Mechanisms of Endocytosis

Doherty, Gary J.; McMahon, Harvey T.

doi:10.1146/annurev.biochem.78.081307.110540

Cited by 2,633 publications

(2,639 citation statements)

References 248 publications

(189 reference statements)

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“…Membrane bending mechanistically occurs by the insertion of amphipathic helices into the cytoplasmic leaflet of the plasma membrane and involves crescent-shaped F-BAR (FCH domain-binamphiphysin-rvs; FCH-BAR)-containing proteins such as FCHo proteins, amphiphysin, endophilin, syndapin as well as the EnTH domain of epsin 57 . The assembling clathrin coat formed from mixed pentagonal and hexagonal arrays of clathrin triskelia provides a scaffold 6,8,14,55 that serves three main purposes. First, it stabilizes the deformed membrane patch 58 , thereby regulating synaptic vesicle size; second, clathrin (and/or adaptor scaffolds) concentrates synaptic vesicle cargo; and third, the assembled clathrin lattice organizes the dynamic flux of endocytic proteins needed for clathrincoated pit maturation, dynamin-mediated fission and uncoating (FIG.…”

Section: Box 1 | Presynaptic Organization -Exocytic and Endocytic Zonesmentioning

confidence: 99%

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Protein scaffolds in the coupling of synaptic exocytosis and endocytosis

2011

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Communication between nerve cells largely occurs at chemical synapses -specialized sites of cell-cell contact where electrical signals trigger the exocytic release of neurotransmitter, which in turn activates postsynaptic receptor channels. The efficacy with which such chemical signals are transmitted is crucial for the functioning of the nervous system. Modulation of neurotransmission enables nerve cells to respond to a vast range of stimulus patterns. Synaptic activity can also be tremendously diverse; from the fast synapses of the hippocampus, to slow neuropeptide-containing synapses. Indeed, some signalling pathways are active in the absence of stimulation, such as those involved in the processing of sensory information, which transmit tonically at high rates of up to 100 Hz or more 1,2 .Intriguing questions arise from these facts, including how high rates of neurotransmission can be maintained over long periods of time, and what limits the ability of a given synapse to release neurotransmitter during sustained periods of activity. Recent data indicate that in many synapses, exocytosis of neurotransmitter is coupled to endocytosis, and that synapses have evolved a specialized apparatus of scaffolding proteins to comply with these demands. Such scaffolds aid the temporal and spatial coupling of exocytosis and endocytosis, and are crucial for maintaining rapid neurotransmission during sustained activity 3 .Exocytosis of neurotransmitter is triggered by stimulusinduced calcium influx into the nerve terminal 4,5 and the subsequent fusion of synaptic vesicles with the presynaptic plasma membrane at specialized regions called active zones (BOX 1). Exocytosed synaptic vesicle membrane proteins and lipids in turn are recycled at the endocytic or periactive zone (BOX 1) that surrounds the release site, to restore functional synaptic vesicle pools for reuse and to ensure long-term functionality of the synapse 6-8 (FIG. 1). Depending on the type of synapse and the stimulation frequency, several modes of endocytosis with different time constants -for example, fast and slow endocytosisseem to operate 7,9,10 . Clathrin-mediated endocytosis arguably represents the main pathway of synaptic vesicle endocytosis 6,8,11 , although other modes -for example, fast kiss-and-run exocytosis and endocytosis -could operate in parallel.Although the machineries for exocytic membrane fusion 12,13 and for endocytic retrieval of synaptic vesicle membranes have been studied separately in some detail 6,14 , comparatively little is known about the coupling between exocytosis and endocytosis. Here we synthesize recent data from physiological, morphological and biochemical studies in several model systems into hypothetical models for scaffold-based mechanisms underlying exocytic-endocytic coupling.The synaptic vesicle cycle Synaptic vesicle pools. Some defining features of chemical synapses are the presence of one or several clusters of synaptic vesicles in the presynaptic nerve terminal, and ultrastructural specializations at the pre-and postsy...

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Section: Box 1 | Presynaptic Organization -Exocytic and Endocytic Zonesmentioning

confidence: 99%

“…Several proteins of the exocytic-endocytic machinery interact with, or regulate, components of the actin cytoskeleton 3,14,66,68,69 . For example, the large multidomain CAZ component piccolo associates with profilin, a proline-rich protein that binds to actin monomers and facilitates ADP to ATP exchange.…”

Section: Super-resolution Light Microscopic Techniquesmentioning

confidence: 99%

Protein scaffolds in the coupling of synaptic exocytosis and endocytosis

2011

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“…Although internalization mechanisms are really diverse, they generally are classified into three main groups: clathrin mediated, lipid raft/caveolae mediated, and macropinocytosis/phagocytosis. 36 Chemical inhibition of these pathways are regularly used in biology. 37 Amiloride, which blocks macropinocytosis; chlorpromazine, which prevents the formation of clathrin coated pits; and filipin III, which inhibits caveole mediated uptake, were incubated with the cells for 1 h. 38 Then solutions containing MDP-capped AuNPs (25 μg mL −1 ) and each inhibitor were added to the culture media and incubated for an additional 4 h. The resulting cells were lysed and subjected to ICP-MS for the detection of gold content.…”

Section: Resultsmentioning

confidence: 99%

Multi-Domain Short Peptide Molecules for in Situ Synthesis and Biofunctionalization of Gold Nanoparticles for Integrin-Targeted Cell Uptake

Gulsuner

Ceylan

Güler

et al. 2015

ACS Appl. Mater. Interfaces

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We describe design and synthesis model of multidomain (modular) peptides (MDPs), which direct a reaction cascade coupling the synthesis and surface functionalization of gold nanoparticles (AuNPs) in a single step. The synthesis is achieved via simple mixing of the aqueous solutions of auric acid and MDPs at room temperature without the addition of any surfactants or toxic intermediate reagents. This method allows facile control over the nanoparticle size between ∼2−15 nm, which opens a practical window for biomedical applications. In contrast to the conventional citrate-mediated methods, peptide-mediated synthesis and stabilization provide increased colloidal stability to AuNPs. As a proof of this concept, we demonstrate active targeting of human breast adenocarcinoma cell line (MCF7) using the one-step-prepared engineered AuNPs. Overall, we propose a single-step, chemically greener, biologically safer method for the synthesis and surface functionalization of gold nanoparticles in a sizecontrolled manner. The chemical versatility of the MDP design broadens the applicability of this strategy, thereby emerging as a successful alternative for the currently available nanoparticle preparation technologies.

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“…These results suggest that Fol-PaC (G3, DSF 5) has negligible cytotoxicity under the present experimental conditions. Cellular association and intracellular distribution As FR, which likely increases local folate concentrations at the plasma membrane to allow its efficient uptake via folate transporters, is a glycosylphosphatidylinositol-linked protein, which is entered by the clathrin-independent carrier/glycophosphatidylinositol-anchored protein-enriched early endosomal compartment pathway, 36 we hypothesized that pDNA complex with Fol-PaC (G3, DSF 5) is entered by clathrin-independent carrier/glycophosphatidylinositol-anchored protein-enriched early endosomal compartment endocytosis pathway. To verify this hypothesis, we examined the cellular association of Alexa --pDNA 1 h after transfection of the complexes of Alexa --pDNA/carriers with or without FA, a competitor for FR, in KB cells by a flow cytometric analysis ( Figure 5).…”

Section: Resultsmentioning

confidence: 99%

Potential use of folate-polyethylene glycol (PEG)-appended dendrimer (G3) conjugate with α-cyclodextrin as DNA carriers to tumor cells

et al. 2012

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We previously reported that polyamidoamine STARBURST dendrimer (generation 3, G3) (dendrimer) conjugate with a-cyclodextrin (a-CyD) having an average degree of substitution of 2.4 of a-CyD (a-CDE) provided remarkable aspects as novel carriers for DNA and small-interfering RNA. To develop novel a-CDE derivatives with tumor cell specificity, we prepared folate-appended a-CDEs (Fol-a-CDEs) and folate-polyethylene glycol (PEG)-appended a-CDEs (Fol-PaCs) with the various degrees of substitution of folate (DSF), and evaluated in vitro and in vivo gene transfer activity, cytotoxicity, cellular association and physicochemical properties. In vitro gene transfer activity of Fol-a-CDEs (G3, DSF 2, 5 or 7) was lower than that of a-CDE (G3) in KB cells, folate receptor (FR)-overexpressing cancer cells. Of the three Fol-PaCs (G3, DSF 2, 5 or 7), Fol-PaC (G3, DSF 5) had the highest gene transfer activity in KB cells. The activity of Fol-PaC (G3, DSF 5) was significantly higher than that of a-CDE (G3) in KB cells, but not in A549 cells, FR-negative cells. Negligible cytotoxicity of the plasmid DNA (pDNA) complex with Fol-PaC (G3, DSF 5) was observed in KB cells or A549 cells up to a charge ratio of 100/1 (carrier/pDNA). The cellular association of the pDNA complex with Fol-PaC (G3, DSF 5) could be mediated by FR on KB cells, resulting in its efficient cellular uptake. Fol-PaC (G3, DSF 5) had a higher binding affinity with folate-binding protein than a-CDE (G3), although the physicochemical properties of pDNA complex with Fol-PaC (G3, DSF 5) were almost comparable to that with a-CDE (G3), although the onset charge ratio and the compaction ability of Fol-PaC (G3, DSF 5) were slightly different. Fol-PaC (G3, DSF 5) tended to show a higher gene transfer activity than a-CDE (G3) 12 h after intratumoral administration in mice. These results suggest that Fol-PaC (G3, DSF 5), not Fol-a-CDEs, could be potentially used as a FR-overexpressing cancer cell-selective DNA carrier.

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Mechanisms of Endocytosis

Cited by 2,633 publications

References 248 publications

Protein scaffolds in the coupling of synaptic exocytosis and endocytosis

Protein scaffolds in the coupling of synaptic exocytosis and endocytosis

Multi-Domain Short Peptide Molecules for in Situ Synthesis and Biofunctionalization of Gold Nanoparticles for Integrin-Targeted Cell Uptake

Potential use of folate-polyethylene glycol (PEG)-appended dendrimer (G3) conjugate with α-cyclodextrin as DNA carriers to tumor cells

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