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Dendritic Snares Add a New Twist to the Old Neuron Theory

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Dendritic Snares Add a New Twist to the Old Neuron Theory PERSPECTIVE Dendritic SNAREs add a new twist to the old neuron theory Saak V. Ovsepian1 and J. Oliver Dolly1 International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland Edited by Thomas C. Südhof, Stanford University School of Medicine, Palo Alto, CA, and approved October 4, 2011 (received for review November 22, 2010) Dendritic exocytosis underpins a broad range of integrative and homeostatic synaptic functions. Emerging data highlight the essential role of SNAREs in trafficking and fusion of secretory organelles with release of peptides and neurotransmitters from dendrites. This Perspective analyzes recent evidence inferring axo-dendritic polarization of vesicular release machinery and pinpoints progress made with existing challenges in this rapidly progressing field of dendritic research. Interpreting the relation of new molecular data to physiological results on secretion from dendrites would greatly advance our understanding of this facet of neuronal mechanisms. dendritic release | neuronal polarization | retrograde transmission lassically, a single neuron exocytosis at dendrites in compliance with its central hydrophilic layer containing receives multimodal informa- the view of highly conserved fusion ma- three conserved glutamines (Q) and one C tion as local electro-chemical chinery among different secretory path- arginine (R) (18). Accordingly, the con- signals through synaptic inputs ways, new findings indicate their notable tributing molecules are grouped into Qa-, converging onto its soma and dendrites. specialization, supporting the premise of Qb-, Qc-, Qbc-, and R-SNAREs (19, 20) After integration, these confined events molecular asymmetry as one of the key (Fig. 1A). In neurons, SNAREs driving are translated into action potentials at the affiliates of neuronal polarization. secretion are represented by a vesicle- axon initial segment, which rapidly prop- associated membrane protein (VAMP, known also as synaptobrevin, R-SNARE), agate to nerve terminals and trigger there SNARE Hypothesis and Secretory plasma membrane anchored-attached syn- quantal release of neurotransmitters. Re- Vesicle Fusion at Synapses cent electrophysiological and imaging data, taxin (Qa-SNARE), and SNAP (compris- however, dispute this rather naïve view of Membrane fusion constitutes one of the ing two SNARE motifs, Qbc-SNARE) fundamental biological processes governing neurons, highlighting unforeseen traits variants (21). Advantageously for research, targeting and merging of intracellular and dynamics of dendritic integration and these proteins constitute natural targets for organelles. Analysis of its mechanisms led communication mechanisms between Clostridial neurotoxins (CNTs, both botu- to the discovery of SNAREs as highly nerve cells. It emerges that neurons, in linum and tetanus toxins), which recognize conserved key nanoengines of various addition to transferring signals through and proteolytically inactivate SNAREs intracellular trafficking steps (11, 12). canonical chemical synapses at the axon with astounding efficiency and specificity, According to the contemporary model of causing blockade of synaptic transmission terminals, also interact via mixed electro- membrane fusion, SNAREs, along with (22–24) (Fig. 1B). Unstructured in mono- chemical and electrical synapses at so- several regulatory proteins, which are lo- meric state, SNAREs when associated matic and dendritic juxtapositions, as well calized in opposing membranes, attach and form highly stable ternary helical com- as through diffuse nonsynaptic volume propel the merger of membranes, using the – fi plexes (syntaxin and VAMP contributing transmission signaling (1 4). Signi cant free energy that is released during the evidence has also accrued suggesting es- one, whereas SNAP-25 provides two formation of a four-helix SNARE bundle. α sential roles for dendritic exocytosis in Although not undisputed, during the last -helices) before vesicular release (13, 18). these and numerous other integrative and 2 decades this model attracted scientific This multireaction process, which was ex- homeostatic processes. These include re- scrutiny from numerous angles and gained plicitly demonstrated at both the ensemble lease of transmitters, neurotrophins, and overwhelming support from functional, and single molecular levels, is initiated modulatory peptides from dendrites, along molecular, and genetic studies (13–15). by the opening of syntaxin and binding of with activity-dependent remodeling of In eukaryotic cells, the SNARE protein Munc18 to the syntaxin Habc N-terminal synaptic connections via regulated ex- family is represented by nine subfamilies, domain (25, 26), a step that promotes pression of receptors and ion channels with a total of 36 members identified in loose and reversible interaction between – (5 7). Although a great body of data humans (16). Originally, a strict separation SNARE motifs of syntaxin with SNAP-25 advocate the involvement of SNAREs in was assumed between these proteins re- and VAMP, leading to anchoring of the trafficking and vesicular fusion at den- siding on the “donor” and “acceptor” synaptic vesicle at the release site (Fig. C drites, nonvesicular release of retrograde membrane compartments, which led to 1 ). Upon binding of complexin, another messengers (e.g., endocannabinoids, their classification as vesicle membrane cytosolic regulatory protein, the transient arachidonic acid, nitric oxide, and carbon SNARE core scaffold gets primed for or target membrane SNAREs (v- and 2+ monoxide) from this location with their t-SNAREs) (17). This categorization, rapid activation by the Ca sensor syn- autocrine and paracrine effects on target however, proved to be inept when homo- aptotagmin (27); the latter enforces the and precursor neurons has additionally typic fusion events were considered and dissociation of complexin from the been documented (8–10). This Perspective especially in cases in which certain SNARE complex and puts into effect the reviews and analyzes key research streams SNAREs function in several transport on SNARE-dependent retrosynaptic steps, with varying partners. The more re- signaling in mammalian central neurons cent and widely accepted classification is, Author contributions: S.V.O. and J.O.D. wrote the paper. and highlights the outstanding issues therefore, based on reactive motifs con- The authors declare no conflict of interest. and challenges in this rapidly progressing tributed by each partner toward the for- This article is a PNAS direct submission. fi fi topic. Despite the well-de ned signi - mation of ultrastable coiled-coil SNARE 1To whom correspondence may be addressed. E-mail: saak. cance of SNAREs for trafficking and complexes during membrane fusion, with [email protected] or [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1017235108 PNAS | November 29, 2011 | vol. 108 | no. 48 | 19113–19120 Downloaded by guest on September 24, 2021 A C SV docking N-terminal SNARE TM domains motif domain Munc18 ATP Complexin Qa-SNARE Releasable 2 Qb-SNARE vesicle SV priming Qc-SNARE Qbc-SNARE 1 3 R-SNARE SV fusion 2+ B Syntaxin 1A 4 Ca ATP SNAP, NSF Synaptobrevin 2 BoNT/C BoNT/A D BoNT/E Synaptobrevin 2 BoNT/F SNAP-25 Syntaxin 1A BoNT/D COOH Extracellular milieu TeNT or BoNT/B Secretory organelle BoNT/G SNAP-25 Fig. 1. SNAREs and vesicular secretion from neurons. (A) Types of SNAREs with their gross structures schematized. The C-terminal of SNAREs corresponds to the transmembrane (TM) domains; the central portion contains the SNARE motif, and the N-terminal of Qa-SNAREs (syntaxins in neurons) possesses antiparallel three-helix bundles. In Qbc SNAREs (SNAP-23 and SNAP-25 in neurons), duplicated SNARE motifs are connected by a linker that is frequently palmitoylated (zig- zag lines) and anchors the protein to the membrane. During vesicular fusion at nerve terminals Qbc SNAREs (SNAP-23/25 variants) contribute two α-helices to the four-helical core complex, with the other two provided by Qa (syntaxin) and R (VAMP) SNAREs. Dashed borders highlight domains that are missing in some subfamily members. Modified with permission from ref. 18. (B) SNAREs constitute molecular targets of Clostridial neurotoxins, which recognize and cleave these fusogenic proteins at specific scissile bonds. Neuronal SNAREs serve as substrate for the protease light chains of tetanus toxin and botulinum neurotoxins: arrows indicate the cleavage sites of individual SNAREs by the different neurotoxins (BoNT, A-G serotypes of botulinum neurotoxin; TeNT, tetanus toxin). Plasma and vesicle membranes are indicated in gray (Left and Right, respectively). (C) Schematic of the SNARE-dependent synaptic vesicle cycle. Conforma- tional shift from a closed to an open state of the N-terminal motif of syntaxin (Qa SNARE, red) conditioned by SM protein Munc18 initiates the loose in- teraction of syntaxin with SNAP-25 (Qbc SNARE, green) and VAMP (R-SNARE, blue), leading to ATP-dependent docking of SVs at the active zone (1, 2). This complex gets primed by complexin and Munc18 for activation by synaptotagmin and Ca2+ (3). Upon Ca2+ influx, synaptotagmin dissociates the complexin from the fusion complex and reacts with membrane phospholipids and the SNAREs, driving membrane fusion (4) and release of vesicular contents into the synaptic cleft. This step is followed by dissociation of the SNARE complex by NSF using the hydrolysis of ATP as energy source, liberating SNAREs for further reuse. (D)A crystal structure of SNARE core complex with four parallel α-helices associated
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