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Review
.2012 May;50(1):58-69.
doi: 10.1016/j.mcn.2012.03.009. Epub 2012 Apr 2.

The SNARE complex in neuronal and sensory cells

Affiliations
Review

The SNARE complex in neuronal and sensory cells

Neeliyath A Ramakrishnan et al. Mol Cell Neurosci.2012 May.

Abstract

Transmitter release at synapses ensures faithful chemical coding of information that is transmitted in the sub-second time frame. The brain, the central unit of information processing, depends upon fast communication for decision making. Neuronal and neurosensory cells are equipped with the molecular machinery that responds reliably, and with high fidelity, to external stimuli. However, neuronal cells differ markedly from neurosensory cells in their signal transmission at synapses. The main difference rests in how the synaptic complex is organized, with active zones in neuronal cells and ribbon synapses in sensory cells (such as photoreceptors and hair cells). In exocytosis/neurosecretion, SNAREs (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors) and associated proteins play a critical role in vesicle docking, priming, fusion and synchronization of neurotransmitter release. Recent studies suggest differences between neuronal and sensory cells with respect to the molecular components of their synaptic complexes. In this review, we will cover current findings on neuronal and sensory-cell SNARE proteins and their modulators. We will also briefly discuss recent investigations on how deficits in the expression of SNARE proteins in humans impair function in brain and sense organs.

Copyright © 2012 Elsevier Inc. All rights reserved.

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Figures

Fig. 1
Fig. 1
Vesicle organization across different types of synapses and steps in synaptic vesicle fusion. (A) Neuronal active zone at the presynaptic terminal, where synaptic vesicles are clustered in the presynaptic area. (B) Neuromuscular junction synapse, where vesicles are organized in a ridge-shaped structure. (C) Sensory cell ribbon synapse, where vesicles are organized around a ribbon-like or spherical structure at the presynaptic terminal. (D) Steps in vesicle fusion include vesicle tethering, docking, priming and finally, fusion. These events are driven by high-affinity interaction between v-SNARE and t-SNARE proteins, regulated by calcium and calcium-binding proteins through their interaction with the SNARE complexes.
Fig. 2
Fig. 2
Isoforms of SNARE proteins and the sites of action of neurotoxins. Syntaxins 1, 2 and 3 share a common functional domain arrangement, with a C-terminal transmembrane domain (TM) and a preceding SNARE motif.Clostridium botulinum neurotoxin (BoNT) serotype C cleaves the C-terminus of all three isoforms of the syntaxin SNARE motif. SNAP-25, a neuronal SNARE protein, and its non-neuronal isoform, SNAP-23, share common features of molecular domains while showing dissimilar sensitivity to neurotoxins. SNAP-25 is cleaved by BoNT/A, C, and E, while SNAP-23 is cleaved by BoNT/A and E. Similarly, the v-SNARE proteins synaptobrevins 1 and 2 share common features. However, synaptobrevin 1 is cleaved by BoNT/B, D and F as well as tetanus toxin (TeTx). Synaptobrevin 2, on the other hand, is cleaved by BoNT/G. Examples above are given for mouse sequences.
Fig. 3
Fig. 3
Vesicle fusion complex in neurosecretory cells from different sources. (A) In neurons, the complex is composed of the core SNARE proteins syntaxin 1A and SNAP-25 (t-SNAREs) and synaptobrevin1 (v-SNARE). The fusion is synchronized by reversible inhibition of SNARE complex formation by complexin 1/2 that interferes in the SNARE helix formation. Voltage-gated calcium channel Cav2.2 opens during depolarization of the cell membrane, allowing calcium entry that is sensed by synaptotagmin1. Synaptotagmin 1 in turn replaces complexin and allows the SNARE formation that brings vesicle and plasma membrane together. Synaptotagmin 1 interacts with PIP2 on the plasma membrane and forces the membranes to fuse, creating a pore for the release of the neurotransmitters. (B) In photoreceptor cells, the basic mechanism of fusion remains the same as for neurons, except that syntaxin 3, paired with SNAP-25, forms the SNARE complex. Synchronous release in photoreceptor cells is believed to be regulated by complexin 3/4. Synaptotagmin 1/2 is thought to be the calcium sensor. Importantly, the L-type channel isoform Cav1.4 mediates calcium current in the ribbon synapses of photoreceptor cells. (C) In mechanosensory auditory and vestibular hair cells, a similar neuronal SNARE model is thought to be operative, as described above. However, there are divergent opinions regarding the identity of the calcium sensors. So far, otoferlin is the only candidate that seems to fit the qualifications required for a calcium sensor in this setting. Differing views of otoferlin's hair-cell function are probably due to themolecule's multiple roles in vesicle recycling/transport and/or in maintaining membrane integrity. Hair cells exhibit synchronous release, similarly to neuronal and photoreceptor cells. However, the nature of the protein that regulates this pivotal step in hair-cell secretion has yet to be identified. The L-type channel isoform Cav1.3 is the major voltage-gated calcium channel expressed in hair cells.
Fig. 4
Fig. 4
Hypothetical model of the porosome and synaptic vesicle, showing involvement of multiple SNARE molecules in vesicle fusion. Porosomes, nano-scale stable membrane invaginations observed at active zones and ribbon synapses, consist of cup-shaped structures with the base of the “cup” facing the vesicle (Jena, 2009b). The outer rim of the cup opens towards the outside and bears eight to twelve protein knobs. The cavity of the porosome is occupied by a mobile “plug” that is thought to move in and out during neurosecretion. Multiple t-SNAREs required for vesicle fusion are shown localized at the cup's base, ready to pair with the v-SNAREs of the vesicle. Voltage-gated calcium channels are thought to be localized close to the fusion machinery via their protein–protein interaction with t-SNARE proteins. Close proximity of channels is required for the formation of calcium nano-domains that support fast exocytosis. It is hypothesized that vesicles attach to the porosome, probably via SNARE formation and are recycled after release. Insets show transmission electron micrograph photos (same micrograph unlabeled and labeled) of hair-cell porosome (orange) with central plug (blue arrowhead) from the sacculus of the rainbow trout. SV, synaptic vesicle; SM, synaptic membrane (cf. Drescher et al., 2011).
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