Neurotransmitter release: The last millisecond in the life of a synaptic vesicle

Südhof TC. (2013) Neurotransmitter release: The last millisecond in the life of a synaptic vesicle. Neuron

Neurons communicate by packaging neurotransmitters in vesicles, a small compartment surrounded by a lipid bilayer, that merge with the cell membrane, a process called vesicular fusion, to release the contents into a synapse. These signaling molecules can then bind to a complimentary receptor on a neighbouring cell. Neuronal communication requires the tightly controlled release of neurotransmitters with temporal and quantal precision and the use of vesicles and vesicular fusion provides this.

The process of releasing vesicles loaded with neurotransmitters begins with the action potential-mediated opening of voltage-gated Ca2+ channels, allowing Ca2+ to influx into the nerve terminal. This shift triggers the fusion of loaded vesicles that are docked at the cell membrane and evokes a fast synchronous neurotransmitter release. Ca2+ binds to synpatotagmins which are evolutionarily conserved transmembrane proteins that have two cytoplasmic C2-domains where Ca2+ binds. C2-domains are also an area high in protein interactions. There are 16 synaptotagmins expressed in the brain, of which 8 bind Ca2+. One commonly studied synaptotagmin, Syt1, binds to syntaxin-1 and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes. Synaptotagmins also require complexin to act as a co-factor to prime SNARE complexes, as an activator for subsequent synaptotagmin action, and to clamp spontaneous release.

To ensure a quick release of neurotransmitter in response to an action potential, the Ca2+ channels are tethered to docked and primed synaptic vesicles in the active zone (the site of neurotransmitter release). A protein complex consisting of multidomain proteins including Rab3-interacting molecule (RIM), a RIM interacting molecule (RIM-BP), and Munc13 regulate docking and priming vesicles in the active zone and recruits Ca2+ channels to the docked and primed vesicles. The role of RIM is to bind small GTP-binding proteins localized to synaptic vesicles to dock them as well as activating Munc13. Munc13 is a priming factor that switches syntaxin-1 from closed to open and promotes the SNARE-complex assembly. RIM and RIM-BP also bind to each other and the Ca2+ channels. Taking these functions together, the role of this complex is to keep synaptic vesicles, Ca2+ channels, and vesicle priming factors near the active zone causing fast coupling of the action potential and neurotransmitter release.

Membrane fusion is mediated by SNARE, which is the main machinery in fusion that provides energy for fusion to occur between a vesicle and the cell membrane, and association and dissociation of Sec-1/Munc18-like (SM) proteins. As well, within the synapse, the vesicle SNARE protein synaptobrevin (VAMP) needs to interact and form a complex with the membrane SNARE proteins syntaxin-1 and SNAP-25. Before SNARE-complex assembly proceeds, syntaxin-1 must “open”. While syntaxin-1 is still “closed” Munc18-1, an SM protein, binds and stays bound until syntaxin-1 begins to “open” and prepare to fuse then Munc18-1 will interact with the SNARE complex. The interaction between the SNARE/SM complex allows fusion to occur, then they dissociate and are recycled.

It is evident that vesicular fusion is a very controlled process that requires the interaction of many different proteins and molecules. This tight control is necessary because signaling must be precise. Each neurotransmitter or chemical signal elicit very specific responses from neighbouring cells and the effect can be significant. If we consider our knowledge of mental illnesses such as depression, anxiety, and bipolar disorder it has been well established that they are due to a neurotransmitter imbalance either through a reduction in production or excess signaling of the neurotransmitter. As well, neurological disorders such as Alzheimer’s disease and Parkinson’s disease have been associated with alterations in neurotransmitter levels. Another disorder that appears to be influenced by defective vesicular fusion is rhizomelia chondrodysplasia punctata (RCDP). RCDP is a severe form of dwarfism with cognitive deficits, caused by an inability to produce plasmalogens, a type of lipid important in vesicular fusion. It is believed that some of the difficulties experienced by the patients with RCDP are caused or exacerbated by an inability or limited ability of vesicles to fuse and allow neurons to communicate. Intracellular communication is fundamental for the health and proper functioning of an organism therefore any deviations or factors that alter vesicular fusion can have considerable effects, seen in the diseases previously described.