Mechanism of neurotransmitter release coming into focus

Abstract

Research for three decades and major recent advances have provided crucial insights into how neurotransmitters are released by Ca -triggered synaptic vesicle exocytosis, leading to reconstitution of basic steps that underlie Ca -dependent membrane fusion and yielding a model that assigns defined functions for central components of the release machinery. The soluble N-ethyl maleimide sensitive factor attachment protein receptors (SNAREs) syntaxin-1, SNAP-25, and synaptobrevin-2 form a tight SNARE complex that brings the vesicle and plasma membranes together and is key for membrane fusion. N-ethyl maleimide sensitive factor (NSF) and soluble NSF attachment proteins (SNAPs) disassemble the SNARE complex to recycle the SNAREs for another round of fusion. Munc18-1 and Munc13-1 orchestrate SNARE complex formation in an NSF-SNAP-resistant manner by a mechanism whereby Munc18-1 binds to synaptobrevin and to a self-inhibited "closed" conformation of syntaxin-1, thus forming a template to assemble the SNARE complex, and Munc13-1 facilitates assembly by bridging the vesicle and plasma membranes and catalyzing opening of syntaxin-1. Synaptotagmin-1 functions as the major Ca sensor that triggers release by binding to membrane phospholipids and to the SNAREs, in a tight interplay with complexins that accelerates membrane fusion. Many of these proteins act as both inhibitors and activators of exocytosis, which is critical for the exquisite regulation of neurotransmitter release. It is still unclear how the actions of these various proteins and multiple other components that control release are integrated and, in particular, how they induce membrane fusion, but it can be expected that these fundamental questions can be answered in the near future, building on the extensive knowledge already available.

Synaptotagmin-1 and Doc2b exhibit distinct membrane remodeling mechanisms

“…Syt1 contains a single transmembrane domain and two cytoplasmic C2 domains (together named C2AB). The C2A and C2B domains can bind three and two Ca 2+ ions, respectively, accompanied by binding to phosphatidylserine in the membrane (2). The C2AB domain also binds to phosphatidylinositol 4,5-bisphosphate and SNARE proteins (3)(4)(5)(6).…”

“…The C2AB domain also binds to phosphatidylinositol 4,5-bisphosphate and SNARE proteins (3)(4)(5)(6). Ca 2+ binding is thought to be the direct trigger for vesicle fusion (1,2,7). Other C2-domain-containing proteins such as Doc2b, which contributes to spontaneous neurotransmitter release, similarly interact with membranes and SNARE proteins to trigger fusion (8,9).…”

Proteome Changes Paralleling the Olfactory Conditioning in the Forager Honey Bee and Provision of a Brain Proteomics Dataset

“…The SNAREs (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors) play a critical role in neurotransmitter release as a part of a highly conserved membrane fusion system and are involved in axonal guidance or neuroregeneration. [18][19][20][21][22][23] BET1 is a constituent of the Q-SNARE driving the vesicular ER-to-Golgi transport, [24] and VAMP-7 regulates the synaptic vesicle pool [25,26] and is included in the exocytotic pathway implicated in neurite, axonal outgrowths, and cell polarity. [27][28][29] Despite the well-known role of SNAREs in neuronal communication, the information on their memory-specific functions is limited.…”

“…This was demonstrated by a decrease of the corresponding proteins in the PER‐conditioned group, most notably the SNARE proteins VAMP7 and BET1‐homolog, or the nicotinic acetylcholine receptor nAChRb1 (Figure d). The SNAREs (soluble N ‐ethylmaleimide‐sensitive fusion protein attachment protein receptors) play a critical role in neurotransmitter release as a part of a highly conserved membrane fusion system and are involved in axonal guidance or neuroregeneration . BET1 is a constituent of the Q‐SNARE driving the vesicular ER‐to‐Golgi transport, and VAMP‐7 regulates the synaptic vesicle pool and is included in the exocytotic pathway implicated in neurite, axonal outgrowths, and cell polarity .…”

Structural Basis for the Clamping and Ca2+Activation of SNARE-mediated Fusion by Synaptotagmin

“…Based on the currently available structural, biochemical and physiological data, several speculative models for Ca 2+ -regulated SV exocytosis have been proposed [44][45][46][47][48] . But the precise molecular architecture that accommodates all the functionally relevant SNARE and membrane interactions of Syt1 is unclear.…”