The Synaptic Vesicle Cycle

Abstract

Neurotransmitter release is mediated by exocytosis of synaptic vesicles at the presynaptic active zone of nerve terminals. To support rapid and repeated rounds of release, synaptic vesicles undergo a trafficking cycle. The focal point of the vesicle cycle is Ca2+-triggered exocytosis that is followed by different routes of endocytosis and recycling. Recycling then leads to the docking and priming of the vesicles for another round of exo- and endocytosis. Recent studies have led to a better definition than previously available of how Ca2+ triggers exocytosis and how vesicles recycle. In particular, insight into how Munc18-1 collaborates with SNARE proteins in fusion, how the vesicular Ca2+ sensor synaptotagmin 1 triggers fast release, and how the vesicular Rab3 protein regulates release by binding to the active zone proteins RIM1 alpha and RIM2 alpha has advanced our understanding of neurotransmitter release. The present review attempts to relate these molecular data with physiological results in an emerging view of nerve terminals as macromolecular machines.

Hypothesis – buttressed rings assemble, clamp, and release SNAREpins for synaptic transmission

“…By contrast, the lower affinity of tripartite C2B (which we suggest is derived from Syt7) binding should not impose a kinetic impediment (~ 8 k B T ; spontaneous rate of dissociation between 1000 and 100 000 s −1 ). Taken together, these considerations make it plausible that our model is consistent with the observed time required from binding of Ca 2+ to opening of the fusion pore of the 0.3–0.5 ms for evoked synchronous quantal release 76.…”

Synaptic transmission at retinal ribbon synapses

“…In neurons, this complex typically consists of an integral vesicle protein, synaptobrevin (also known as vesicle-associated membrane protein [VAMP]), and two plasma membrane associated proteins, syntaxin 1 and SNAP-25 (synaptosomal-associated protein-25 kDa). These proteins bind to each other and together constitute the minimal core complex necessary for membrane fusion (reviewed by Bruns and Jahn, 2002;Sudhof, 2004). Syntaxin 1 also interacts at the molecular level with N-type calcium channels (Sheng et al, 1994).…”

Ultrastructural readout of functional synaptic vesicle pools in hippocampal slices based on FM dye labeling and photoconversion

“…In the central nervous system, fast neuron-neuron information transfer primarily takes place at chemical synapses, specialized and ultrastructurally distinct junction points at which presynaptic and postsynaptic structures lie closely apposed 1 . The presynaptic terminal is characterized by a cluster of neurotransmitter-containing synaptic vesicles and transmission proceeds with their activity-driven fusion leading to the discharge of chemical transmitter towards postsynaptic receptors.…”