Proteins SNARE

A second mechanism that impinges on the localization of transporters is through the association with proteins, the most prominent example being syntaxin. Syntaxin is a t-SNARE protein necessary for the fusion of vesicles with the plasma membrane (see the chapter on exocytosis). On the cell surface syntaxin consistently stabilizes the localization of GABA, noradrenaline, glycine, and 5HT transporters the PKCa isoform can sever the interaction with syntaxin suggesting a general mechanism for transporter internalization. 

Based largely on a proposal by Rothman and colleagues, anterograde vesicular transport can be considered to occur in eight steps (Figure 46-7). The basic concept is that each transport vesicle bears a unique address marker consisting of one or more v-SNARE proteins, while each target membrane bears one or more complementary t-SNARE proteins with which the former interact specifically. 

Most transport vesicles bud off as coated vesicles, with a unique set of proteins decorating their cytosolic surface 141 GTP-binding proteins, such as the small monomeric GTPases and heterotrimeric GTPases (G proteins) facilitate membrane transport 142 SNARE proteins and Rabs control recognition of specific target membranes 143... 

Catterall WA (1999) Interactions of presynaptic Ca2+ channels and snare proteins in neurotransmitter release. Ann N Y Acad Sci 868 144—159... 

All botulin neurotoxins act in a similar way. They only differ in the amino-acid sequence of some protein parts (Prabakaran et al., 2001). Botulism symptoms are provoked both by oral ingestion and parenteral injection. Botulin toxin is not inactivated by enzymes present in the gastrointestinal tracts. Foodborne BoNT penetrates the intestinal barrier, presumably due to transcytosis. It is then transported to neuromuscular junctions within the bloodstream and blocks the secretion of the neurotransmitter acetylcholine. This results in muscle limpness and palsy caused by selective hydrolysis of soluble A-ethylmalemide-sensitive factor activating (SNARE) proteins which participate in fusion of synaptic vesicles with presynaptic plasma membrane. SNARE proteins include vesicle-associated membrane protein (VAMP), synaptobrevin, syntaxin, and synaptosomal associated protein of 25 kDa (SNAP-25). Their degradation is responsible for neuromuscular palsy due to blocks in acetylcholine transmission from synaptic terminals. In humans, palsy caused by BoNT/A lasts four to six months. 

Single transmembrane helix Ca2+ receptor N terminus in vesicle SNARE proteins, C termini in vesicle Integral membrane protein Integral membrane protein, Cl- transporter Integral membrane protein Integral membrane protein 13 subunits H+ generator... 

Araque A., Li N., Doyle R. T., and Haydon P. G. (2000). SNARE protein-dependent glutamate release from astrocytes. J. Neurosci. 20 666-673. 

Most neurotransmitter release occurs by exocytosis of secretory vesicles, which involves the fusion of the secretory vesicles (synaptic vesicles and LDCVs) with the plasma membrane. All intracellular membrane fusion (except for mitochondrial fusion) is thought to operate by the same fundamental mechanism that involves a core machinery composed of four classes of proteins SNARE-proteins, SM-proteins (for... 

Membrane fusion consists of merging two negatively charged phospholipid bilayers, and thus requires overcoming a major energy barrier (Jahn et al., 2003). SNARE proteins represent a family of membrane proteins that are present on opposing membranes destined to fuse. As first proposed by Jahn, Heuser, Rothman and colleagues... 

Synaptic exocytosis involves three SNARE proteins the R-SNARE synaptobrevin/VAMP (isoforms 1 and 2) on the vesicle, and the Q-SNAREs syntaxin (isoforms 1 and 2) and SNAP-25 on the plasma membrane (Figure 4). Since SNAP-25 has two SNARE-motifs, synaptobrevin, syntaxin, and SNAP-25 together have four SNARE-motifs. Synaptobrevins and SNAP-25 are relatively simple SNARE proteins that are composed of little else besides SNARE motifs and membrane-attachment sequences (a transmembrane region for synaptobrevin, and a cysteine-rich palmitoylated sequence for SNAP-25). Syntaxins, in contrast, are complex proteins. The N-terminal two-thirds of syntaxins include a separate, autonomously folded domain (the so-called Habc-domain), while the C-terminal third is composed of a SNARE motif and transmembrane region just like synaptobrevin. 

Each intracellular fusion reaction exhibits characteristic properties, and involves a different combination of SM and SNARE proteins. The specificity of fusion reactions appears to be independent of SNARE proteins because SNARE complex formation is nonspecific as long as the Q/R-rule is not violated (i.e., the fact that SNARE complexes need to be formed by SNARE proteins containing R-, Qa-, Qb-, and Qc-SNARE motifs), and of SM proteins because SM proteins often function in... 

Yokoyama CT, Myers SJ, Fu J, Mockus SM, Scheuer T, Catterall WA (2005) Mechanism of SNARE protein binding and regulation of Cav2 channels by phosphorylation of the synaptic protein interaction site. Mol Cell Neurosci 28 1-17 Yokoyama CT, Sheng ZH, Catterall WA (1997) Phosphorylation of the synaptic protein interaction site on N-type calcium channels inhibits interactions with SNARE proteins. J Neurosci 17 6929-38... 

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