Room for Two: The Synaptophysin/Synaptobrevin Complex.

Dustin N White,Michael H B Stowell

doi:10.3389/fnsyn.2021.740318

Dustin N White, Michael H B Stowell

Open Access

https://doi.org/10.3389/fnsyn.2021.740318

Copy DOI

Abstract

Synaptic vesicle release is regulated by upwards of 30 proteins at the fusion complex alone, but disruptions in any one of these components can have devastating consequences for neuronal communication. Aberrant molecular responses to calcium signaling at the pre-synaptic terminal dramatically affect vesicle trafficking, docking, fusion, and release. At the organismal level, this is reflected in disorders such as epilepsy, depression, and neurodegeneration. Among the myriad pre-synaptic proteins, perhaps the most functionally mysterious is synaptophysin (SYP). On its own, this vesicular transmembrane protein has been proposed to function as a calcium sensor, a cholesterol-binding protein, and to form ion channels across the phospholipid bilayer. The downstream effects of these functions are largely unknown. The physiological relevance of SYP is readily apparent in its interaction with synaptobrevin (VAMP2), an integral element of the neuronal SNARE complex. SNAREs, soluble NSF attachment protein receptors, comprise a family of proteins essential for vesicle fusion. The complex formed by SYP and VAMP2 is thought to be involved in both trafficking to the pre-synaptic membrane as well as regulation of SNARE complex formation. Recent structural observations specifically implicate the SYP/VAMP2 complex in anchoring the SNARE assembly at the pre-synaptic membrane prior to vesicle fusion. Thus, the SYP/VAMP2 complex appears vital to the form and function of neuronal exocytotic machinery.

Highlights

Communication between neurons is a fundamental process of the nervous system
Though past studies saw no change in ion channel activity in response to fluctuation in Ca2+ concentration, SYP is known to bind cytoplasmic calcium (Rehm et al, 1986)
At terminals with depleted readily releasable pool (RRP), the rate of vesicle recycling is significantly impacted by the absence of VAMP2 (Deák et al, 2004). ‘‘Slow endocytosis’’ is VAMP2 dependent, but appears to rely on the activity of additional SNAREs syntaxin and SNAP-25 (Xu et al, 2013a). This dual role of VAMP2 heavily implicates it in the cycle of exoand endocytosis required to maintain the RRP

Summary

INTRODUCTION

Communication between neurons is a fundamental process of the nervous system. Regulated neurotransmitter release contributes to everything from memory consolidation to mood regulation (Jurado et al, 2013; Kandel et al, 2014; Metzger et al, 2017). Vesicle endocytosis, synaptobrevin trafficking during SNARE assembly, and the kiss-and-run archetype of dense-core vesicle fusion (Gincel and Shoshan-Barmatz, 2002; Kwon and Chapman, 2011; Harper et al, 2017; Chang et al, 2021) Probing these functions has proved difficult, due to the compensatory nature of various physin family proteins (Janz et al, 1999). ‘‘Slow endocytosis’’ is VAMP2 dependent, but appears to rely on the activity of additional SNAREs syntaxin and SNAP-25 (Xu et al, 2013a) This dual role of VAMP2 heavily implicates it in the cycle of exoand endocytosis required to maintain the RRP. The neuronal SNARE fusion complex at the pre-synaptic plasma membrane results from the assembly of numerous fusion proteins, including syntaxin, SNAP-25, and synaptobrevin (VAMP2; Brunger, 2005). While the identity of these proteins is unknown, it is clear that their assembly is dependent

Article title

Contextual Roles