Abstract
Communication between neurons relies on neurotransmitters which are released from synaptic vesicles (SVs) upon Ca2+ stimuli. To efficiently load neurotransmitters, sense the rise in intracellular Ca2+ and fuse with the presynaptic membrane, SVs need to be equipped with a stringently controlled set of transmembrane proteins. In fact, changes in SV protein composition quickly compromise neurotransmission and most prominently give rise to epileptic seizures. During exocytosis SVs fully collapse into the presynaptic membrane and consequently have to be replenished to sustain neurotransmission. Therefore, surface-stranded SV proteins have to be efficiently retrieved post-fusion to be used for the generation of a new set of fully functional SVs, a process in which dedicated endocytic sorting adaptors play a crucial role. The question of how the precise reformation of SVs is achieved is intimately linked to how SV membranes are retrieved. For a long time both processes were believed to be two sides of the same coin since Clathrin-mediated endocytosis (CME), the proposed predominant SV recycling mode, will jointly retrieve SV membranes and proteins. However, with the recent proposal of Clathrin-independent SV recycling pathways SV membrane retrieval and SV reformation turn into separable events. This review highlights the progress made in unraveling the molecular mechanisms mediating the high-fidelity retrieval of SV proteins and discusses how the gathered knowledge about SV protein recycling fits in with the new notions of SV membrane endocytosis.
Highlights
Communication between neurons is based on the release of neurotransmitters at the presynapse which bind to postsynaptic receptors thereby inducing electrical signals
To allow for sustained neurotransmission synaptic vesicles (SVs) exocytosis needs to be tightly balanced by endocytosis for three main reasons: (1) the expansion of the active zone needs to be reversed to preserve the alignment of the release sites with postsynaptic receptors and to restore membrane tension; (2) the release sites have to be cleared from exocytosed material to be available for new Adaptors in Synaptic Vesicle Recycling rounds of SV fusion; and (3) since synapses are mostly located far away from the cell body, SV membrane proteins have to be retrieved for the local reformation of SVs to replenish the SV pool
Upon stimulation with more than two action potentials, the majority of SV membrane seems not to be internalized with subsecond kinetics, but rather over several seconds (Soykan et al, 2017). These results suggest that the retrieval capacity of ultrafast endocytosis (UFE) might be limited to the amount of SV membrane exocytosed in response to stimulation with single or very few action potentials
Summary
Communication between neurons is based on the release of neurotransmitters at the presynapse which bind to postsynaptic receptors thereby inducing electrical signals. Surface-stranded SV proteins have to be efficiently retrieved post-fusion to be used for the generation of a new set of fully functional SVs, a process in which dedicated endocytic sorting adaptors play a crucial role.
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