Exocytosis and Endocytosis: Modes, Functions, and Coupling Mechanisms

Abstract

Vesicle exocytosis releases content to mediate many biological events, including synaptic transmission essential for brain functions. Following exocytosis, endocytosis is initiated to retrieve exocytosed vesicles within seconds to minutes. Decades of studies in secretory cells reveal three exocytosis modes coupled to three endocytosis modes: (a) full-collapse fusion, in which vesicles collapse into the plasma membrane, followed by classical endocytosis involving membrane invagination and vesicle reformation; (b) kiss-and-run, in which the fusion pore opens and closes; and (c) compound exocytosis, which involves exocytosis of giant vesicles formed via vesicle-vesicle fusion, followed by bulk endocytosis that retrieves giant vesicles. Here we review these exo- and endocytosis modes and their roles in regulating quantal size and synaptic strength, generating synaptic plasticity, maintaining exocytosis, and clearing release sites for vesicle replenishment. Furthermore, we highlight recent progress in understanding how vesicle endocytosis is initiated and is thus coupled to exocytosis. The emerging model is that calcium influx via voltage-dependent calcium channels at the calcium microdomain triggers endocytosis and controls endocytosis rate; calmodulin and synaptotagmin are the calcium sensors; and the exocytosis machinery, including SNARE proteins (synaptobrevin, SNAP25, and syntaxin), is needed to coinitiate endocytosis, likely to control the amount of endocytosis.

Differential vesicular sorting of AMPA and GABA A receptors

“…Receptor exocytosis occurs when an intracellular vesicle, which carries assembled receptor complexes, fuses to the plasma membrane and the receptor complexes are delivered to the plasma membrane (27). This process highly depends on SNARE proteins, which can be cleaved by different Botoxs (19).…”

The evidence for open and closed exocytosis as the primary release mechanism

“…When an action potential arrives in the nerve terminal, the membrane depolarizes and voltage-gated Ca 2+ channels open. The subsequent Ca 2+ influx triggers exocytosis of synaptic vesicles, resulting in the release of neurotransmitter into the synaptic gap between two neighboring neurons (Jahn & Sudhof, 1994;Lawson et al 1977;Steyer et al 1997;Tsai et al 2008;Wu et al 2014;Zucker, 1996). Exocytosis has become a key area for research providing understanding of the molecular mechanisms that control the process of chemical communication between neurons.…”

“…The formation of this fusion pore allows neurotransmitter molecules to exit the pore as it expands. The general theory of exocytosis suggests that it is an all or none process and that the synaptic vesicle membrane and proteins are then rapidly retrieved and reutilized for the formation of new synaptic vesicles, a process called endocytosis (Foley et al 2011;Wu et al 2014). These vesicles are reloaded with transmitter for another round of exocytosis, a cycle that is repeated many times and can be studied in nerve terminals that have no connection with the neuronal cell body.…”

“…These vesicles are reloaded with transmitter for another round of exocytosis, a cycle that is repeated many times and can be studied in nerve terminals that have no connection with the neuronal cell body. Thus, the presynaptic compartment consists of an autonomous unit that contains all components required for repetitive exocytosis and membrane recycling (Foley et al 2011;Jin et al 2008;Wu et al 2014). To get more insight, transmission electron microscopy (TEM) methods have been widely used in the last decades to visualize the ultrastructure of the cell and acquire information about the small-sized vesicle compartments in cells, especially during exocytosis process.…”

‘Full fusion’ is not ineluctable during vesicular exocytosis of neurotransmitters by endocrine cells

“…In neurons and endocrine cells neurotransmitters are transported as cargo by vesicles, tailored and loaded in the Golgi apparatus and delivered at specific release sites of the cell membrane where they dock to finally release neurotransmitters through a fusion pore connecting the cell and vesicle membranes [7][8][9][10][11][12]. In endocrine cells, release through the initial fusion pore is minute and the pore may close or flicker (Kiss and Run) [13][14][15][16][17][18][19][20][21], as occurs in neurons [22][23][24]; however, generally the pore rapidly expands [25] to release a massive flux of neurotransmitters that is precisely quantifiable by amperometry at carbon-fibre micro-and nanoelectrodes [22][23][24][26][27][28][29][30][31][32][33][34].…”