Synaptic transmission, the central process for neuronal communication, occurs when signaling molecules, called neurotransmitters, are released by one neuron target and activate the receptors of another neuron. This process plays crucial functions in neuronal growth and development, synapse formation, and signal transduction. Neuroscientists have put tremendous effort into elucidating the molecular mechanism of synaptic transmission, but many questions still remain.

Synaptic transmission consists of three steps: (1) intracellular vesicles loaded with neurotransmitters are targeted to the presynaptic membrane; (2) an action potential triggers exocytosis to release the neurotransmitters to the synaptic cleft between two neurons; and (3) neurotransmitters bind to the receptors on the postsynaptic membrane to activate the signal transduction pathway.

Synaptic exocytosis is caused by Ca2+-triggered membrane fusion, one of the main focuses of synaptic transmission research for the last two decades. Membrane fusion is a cellular process by which two initially separate lipid bilayers merge to form one interconnected structure. Intracellular trafficking and communication between neurons are important examples of the many processes that rely on this mechanism. Membrane fusion in eukaryotic cells requires the action of a conserved family of proteins called soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). The SNARE complex consists of a parallel four helix-bundle via association of their shared motifs composed of 15 hydrophobic core layers. SNAREs form sets of three or four individual proteins that have been classified as either Q- or R-SNAREs based on the identity of the residue at the zero layer. In response to presynaptic depolarization, neurotransmitters encapsulated within synaptic vesicles in the axonal terminal are released into the synaptic cleft in <1ms. This fast Ca2+-triggered neurotransmitter release is the result of the fusion of a few synaptic vesicles to the plasma membrane. The synaptic machinery, consisting of SNAREs and other factors including synaptotagmin, complexin, and Munc18, are responsible for this fast neurotransmitter release.

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Frontiers in Molecular Neuroscience

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