Synaptotagmins

Littleton, JT and Bellen, HJ (1995) Synaptotagmin controls and modulates synaptic-vesicle fusion in a Ca + dependent manner. Trends Neurosci. 18 177-183. 

Upon activation, neurons begin trafficking TRPVl to the membrane where the receptors become activated, desensitized and then recycled to the intracellular compartments. Translocation of TRPVl to the cell membrane occurs via SNARE (snapin and synaptotagmin IX)-mediated exocytosis [37]. Broadly speaking, activation involves phosphorylation by protein kinases (most notably, protein kinase A [PKA] and C [PKC]) and desensitization involves de-phosphorylation by phosphatases (e.g. calcineurin) [38]. Among PKC isozymes, PKCp seems to be of particular importance [39]. 

Annexin V-functionalized crosslinked iron oxide (CLIO) was designed as a contrast agent for MRI, which was additionally labeled with Cy5.5 to allow colocalization with optical imaging techniques [98]. Alternatively, conjugation of multiple Gd-DTPA molecules or SPIO particles to the C2 domain of synaptotagmin I was shown to allow the detection of apoptotic cells in vitro [99]. Zhao et al. [100] were the first to apply a C2 domain-functionalized SPIO and showed very promising results for future in vivo applications of MR contrast agents for the detection of apoptotic sites. 

Shao, X., Fernandez, I., Sudhof, T. C. and Rizo, J. Solution structures of the Ca2+-free and Ca2+-bound C2A domain of synaptotagmin I does Ca2+ induce a conformational change Biochemistry 37 16106-16115,1998. 

Synaptotagmins Membrane proteins with at least 15 isoforms that contain C2 domains bind Ca2+ and phospholipids and interact with neurexins, AP2 and syntaxins. Synaptotagmins 1 and 2 may function as Ca2+ sensors in fast Ca2+-dependent neurotransmitter release... 

Amphiphysin Nerve-terminal protein that associates with synaptic vesicles probably via AP2 bound to synaptotagmin. May function in endocytosis. 

SNAP-25 Syntaxins Paimitoylated peripheral membrane protein that is cleaved by botulinum toxins A and E and binds to syntaxins. Ubiquitous membrane proteins that are cleaved by botulinum toxin Cl and bind to synaptotagmins, SNAP-25,... 

Fernandez-Chacon, R., Konigstorfer, A, Gerber, S. H. et al. Synaptotagmin I functions as a calcium regulator of release probability. Nature 410 41-49, 2001. 

Bai, J., Tucker, W. C. and Chapman, E. R. PIP2 increases the speed of response of synaptotagmin and steers its membrane-penetration activity toward the plasma membrane. Nat. Struct. Mol. Biol. 11 36-44,2004. 

Synaptotagmins are yet another family of Ca2+-binding proteins, localized on the membranes of synaptic vesicles, where they seem to be involved in the release of neurotransmitters. While the mechanism by which they are involved in Ca2+-mediated synaptic transmission is unclear, it seems likely that the neurotoxicity of heavy metals such as Pb is due to a higher affinity of synaptotagmins for Pb2+ than for Ca2+. 

Huynh, D. P., et al.. The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XL Hum Mol Genet, 2003, 12(20), 2587-97. 

Structure of the first C2 domain of synaptotagmin I a novel calcium/phosphohpid-binding fold. Cell 80 929-938. 

Recent evidence indicates that PD might affect synaptic function adversely. In parkin-deficient mice, higher stimulation of corticostriatal afferents were required to evoke EPSPs in striatal spiny neurons suggesting that excitability of spiny neurons was reduced." Also, parkin, which is an ubiquitin ligase" has been shown to interact with and ubiquitinate synaptotagmin XI." " ... 

The decisive element in exocytosis is the interaction between proteins known as SNAREs that are located on the vesicular membrane (v-SNAREs) and on the plasma membrane (t-SNAREs). In the resting state (1), the v-SNARE synaptobrevin is blocked by the vesicular protein synaptotagmin. When an action potential reaches the presynaptic membrane, voltage-gated Ca "" channels open (see p. 348). Ca "" flows in and triggers the machinery by conformational changes in proteins. Contact takes place between synaptobrevin and the t-SNARE synaptotaxin (2). Additional proteins known as SNAPs bind to the SNARE complex and allow fusion between the vesicle and the plasma membrane (3). The process is supported by the hydrolysis of GTP by the auxiliary protein Rab. 

Details of the control of exocytosis are also uncertain. Synaptotagmin I, which contains two Ca2+-binding domains, is probably the sensor that detects the rapid influx of Ca2+ that initiates exocytosis.576 578b... 

Synapsins la, lb, Ha, lib Rab3, rabphilin Cysteine string proteins (CSP) Synaptotagmins... 

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