The role of non-canonical SNAREs in synaptic vesicle recycling

Abstract

An increasing number of studies suggest that distinct pools of synaptic vesicles drive specific forms of neurotransmission. Interspersed with these functional studies are analyses of the synaptic vesicle proteome which have consistently detected the presence of so-called "non-canonical" SNAREs that typically function in fusion and trafficking of other subcellular structures within the neuron. The recent identification of certain non-canonical vesicular SNAREs driving spontaneous (e.g., VAMP7 and vti1a) or evoked asynchronous (e.g., VAMP4) release integrates and corroborates existing data from functional and proteomic studies and implies that at least some complement of non-canonical SNAREs resident on synaptic vesicles function in neurotransmission. Here, we discuss the specific roles in neurotransmission of proteins homologous to each member of the classical neuronal SNARE complex consisting of synaptobrevin2, syntaxin-1, and SNAP-25.

Figure 1. This cartoon depicts an emerging model on the distributions of vesicular SNAREs syb2, vti1a and VAMP7 among synaptic vesicle pools. At central synapses, syb2 is the predominant vesicular SNARE that ensures rapid execution of synaptic vesicle fusion. However, loss-of-function studies of syb2 suggest that a parallel pathway involving non-canonical SNAREs may mediate fusion and recycling of a subset of vesicles. Recent studies revealed that both vti1a and VAMP7 could fulfill this role and specifically traffic at rest. Vti1a possesses a more prominent intracellular pool and more robust trafficking in the absence of activity compared with VAMP7. On the other hand, vesicles containing vti1a or VAMP7 show relatively reluctant responses to action potential evoked stimulation compared with swift mobilization of syb2-containing vesicles during evoked neurotransmission. Given their relative reluctance for mobilization VAMP7 containing vesicles could constitute at least a fraction of the vesicles within the resting pool. The co-existence of molecularly distinct synaptic vesicle populations with different fusion properties may allow certain regulatory pathways to impact a particular type of neurotransmission selectively, thereby triggering a specific cellular response. In this way, the nature of presynaptic activity can determine the impact of downstream postsynaptic signaling events.

Figure 2. Recent work supports a model where the vesicle-associated SNARE VAMP4 functionally diverges from the key vesicular SNARE syb2 and predominantly maintains asynchronous release. Experiments using a combination of electrophysiology and optical imaging indicate that a small but significant population of vesicles appears to be enriched in VAMP4, follows a distinct route of stimulation-dependent trafficking facilitated by VAMP4's N-terminal di-leucine motif and selectively supports asynchronous release. According to this model, sustained activity can generate a synaptic vesicle population enriched in VAMP4. A VAMP4-dependent SNARE complex formed after recruitment of these vesicles provides a substrate upon which a Ca²⁺ sensor acts to drive asynchronous release.