Synapsins as major neuronal Ca2+/S100A1-interacting proteins

Heierhorst, Jörg; Mitchelhill, Ken I.; Mann, Richard J.; Tiganis, Tony; Czernik, Andrew J.; Greengard, Paul; Kemp, Bruce E.

doi:10.1042/0264-6021:3440577

Cited by 19 publications

(41 citation statements)

References 28 publications

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“…Tissue samples were ground to a fine powder under liquid N 2 using a mortar and pestle and lysed in protein buffer (20 mM HEPES [pH 7.4], 1 mM EGTA, 5 mM magnesium acetate, 1 mM dithiothreitol, protease inhibitor cocktail [Sigma], 1% Triton X-100, 5 mM sodium pyrophosphate, 50 sodium fluoride) or RNeasy buffer (Qiagen). Protein extracts were separated by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis, transferred onto polyvinylidene difluoride membranes, and probed with antibodies against actin (Chemicon), calmodulin (Upstate Biotechnology), desmin (Santa Cruz Biotechnology), phospholamban (PLB) and phosho-Ser 16 -PLB (Research Diagnostics), S100A1 (19), sarcoendoplasmic reticulum Ca 2ϩ ATPase 2a (SERCA-2a; Santa Cruz Biotechnology), or vimentin (Santa Cruz Biotechnology), followed by secondary peroxidase-conjugated antibodies and enhanced chemiluminescence reagents (Amersham Pharmacia). Left-ventricular total RNA was isolated with RNeasy kits (Qiagen), and 0.5 g per sample was transferred onto GeneScreen Plus membranes (NEN) with a slot blot apparatus (Bio-Rad), hybridized with 32 P-labeled probes using standard conditions, and analyzed by using phosphorimaging and Molecular Dynamics software.…”

Section: Methodsmentioning

confidence: 99%

Impaired Cardiac Contractility Response to Hemodynamic Stress in S100A1-Deficient Mice

Cole

Tenis

et al. 2002

Molecular and Cellular Biology

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Ca2؉ signaling plays a central role in cardiac contractility and adaptation to increased hemodynamic demand. We have generated mice with a targeted deletion of the S100A1 gene coding for the major cardiac isoform of the large multigenic S100 family of EF hand Ca 2؉ -binding proteins. S100A1 ؊/؊ mice have normal cardiac function under baseline conditions but have significantly reduced contraction rate and relaxation rate responses to ␤-adrenergic stimulation that are associated with a reduced Ca 2؉ sensitivity. In S100A1 ؊/؊ mice, basal left-ventricular contractility deteriorated following 3-week pressure overload by thoracic aorta constriction despite a normal adaptive hypertrophy. Surprisingly, heterozygotes also had an impaired response to acute ␤-adrenergic stimulation but maintained normal contractility in response to chronic pressure overload that coincided with S100A1 upregulation to wild-type levels. In contrast to other genetic models with impaired cardiac contractility, loss of S100A1 did not lead to cardiac hypertrophy or dilation in aged mice. The data demonstrate that high S100A1 protein levels are essential for the cardiac reserve and adaptation to acute and chronic hemodynamic stress in vivo.

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Section: Methodsmentioning

confidence: 99%

Impaired Cardiac Contractility Response to Hemodynamic Stress in S100A1-Deficient Mice

Cole

Tenis

et al. 2002

Molecular and Cellular Biology

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112

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“…Although synapsins were reported to be major neuronal S100A1‐interacting proteins in vitro (Heierhorst et al . 1999), evidence for their codistribution in mature neuronal tissue is still lacking.…”

Section: S100a1 Is Present In Nerve Terminals Isolated From Rat Brainmentioning

confidence: 99%

“…2002). Recently, S100A1 has been shown to interact with synapsins in vitro (Heierhorst et al . 1999).…”

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S100A1 codistributes with synapsin I in discrete brain areas and inhibits the F‐actin‐bundling activity of synapsin I

Benfenati

Ferrari

Onofri

et al. 2004

Journal of Neurochemistry

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The Ca 2+ -sensor protein S100A1 was recently shown to bind in vitro to synapsins, a family of synaptic vesicle phosphoproteins involved in the regulation of neurotransmitter release. In this paper, we analyzed the distribution of S100A1 and synapsin I in the CNS and investigated the effects of the S100A1/synapsin binding on the synapsin functional properties. Subcellular fractionation of rat brain homogenate revealed that S100A1 is present in the soluble fraction of isolated nerve endings. Confocal laser scanning microscopy and immunogold immunocytochemistry demonstrated that S100A1 and synapsin codistribute in a subpopulation (5-20%) of nerve terminals in the mouse cerebral and cerebellar cortices. By forming heterocomplexes with either dephosphorylated or phosphorylated synapsin I, S100A1 caused a dose-and Ca 2+ -dependent inhibition of synapsininduced F-actin bundling and abolished synapsin dimerization, without affecting the binding of synapsin to F-actin, G-actin or synaptic vesicles. These data indicate that: (i) synapsins and S100A1 can interact in the nerve terminals where they are coexpresssed; (ii) S100A1 is unable to bind to SV-associated synapsin I and may function as a cytoplasmic store of monomeric synapsin I; and (iii) synapsin dimerization and interaction with S100A1 are mutually exclusive, suggesting an involvement of S100A1 in the Ca S100 is a multigenic family of Ca 2+ -modulated proteins of the EF-hand type expressed in a rather cell-specific manner and implicated in the regulation of a variety of cellular activities via interaction with effector proteins (Schäfer and Heizmann 1996;Donato 1999). S100A1 is expressed abundantly in cardiac and skeletal muscle cells and in some neuronal populations Kato 1987, 1988;Donato et al. 1989;Rambotti et al. 1999;Arcuri et al. 2002). The protein has been implicated in the regulation of the dynamics of microtubule and type III intermediate filaments (Donato 1988;Bianchi et al. 1993;Garbuglia et al. 1996;Sorci et al. 2000), the release of Ca 2+ from intracellular stores via interaction with the ryanodine receptor (Fanò et al. 1989;Treves et al. 1997), the activity of the myosin-associated protein kinase twitchin and the interaction of the giant sarcomeric kinase, titin, with F-actin (Heierhorst et al. 1996;Yamasaki et al. 2001;Du et al. 2002). Recently, S100A1 has been shown to interact with synapsins in vitro (Heierhorst et al. 1999).Synapsins I and II are neuron-specific proteins that anchor synaptic vesicles (SV) to F-actin in nerve terminals and regulate SV availability for exocytosis in a phosphorylationdependent fashion (Bähler and Greengard 1987;Benfenati et al. 1992aBenfenati et al. , 1993bCeccaldi et al. 1995;Chi et al. 2001Chi et al. , 2003. These proteins have been shown to be crucial for the regulation of neurotransmitter release and during synaptogenesis (see Greengard et al. 1993;Hilfiker et al. 1999; for Received December 23, 2003; revised manuscript received January 26, 2004; accepted January 30, 2004. Address correspondence an...

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“…Rab3 is a small G-protein binding protein that is as a master switch that determines the compatibility of SV for release [53]. The binding of Syt for some partners is not only Ca2+ phosphorylation dependent but directly Ca2+ dependent (i.e., S100A) [54]. In addition to the molecular and cellular level, mutations or polymorphic sites of these genes associated with neurological impairments [55,56].…”

Section: Introductionmentioning

confidence: 99%

Synaptic proteins as multi-sensor devices of neurotransmission

2006

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Neuronal communication is tightly regulated in time and space. Following neuronal activation, an electrical signal triggers neurotransmitter (NT) release at the active zone. The process starts by the signal reaching the synapse followed by a fusion of the synaptic vesicle (SV) and diffusion of the released NT in the synaptic cleft. The NT then binds to the appropriate receptor and induces a membrane potential change at the target cell membrane. The entire process is controlled by a fairly small set of synaptic proteins, collectively called SYCONs. The biochemical features of SYCONs underlie the properties of NT release.SYCONs are characterized by their ability to detect and respond to changes in environmental signals. For example, consider synaptotagmin I (Syt1), a prototype of a protein family with over 20 gene and variants in mammals. Syt1 is a specific example of a multi-sensor device with a large repertoire of discrete states. Several of these states are stimulated by a local concentration of signaling molecules such as Ca2+. The ability of this protein to sense signaling molecules and to adopt multiple biochemical states is shared by other SYCONs such as the synapsins (Syns). Specific biochemical states of Syns determine the accessibility of SV for NT release. Each of these states is defined by a specific alternative spliced variant with a unique profile of phosphorylation modified sites.The plasticity of the synapse is a direct reflection of SYCON's multiple biochemical states. State transitions occurs in a wide range of time scales, and therefore these molecules need to cope with events that last milliseconds (i.e., exocytosis in fast responding synapses) and with events that can carry on for many minutes (i.e., organization of SV pools). We suggest that SYCONs are optimized throughout evolution as multi-sensor devices. A full repertoire of the switches leading to alternation of protein states and a detailed characterization of protein-protein network within the synapse is critical for the development of a dynamic model of synaptic transmission.

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Synapsins as major neuronal Ca2+/S100A1-interacting proteins

Cited by 19 publications

References 28 publications

Impaired Cardiac Contractility Response to Hemodynamic Stress in S100A1-Deficient Mice

Impaired Cardiac Contractility Response to Hemodynamic Stress in S100A1-Deficient Mice

S100A1 codistributes with synapsin I in discrete brain areas and inhibits the F‐actin‐bundling activity of synapsin I

Synaptic proteins as multi-sensor devices of neurotransmission

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