Vesicle Trafficking Presynaptic Signaling
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Neuronal communication is a very connective process. Transfer of information between neurons occurs at the synapse, where the neuronal information is converted from electrical action potentials into neurochemical signals. The synapse comprises a presynaptic active zone (a clustering of vesicle fusion sites and calcium channels on the presynaptic cell membrane), the synaptic cleft, and the postsynaptic density, an electron-dense domain of the postsynaptic neuron specializing in the reception and integration of synaptic signals. Intracellular vesicles containing neurotransmitter (NT) rapidly fuse to the presynaptic membrane and release their contents into the synaptic cleft upon arrival of an action potential—a type of neurotransmission termed synchronous release. The docking, priming, and fusion of these vesicles is carried out by SNARE family and other chaperone proteins located on both the vesicle and presynaptic cell membrane. Synaptic vesicles dock to predetermined sites in the active zone through the interaction of vesicle-associated Rab3 (or Rab27) with RIM, which can bind to calcium channels directly and via RIM-BP (A). SNARE proteins might also play a role in docking based on studies of non-neuronal cells, but there is no conclusive evidence for such a role in mammalian neurons. The vesicle SNARE protein, VAMP (also called synaptobrevin), binds to SNARE proteins on the cell membrane, syntaxin 1 and SNAP25, priming the vesicle for fusion (B). Munc18-1 binds to monomeric syntaxin 1 as well the SNARE complex and assists with complex assembly. The co-chaperone protein complexin and the calcium-binding protein synaptotagmin 1 (SYT1) associate with SNARE proteins to form tight complexes, bringing the lipid membranes together (C). When an action potential in the presynaptic neuron opens voltage-gated calcium channels, calcium binds to SYT1 and allows SYT1 to interact with the SNARE complex as well as the plasma membrane resulting in membrane fusion and release of NT into the synaptic cleft (D). The fast response to an action potential is due in part to the proteins RIM, RIM-BP, and Munc13, which form physical interactions between the vesicle, the cell membrane, and calcium channels, bringing the three necessary elements into close proximity. Released NT can be recycled through specific transporters such as EAATs (reuptake of glutamate) or a monoamine transporter, such as SERT (reuptake of serotonin) or DAT (reuptake of dopamine) back into the cytoplasm of the neuron.
Selected Reviews:
- Blakely RD, Edwards RH. Vesicular and plasma membrane transporters for neurotransmitters. Cold Spring Harb Perspect Biol. 2012;4(2)
- Jahn R, Fasshauer D. Molecular machines governing exocytosis of synaptic vesicles. Nature. 2012;490(7419):201-7.
- Saheki Y, De camilli P. Synaptic vesicle endocytosis. Cold Spring Harb Perspect Biol. 2012;4(9):a005645.
- Südhof TC. Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron. 2013;80(3):675-90.
- Südhof TC. A molecular machine for neurotransmitter release: synaptotagmin and beyond. Nat Med. 2013;19(10):1227-31.
- Südhof TC. The presynaptic active zone. Neuron. 2012;75(1):11-25.
We would like to thank Taulant Bacaj, Stanford School of Medicine, Palo Alto, CA for reviewing this diagram.
created December 2016