of Rab4, Rab5, and Rab11. J Cell Biol. 2000;149(4):901–914. [PMC free article: PMC2174575] [PubMed: 10811830]
32.
Christoforidis S, McBride HM, Burgoyne RD. et al. The Rab5 effector EEA1 is a core component of endosome docking. Nature. 1999;397(6720):621–625. [PubMed: 10050856]
33.
Lawe DC, Patki V, Heller-Harrison R. et al. The FYVE domain of early endosome antigen 1 is required for both phosphatidylinositol 3-phosphate and Rab5 binding. Critical role of this dual interaction for endosomal localization. J Biol Chem. 2000;275(5):3699–3705. [PubMed: 10652369]
34.
Nielsen E, Christoforidis S, Uttenweiler-Joseph S. et al. Rabenosyn-5, a novel Rab5 effector, is complexed with hVPS45 and recruited to endosomes through a FYVE finger domain. J Cell Biol. 2000;151(3):601–612. [PMC free article: PMC2185588] [PubMed: 11062261]
35.
Simonsen A, Lippe R, Christoforidis S. et al. EEA1 links PI(3)K function to Rab5 regulation of endosome fusion. Nature. 1998;394(6692):494–498. [PubMed: 9697774]
36.
Stenmark H, Vitale G, Ullrich O. et al. Rabaptin-5 is a direct effector of the small GTPase Rab5 in endocytic membrane fusion. Cell. 1995;83(3):423–432. [PubMed: 8521472]
37.
Mills IG, Jones AT, Clague MJ. Involvement of the endosomal autoantigen EEA1 in homotypic fusion of early endosomes. Curr Biol. 1998;8(15):881–884. [PubMed: 9705936]
38.
Misra S, Hurley JH. Crystal structure of a phosphatidylinositol 3-phosphate-specific membrane-targeting motif, the FYVE domain of Vps27p. Cell. 1999;97(5):657–666. [PubMed: 10367894]
39.
Sankaran VG, Klein DE, Sachdeva MM. et al. High-affinity binding of a FYVE domain to phosphatidylinositol 3-phosphate requires intact phospholipid but not FYVE domain oligomerization. Biochemistry. 2001;40(29):8581–8587. [PubMed: 11456498]
40.
Gillooly DJ, Morrow IC, Lindsay M. et al. Localization of phosphatidylinositol 3-phosphate in yeast and mammalian cells. EMBO J. 2000;19(17):4577–4588. [PMC free article: PMC302054] [PubMed: 10970851]
41.
Cowles CR, Odorizzi G, Payne GS. et al. The AP-3 adaptor complex is essential for cargo-selective transport to the yeast vacuole. Cell. 1997;91(1):109–118. [PubMed: 9335339]
42.
Stepp JD, Huang K, Lemmon SK. The yeast adaptor protein complex, AP-3, is essential for the efficient delivery of alkaline phosphatase by the alternate pathway to the vacuole. J Cell Biol. 1997;139(7):1761–1774. [PMC free article: PMC2132655] [PubMed: 9412470]
43.
Kretzschmar D, Poeck B, Roth H. et al. Defective pigment granule biogenesis and aberrant behavior caused by mutations in the Drosophila AP-3beta adaptin gene ruby. Genetics. 2000;155(1):213–223. [PMC free article: PMC1461058] [PubMed: 10790396]
44.
Mullins C, Hartnell LM, Wassarman DA. et al. Defective expression of the mu3 subunit of the AP-3 adaptor complex in the Drosophila pigmentation mutant carmine. Mol Gen Genet. 1999;262(3):401–412. [PubMed: 10589826]
45.
Ooi CE, Moreira JE, Dell'Angelica EC. et al. Altered expression of a novel adaptin leads to defective pigment granule biogenesis in the Drosophila eye color mutant garnet. EMBO J. 1997;16(15):4508–4518. [PMC free article: PMC1170077] [PubMed: 9303295]
46.
Le Borgne R, Alconada A, Bauer U. et al. The mammalian AP-3 adaptor-like complex mediates the intracellular transport of lysosomal membrane glycoproteins. J Biol Chem. 1998;273(45):29451–29461. [PubMed: 9792650]
47.
Yang W, Li C, Ward DM. et al. Defective organellar membrane protein trafficking in Ap3b1-deficient cells. J Cell Sci. 2000;113(Pt 22):4077–4086. [PubMed: 11058094]
48.
Faundez V, Horng JT, Kelly RB. ADP ribosylation factor 1 is required for synaptic vesicle budding in PC12 cells. J Cell Biol. 1997;138(3):505–515. [PMC free article: PMC2141633] [PubMed: 9245782]
49.
Horng JT, Tan CY. Biochemical characterization of the coating mechanism of the endosomal donor compartment of synaptic vesicles. Neurochem Res. 2004;29(7):1411–1416. [PubMed: 15202773]
50.
Blumstein J, Faundez V, Nakatsu F. et al. The neuronal form of adaptor protein-3 is required for synaptic vesicle formation from endosomes. J Neurosci. 2001;21(20):8034–8042. [PubMed: 11588176]
51.
Faundez V, Horng JT, Kelly RB. A function for the AP3 coat complex in synaptic vesicle formation from endosomes. Cell. 1998;93(3):423–432. [PubMed: 9590176]
52.
Hannah MJ, Schmidt AA, Huttner WB. Synaptic vesicle biogenesis. Annu Rev Cell Dev Biol. 1999;15:733–798. [PubMed: 10611977]
53.
Kantheti P, Qiao X, Diaz ME. et al. Mutation in AP-3 delta in the mocha mouse links endosomal transport to storage deficiency in platelets, melanosomes, and synaptic vesicles. Neuron. 1998;21(1):111–122. [PubMed: 9697856]
54.
Miller CL, Burmeister M, Stevens KE. Hippocampal auditory gating in the hyperactive mocha mouse. Neurosci Lett. 1999;276(1):57–60. [PubMed: 10586974]
55.
Vogt K, Mellor J, Tong G. et al. The actions of synaptically released zinc at hippocampal mossy fiber synapses. Neuron. 2000;26(1):187–196. [PubMed: 10798403]
56.
Nakatsu F, Okada M, Mori F. et al. Defective function of GABA-containing synaptic vesicles in mice lacking the AP-3B clathrin adaptor. J Cell Biol. 2004;167(2):293–302. [PMC free article: PMC2172536] [PubMed: 15492041]
57.
Blagoveshchenskaya AD, Norcott JP, Cutler DF. Lysosomal targeting of P-selectin is mediated by a novel sequence within its cytoplasmic tail. J Biol Chem. 1998;273(5):2729–2737. [PubMed: 9446579]
58.
Partoens P, Slembrouck D, Quatacker J. et al. Retrieved constituents of large dense-cored vesicles and synaptic vesicles intermix in stimulation-induced early endosomes of noradrenergic neurons. J Cell Sci. 1998;111(Pt 6):681–689. [PubMed: 9471997]
59.
Munoz DG. The distribution of chromogranin A-like immunoreactivity in the human hippocampus coincides with the pattern of resistance to epilepsy-induced neuronal damage. Ann Neurol. 1990;27(3):266–275. [PubMed: 2327736]
60.
Annaert WG, Quatacker J, Llona I. et al. Differences in the distribution of cytochrome b561 and synaptophysin in dog splenic nerve: A biochemical and immunocytochemical study. J Neurochem. 1994;62(1):265–274. [PubMed: 7505312]
61.
Kittler JT, Delmas P, Jovanovic JN. et al. Constitutive endocytosis of GABAA receptors by an association with the adaptin AP2 complex modulates inhibitory synaptic currents in hippocampal neurons. J Neurosci. 2000;20(21):7972–7977. [PubMed: 11050117]
62.
van Rijnsoever C, Sidler C, Fritschy JM. Internalized GABA-receptor subunits are transferred to an intracellular pool associated with the postsynaptic density. Eur J Neurosci. 2005;21(2):327–338. [PubMed: 15673433]
63.
Herring D, Huang R, Singh M. et al. Constitutive GABAA receptor endocytosis is dynamin-mediated and dependent on a dileucine AP2 adaptin-binding motif within the beta 2 subunit of the receptor. J Biol Chem. 2003;278(26):24046–24052. [PubMed: 12707262]
64.
Buttner C, Sadtler S, Leyendecker A. et al. Ubiquitination precedes internalization and proteolytic cleavage of plasma membrane-bound glycine receptors. J Biol Chem. 2001;276(46):42978–42985. [PubMed: 11560918]
65.
Rasmussen H, Rasmussen T, Triller A. et al. Strychnine-blocked glycine receptor is removed from synapses by a shift in insertion/degradation equilibrium. Mol Cell Neurosci. 2002;19(2):201–215. [PubMed: 11860273]
66.
Sheng M, Lee SH. AMPA receptor trafficking and the control of synaptic transmission. Cell. 2001;105(7):825–828. [PubMed: 11439178]
67.
Man HY, Lin JW, Ju WH. et al. Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization. Neuron. 2000;25(3):649–662. [PubMed: 10774732]
68.
Beattie EC, Carroll RC, Yu X. et al. Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD. Nat Neurosci. 2000;3(12):1291–1300. [PubMed: 11100150]
69.
Carroll RC, Lissin DV, von Zastrow M. et al. Rapid redistribution of glutamate receptors contributes to long-term depression in hippocampal cultures. Nat Neurosci. 1999;2(5):454–460. [PubMed: 10321250]
70.
Lin JW, Ju W, Foster K. et al. Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization. Nat Neurosci. 2000;3(12):1282–1290. [PubMed: 11100149]
71.
Luscher C, Xia H, Beattie EC. et al. Role of AMPA receptor cycling in synaptic transmission and plasticity. Neuron. 1999;24(3):649–658. [PubMed: 10595516]
72.
Malinow R, Malenka RC. AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci. 2002;25:103–126. [PubMed: 12052905]
73.
Passafaro M, Sheng M. Synaptogenesis: The MAP location of GABA receptors. Curr Biol. 1999;9(7):R261–263. [PubMed: 10209115]
74.
Pickard L, Noel J, Duckworth JK. et al. Transient synaptic activation of NMDA receptors leads to the insertion of native AMPA receptors at hippocampal neuronal plasma membranes. Neuropharmacology. 2001;41(6):700–713. [PubMed: 11640924]
75.
Ashby MC, De La Rue SA, Ralph GS. et al. Removal of AMPA receptors (AMPARs) from synapses is preceded by transient endocytosis of extrasynaptic AMPARs. J Neurosci. 2004;24(22):5172–5176. [PMC free article: PMC3309030] [PubMed: 15175386]
76.
Racz B, Blanpied TA, Ehlers MD. et al. Lateral organization of endocytic machinery in dendritic spines. Nat Neurosci. 2004;7(9):917–918. [PubMed: 15322548]
77.
Ehlers MD. Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting. Neuron. 2000;28(2):511–525. [PubMed: 11144360]
78.
Lee SH, Simonetta A, Sheng M. Subunit rules governing the sorting of internalized AMPA receptors in hippocampal neurons. Neuron. 2004;43(2):221–236. [PubMed: 15260958]
79.
Lee SH, Liu L, Wang YT. et al. Clathrin adaptor AP2 and NSF interact with overlapping sites of GluR2 and play distinct roles in AMPA receptor trafficking and hippocampal LTD. Neuron. 2002;36(4):661–674. [PubMed: 12441055]
80.
Burbea M, Dreier L, Dittman JS. et al. Ubiquitin and AP180 regulate the abundance of GLR-1 glutamate receptors at postsynaptic elements in C. elegans. Neuron. 2002;35(1):107–120. [PubMed: 12123612]
81.
Dikic I. Mechanisms controlling EGF receptor endocytosis and degradation. Biochem Soc Trans. 2003;31(Pt 6):1178–1181. [PubMed: 14641021]
82.
Hicke L, Dunn R. Regulation of membrane protein transport by ubiquitin and ubiquitin-binding proteins. Annu Rev Cell Dev Biol. 2003;19:141–172. [PubMed: 14570567]
83.
Ahmadian G, Ju W, Liu L. et al. Tyrosine phosphorylation of GluR2 is required for insulin-stimulated AMPA receptor endocytosis and LTD. EMBO J. 2004;23(5):1040–1050. [PMC free article: PMC380981] [PubMed: 14976558]
84.
Park M, Penick EC, Edwards JG. et al. Recycling endosomes supply AMPA receptors for LTP. Science. 2004;305(5692):1972–1975. [PubMed: 15448273]
85.
Li Y, Chin LS, Levey AI. et al. Huntingtin-associated protein 1 interacts with hepatocyte growth factor-regulated tyrosine kinase substrate and functions in endosomal trafficking. J Biol Chem. 2002;277(31):28212–28221. [PubMed: 12021262]
86.
Colledge M, Snyder EM, Crozier RA. et al. Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron. 2003;40(3):595–607. [PMC free article: PMC3963808] [PubMed: 14642282]
87.
Kittler JT, Thomas P, Tretter V. et al. Huntingtin-associated protein 1 regulates inhibitory synaptic transmission by modulating gamma-aminobutyric acid type A receptor membrane trafficking. Proc Natl Acad Sci USA. 2004;101(34):12736–12741. [PMC free article: PMC515122] [PubMed: 15310851]
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