Synapsins protein phosphorylation

Along with ion channel activity, protein phosphorylation plays a fundamental role in regulating the release of neurotransmitters from synaptic terminals. A protein selectively associated with vertebrate nerve terminals, synapsin I, may be particularly important in this respect. Strong experimental evidence indicates, in fact, that the state of phosphorylation of this protein participates in regulating the number of neurotransmitter-containing vesicles that are immediately available for exocytosis. ... 

Synapsins la, lb, Ha and lib Monotopic membrane proteins with common N-terminal domains, with phosphorylation sites for CaMKI and... 

Synaptobrevins (VAMPs) Synaptogyrin Synaptophysins PKA but diverge C-terminally. Synapsins Ia/b contain C-terminal phosphorylation sites for CaMKII and CDK 5. Interact with microfilaments, neurofilaments, microtubules, SH3 domains, calmodulin and annexin VI in vitro. Small-membrane proteins that are cleaved by tetanus toxin and by botulinum toxins B, D, F and G. Polytopic membrane protein that is tyrosine-phosphorylated. Function unknown. Polytopic membrane proteins, including synaptoporin, that are tyrosine-phosphorylated and bind to synaptobrevins. May regulate SNARE function... 

Ca2+,calmodulin-dependent May transiently associate with synaptic vesicles to phosphorylate synapsins and rabphilin-3A. May regulate various protein kinases I and II steps in neurotransmitter release. 

Coffey ET, Sihra TS, Nicholls DG et al (1994b) Phosphorylation of synapsin I and MARCKS in nerve terminals is mediated by Ca2+ entry via an Aga-GI sensitive Ca2+ channel which is coupled to glutamate exocytosis. FEBS Lett 353 264-8 Colby KA, Blaustein MP (1988) Inhibition of voltage-gated K channels in synaptosomes by sn-1,2-dioctanoylglycerol, an activator of protein kinase C. J Neurosci 8 4685-92... 

Hiding H, Scheller RH (1996) Phosphorylation of synaptic vesicle proteins modulation of the alpha SNAP interaction with the core complex. Proc Natl Acad Sci USA 93 11945-9 Hirokawa N, Sobue K, Kanda K et al (1989) The cytoskeletal architecture of the presynaptic terminal and molecular structure of synapsin 1. J Cell Biol 108 111-26 Ho MF, Bahler M, Czernik AJ et al (1991) Synapsin I is a highly surface-active molecule. J Biol Chem 266 5600-7... 

Petrucci TC, Morrow JS (1987) Synapsin I an actin-bundling protein under phosphorylation control. J Cell Biol 105 1355-63... 

Effect of dysbindin-1 overexpression or knockdown on neuronal proteins (a and b), cell viability (c and d), and glutamate release (e and f) in primary cultures of rat cerebrocortical neurons. Overexpression increases Akt phosphorylation and levels of SNAP-25 and synapsin 1, whereas knockdown has the opposite effect (see text Q Sections 2.2.6.53 and Q 2.2.6.S.6 for discussion). The symbols 0 and + in (a) and (b) refer to wild type and expression-altered conditions. GFP green fluorescent protein HK+ high KCL condition HS horse serum LY the PI3K inhibitor LY294002 Adapted with from Numakawa et al. (2004)... 

Figure 7.3. Mechanism of transmitter release, a Thepresynap-tic action potential opens voltage-gated Ca channels. Ca triggers exocytosis of neurotransmitters stored in piesynaptic vesicles. b Some proteins (out of mat r more) that are involved in exocytosis. Ca is involved at multiple stages. By binding to calmodulin (CaM), it promotes phosphorylation of synapsin, which primes the transmitter vesicle but does not immediately lead to exocytosis. Adhesion of primed vesicles to the presynap-tic membrane is mediated by synaptobrevin and other SNARE proteins. Synaptotagmin is activated directly by Ca and participates in the final step of secretiom...

CaM kinase II participates in the phosphorylation of tau (Baudier and Cole, 1987 Steiner et al., 1990). It phosphorylates a nnmber of other substrates in vitro, including MAP-2, tyrosine hydroxylase, synapsin 1, APP, and varions intermediate filament proteins such as vimentin, desmin, and GFAP (Colbran et al., 1989). In vitro, CaM kinase Il-phosphorylated tau inhibits microtnbnle assembly (Yamamoto et al., 1983 Yamamoto et al., 1985, 1988). It phosphorylates tau in vitro in such a way to slow its electrophoretic mobility (Baudier and Cole, 1987). Serine " (numbered according to the longest human tau isoform) is one of the major phosphorylation sites for CaM kinase II in vitro (Steiner et al., 1990). Immnnostaining of AD brain showed serine " phosphorylation only in neuronal soma, bnt not in neuropil threads and dystrophic neurites (Yamamoto et al., 2005). Tau phosphorylation in glia cells is unlikely due to CaM kinase II. 

Fig. 6.4 Model for protein-mediated membrane fusion and exocytosis. a The release of acetylcholine from the vesicles is mediated by a series of proteins collectively called SNARE proteins. Synaptotagmin is the neuronal Ca " receptor detecting C entry. Synaptobrevin (i.e. vesicle-associated membrane protein, VAMP) is a filament-like protein on the vesicle, b During depolarisation and calcium entry, synaptobrevin on the vesicle unfolds and forms a ternary complex with syntaxin/SNAP-25. This process is facilitated by phosphorylation of synapsin, also present on the vesicle membrane, c Assembly of the ternary complex forces the vesicle in close apposition to the nerve membrane at the active zone with release of its contents, acetylcholine. The fusion is disassembled, and the vesicle is recycled. (From Martyn 2005, p 864 copyright Elsevier)...

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