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  • Review Article
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Temporal and spatial coordination of exocytosis and endocytosis

Key Points

  • In all eukaryotic cells, the constitutive processes of exocytosis and endocytosis maintain the flow of material to and from the cell surface. In secretory active cells, these processes have to be tightly balanced and co-regulated.

  • In the chemical synapses of nerve cells, where large amounts of neurotransmitter are released from synaptic vesicles at defined sites of the cell membrane (the active zones), the coupling of exocytosis and endocytosis has been studied in some detail. In addition, catecholamine-secreting chromaffin cells are well-studied non-neuronal models.

  • Compensatory retrieval of secretory vesicles can be accomplished by two fundamentally different modes, that is, either by clathrin-mediated endocytosis after full fusion of the vesicle with the cell membrane or by a so-called 'kiss-and-run' mechanism. The latter mode is characterized by a brief opening of a fusion pore between the vesicle and the cell membrane, which leads to the release of the vesicle content without the whole vesicle collapsing into the cell membrane.

  • Vesicle recycling by kiss-and-run-type mechanisms can occur within a few hundred milliseconds, whereas retrieval by clathrin-mediated endocytosis can take several seconds to minutes.

  • In chemical synapses, clathrin-mediated endocytosis takes place adjacent to the active zone of exocytosis, whereas, in the 'kiss-and-run' mode, retrieval occurs in the same position as exocytosis.

  • Distinct organizing elements in the cell membrane and the underlying cytoskeleton are thought to define the sites of exocytosis and endocytosis. These elements include specific lipid domains in the cell membrane, a special configuration of the actin–spectrin-based cytoskeleton, and/or, in particular in chemical synapses, a specialized cytoskeletal matrix that is assembled at the active zone the CAZ ('cytomatrix assembled at the active zone').

  • The bivalent calcium ion, which is the trigger for regulated exocytosis, also seems to act as the main mediator that controls the mode of compensatory endocytosis.

Abstract

In secretory cells, exocytosis and compensatory endocytosis are tightly coupled membrane trafficking processes that control the surface area and composition of the plasma membrane. While exocytic and endocytic processes have been studied independently in great detail, at present there is much interest in understanding the mode of their coupling. This review discusses emerging insights into the coupling of these processes, both in the chemical synapses of neurons and in non-neuronal cells.

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Figure 1: Exocytic and endocytic membrane trafficking events at the presynaptic membrane — the synaptic vesicle cycle.
Figure 2: Synaptic-vesicle pools in presynaptic boutons.
Figure 3: Spatial organization of the sites of exocytosis and endocytosis in nerve terminals.
Figure 4: Elements with an ability to compartmentalize the plasma membrane and thereby organize the machineries for membrane trafficking processes.

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Acknowledgements

We thank our colleagues T. Dresbach, J. Klingauf, J. Rettig and C. Seidenbecher for their helpful comments on this manuscript, and L. Brodin, H. Gad, J. Roos and O. Shupliakov for providing images. Work on this topic in the authors' laboratories is supported by the Deutsche Forschungsgemeinschaft, the Land Sachsen-Anhalt and the Fonds der Chemischen Industrie.

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Correspondence to Eckart D. Gundelfinger, Michael M. Kessels or Britta Qualmann.

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DATABASES

LocusLink

calcium channels

clathrin

dynamin

endophilin

epsin

HIP1R

intersectin

Munc13

Munc18

Piccolo/Aczonin

profilin

rabphilin

scinderin

stoned/stonin

syndapin

synaptobrevin/VAMP

synaptojanin

synaptotagmins

Swiss-Prot

Abp1

amphiphysin

Bassoon

DAP160

Rab3a

RIM

FURTHER INFORMATION

Eckart D. Gundelfinger's laboratory

Britta Qualmann's and Michael M. Kessels' research groups ('Membrane trafficking and cytoskeleton')

synProt — Visualisation of Protein Interactions at Synapses

Glossary

ENDOCRINE AND EXOCRINE CELLS

Endocrine cells secrete their products (hormones) into the blood or into surrounding tissues, whereas exocrine cells deliver their products (sweat, tears or mucus) into ducts or to the body surface.

CHEMICAL SYNAPSE

A highly specialized cell–cell junction that is designed for efficient communication between a nerve cell and its target cell, that is, another neuron, a muscle cell or a gland cell.

SYNAPTIC VESICLE

A membrane-enclosed compartment for the storage of neurotransmitter in presynaptic boutons.

PRESYNAPSE

Part of the chemical synapse, from which neurotransmitter is released by regulated exocytosis.

ACTIVE ZONE

A specialized area of the presynaptic plasma membrane where synaptic vesicles fuse and release their neurotransmitter content.

PRESYNAPTIC BOUTON

A compartment of the presynaptic neuron that is specialized for neurotransmitter release and contains the various synaptic vesicle pools and one or several active zones.

TONIC NEUROTRANSMITTER RELEASE

The persistent release of neurotransmitter at highly specialized chemical synapses, such as ribbon synapses.

BIOGENIC AMINES

A class of neurotransmitters that includes dopamine, adrenaline and noradrenaline, and 5-hydroxytryptamine (serotonin).

RIBBON SYNAPSE

A synapse that is specialized for the high-throughput release of transmitter; it is characterized by an elaborate, electron-dense presynaptic specialization (the synaptic ribbon), which mediates the efficient transport of synaptic vesicles to the active zone.

ACTION POTENTIAL

An electrical signal that travels along presynaptic neuronal extensions (axons) and elicits neurotransmitter release by depolarizing the presynaptic plasma membrane and triggering Ca2+ influx into presynaptic boutons.

LARGE DENSE-CORE VESICLE

(LDCV) A secretory vesicle that is characterized by an electron-dense core when visualized by electron microscopy. It usually contains neuroactive peptides or hormones and, in neurons, fuses with the plasma membrane outside the active zone.

FLUORESCENT STYRYL DYE

A water-soluble lipid that becomes fluorescent when it reversibly enters lipid bilayers.

SHIBIRE MUTANT

A Drosophila melanogaster mutant strain that carries a temperature-sensitive mutation in the shibire gene, which encodes the Drosophila dynamin homologue.

CORTICAL GRANULE

A large secretory vesicle that is localized next to the plasma membrane of a sea-urchin egg cell. It contains proteinaceous material that is secreted during egg activation.

CYTOMATRIX

A cytoplasmic matrix; an insoluble gel-like matrix of the cytoplasm of a cell. It consists primarily of cytoskeletal and cytoskeleton-associated elements.

PLECKSTRIN-HOMOLOGY DOMAIN

(PH). A protein module of 100 amino acids (originally identified in the platelet protein pleckstrin) that is present in a range of proteins, which are involved in intracellular signalling or are constituents of the cytoskeleton. A proposed function of PH domains is that they bind phosphatidylinositol-4,5-bisphosphate.

SYNAPTOPHYSIN

A tetraspan protein of the synaptic-vesicle membrane. It is used frequently as a synaptic marker molecule.

C2 DOMAIN

(conserved region 2 of protein kinases C). C2 domains are 100 amino-acids long and bind phospholipids and Ca2+ interdependently. They are present in many proteins that are involved in Ca2+ signalling.

STONED PROTEINS

Proteins encoded by the stoned locus of Drosophila melanogaster and their vertebrate homologues.

SRC-HOMOLOGY-3 DOMAIN

(SH3). A protein module of 50 amino acids that can interact with the proline-rich motifs of proteinaceous binding partners.

SNARES

(soluble N-ethylmaleimide-sensitive factor attachment protein receptors). A family of membrane-tethered coiled-coil proteins that regulate membrane fusion events.

EC50

The EC50 defines the ligand (for example, Ca2+) concentration that elicits 50% of the maximum possible activity of a biochemical reaction (for example, exocytic activity).

Kd

The dissociation constant (Kd) is a measure of the affinity of a protein for a particular binding partner (small compound or other protein). Low Kd values indicate high affinity.

AMPA-TYPE GLUTAMATE RECEPTORS

One class of receptors for the excitatory neurotransmitter glutamate, which can be operated artificially by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate.

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Gundelfinger, E., Kessels, M. & Qualmann, B. Temporal and spatial coordination of exocytosis and endocytosis. Nat Rev Mol Cell Biol 4, 127–139 (2003). https://doi.org/10.1038/nrm1016

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