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9.B.130 The Tetraspan Vesicle Membrane Protein (TVP) Family

Synaptoporins, synaptophysins, synaptogyrins and cellugyrins are homologous major membrane proteins in synaptic vesicles of animals.  All have 4 TMSs, belong to the MARVEL domain superfamily in Pfam, and are called tetraspan vesicle membrane proteins (TVPs).  They have cytoplasmically located end domains and are ubiquitous and abundant components of vesicles in most, if not all, cells of multicellular organisms (Hübner et al. 2002).  They have been shown to form ion conducting ion channels (Woodbury 1995), but they also regulate various transport processes (Chang et al. 2021). They are subject to protein modification, e.g., phosphorylation, and are part of multimeric complexes. TVPs contribute to vesicle trafficking and membrane morphogenesis (Hübner et al. 2002).

TVP-containing vesicles shuttle between various membranous compartments and are localized in biosynthetic and endocytotic pathways. Based on gene organization and amino acid sequence similarities, TVPs can be grouped into three distinct families that are referred to as physins, gyrins, and secretory carrier-associated membrane proteins (SCAMPs). In mammals, synaptophysin, synaptoporin, pantophysin, and mitsugumin29 constitute the physins, synaptogyrin 1-4 the gyrins, and SCAMP1-5 the SCAMPs. Members of each family are cell-type-specifically synthesized, resulting in unique patterns of TVP coexpression and subcellular colocalization (Hübner et al. 2002).

TVP orthologs have been identified in most multicellular organisms, including diverse animal and plant species, but have not been detected in unicellular organisms. They are subject to protein modification, most notably to phosphorylation, and are part of multimeric complexes. TVPs contribute to vesicle trafficking and membrane morphogenesis (Hübner et al. 2002).  Defects in these proteins may play a role in Schizophrenia.These proteins may function as part of the synaptic vesicle recycling machinery (Abraham et al. 2011). 

Synaptobrevin II (sybII) is a key fusogenic molecule on synaptic vesicles (SVs); therefore, the active maintenance of both its conformation and location in sufficient numbers on this organelle is critical in both mediating and sustaining neurotransmitter release. Three proteins play key roles in the presentation, trafficking and retrieval of sybII during the fusion and endocytosis of SVs. The nerve terminal protein α-synuclein catalyses sybII entry into SNARE complexes, whereas the monomeric adaptor protein AP-180 is required for sybII retrieval during SV endocytosis. Overarching these events is the tetraspan SV protein synaptophysin, which is a major sybII interaction partner on the SV. Working models for the control of sybII traffic by synaptophysin and other Sybtraps (sybII trafficking partners) have been proposed, suggesting how dysfunction in sybII traffic may contribute to human diseases (Gordon and Cousin 2014).

Synaptophysin (syp) is a major integral membrane protein of secretory vesicles. Syp functions in synaptic vesicle cycling, endocytosis, and synaptic plasticity, and plays a role in the process of membrane fusion during Ca2+-triggered exocytosis. Syp resides on both large dense-core and small synaptic vesicles where it mediates catecholamine release from single vesicles of chromaffin cells with altered levels of syp and the related tetraspanner protein synaptogyrin (syg). Knocking out syp slightly reduced the frequency of vesicle fusion events below wild-type levels, but knocking out both syp and syg reduced the frequency two-fold. Knocking out both proteins stabilized initial fusion pores, promoted fusion pore closure (kiss-and-run), and reduced late-stage fusion pore expansion (Chang et al. 2021). Introduction of a syp construct lacking its C-terminal dynamin-binding domain in syp knock-outs increased the duration and fraction of kiss-and-run events, increased total catecholamine release per event, and reduced late-stage fusion pore expansion. Thus, syp and syg regulate dense-core vesicle function at multiple stages to initiate fusion, control the choice of mode between full fusion and kiss-and-run, and influence the dynamics of both initial and late-stage fusion pores. The transmembrane domain influences small initial fusion pores, and the C-terminal domain influences large late-stage fusion pores, possibly through an interaction with dynamin. These proteins influence fusion pores at multiple stages and control the choice between kiss-and-run and full fusion. The transmembrane domain influences the initial fusion pore, while the C-terminal domain influences later stages after fusion pore expansion (Chang et al. 2021).

Synaptic vesicle release is regulated by upwards of 30 proteins at the fusion complex, but disruption in any one of these components can have devastating consequences for neuronal communication. Aberrant molecular responses to calcium signaling at the pre-synaptic terminal affect vesicle trafficking, docking, fusion, and release (White and Stowell 2021). At the organismal level, this is reflected in disorders such as epilepsy, depression, and neurodegeneration. Synaptophysin (SYP) may function as a calcium sensor and a cholesterol-binding protein, and it may form ion channels across the phospholipid bilayer. 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. Structural observations specifically implicate the SYP/VAMP2 complex in anchoring the SNARE assembly at the pre-synaptic membrane prior to vesicle fusion (White and Stowell 2021).

References associated with 9.B.130 family:

Abraham, C., L. Bai, and R.E. Leube. (2011). Synaptogyrin-dependent modulation of synaptic neurotransmission in Caenorhabditis elegans. Neuroscience 190: 75-88. 21689733
Chang, C.W., Y.T. Hsiao, and M.B. Jackson. (2021). Synaptophysin Regulates Fusion Pores and Exocytosis Mode in Chromaffin Cells. J. Neurosci. [Epub: Ahead of Print] 33664131
Gordon, S.L. and M.A. Cousin. (2014). The Sybtraps: control of synaptobrevin traffic by synaptophysin, α-synuclein and AP-180. Traffic 15: 245-254. 24279465
Hsiao, Y.T. and M.B. Jackson. (2022). Synaptophysin transmembrane domain III controls fusion pore dynamics in Ca-triggered exocytosis. Biophys. J. [Epub: Ahead of Print] 36168290
Hübner, K., R. Windoffer, H. Hutter, and R.E. Leube. (2002). Tetraspan vesicle membrane proteins: synthesis, subcellular localization, and functional properties. Int Rev Cytol 214: 103-159. 11893164
Knaus, P., B. Marquèze-Pouey, H. Scherer, and H. Betz. (1990). Synaptoporin, a novel putative channel protein of synaptic vesicles. Neuron. 5: 453-462. 2206533
White, D.N. and M.H.B. Stowell. (2021). Room for Two: The Synaptophysin/Synaptobrevin Complex. Front Synaptic Neurosci 13: 740318. 34616284
Woodbury, D.J. (1995). Evaluation of the evidence for ion channels in synaptic vesicles. Mol. Membr. Biol. 12: 165-171. 7540913