Neurotrophins stimulate phosphorylation of synapsin I by MAP kinase and regulate synapsin I-actin interactions.

Jovanovic, Jasmina N.; Benfenati, Fabio; Siow, Yaw L.; Sihra, Talvinder S.; Sanghera, Jasbinder S.; Pelech, Steven; Greengard, Paul; Czernik, Andrew J.

doi:10.1073/pnas.93.8.3679

Cited by 373 publications

(345 citation statements)

References 47 publications

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“…Neurotrophins influence the development of synaptic connections, affect the expression and modification of synaptic proteins, and modulate synaptic function at both pre-and post-synaptic levels (45)(46)(47)(48)(49). Our results indicate that agrin gene expression is also a synapse-related target of neurotrophin action.…”

Section: Figmentioning

confidence: 65%

Selective Regulation of Agrin mRNA Induction and Alternative Splicing in PC12 Cells by Ras-dependent Actions of Nerve Growth Factor

Smith¹,

Fanger²,

O'Connor³

et al. 1997

Journal of Biological Chemistry

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The extracellular matrix protein agrin plays an important role in the formation and maintenance of the neuromuscular junction. However, regulation of agrin gene expression and pre-mRNA splicing, important in determining the biological actions of agrin, is not well understood. To begin to identify mechanisms controlling agrin expression, quantitative polymerase chain reaction techniques were used to analyze the effect of growth factors on the expression of agrin mRNA isoforms in rat pheochromocytoma (PC12) cells. Agrin transcripts in untreated cells lacked inserts in the Y and Z sites (agrin y0z0 ), encoding agrin isoforms with low acetylcholine receptor aggregating activity and a primarily non-neuronal tissue distribution. Transcripts encoding isoforms with high aggregating activity and neuronal tissue distribution (agrin y4z8 , agrin y4z11 , and agrin y4z19 ) were not detected. Treatment of PC12 cells with nerve growth factor (NGF) caused a significant increase in total agrin mRNA. In contrast, exposure to epidermal growth factor had no effect. Analysis of alternative splicing of agrin mRNA revealed that NGF elicited a specific increase in agrin y4 and agrin z8 mRNAs that did not occur in the presence of epidermal growth factor, insulin, dexamethasone, or retinoic acid. Analysis of PC12 sublines stably overexpressing a dominant inhibitory form of p21 Ras indicated that NGF induced changes in levels of agrin mRNA and alternative splicing required Ras activity. The results show that NGF can influence important aspects of neuronal differentiation by regulating alternative splicing. Furthermore, these data provide insight into the mechanisms governing agrin gene expression and suggest that neurotrophic factors may play a role in regulating agrin expression in vivo.

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Section: Figmentioning

confidence: 65%

Selective Regulation of Agrin mRNA Induction and Alternative Splicing in PC12 Cells by Ras-dependent Actions of Nerve Growth Factor

Smith¹,

Fanger²,

O'Connor³

et al. 1997

Journal of Biological Chemistry

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“…MAP kinasedependent phosphorylation of synapsin I may contribute to the modulation of neurotransmitter release and synaptic plasticity [35] . In the current study, phosphorylation of synapsin I was significantly increased in the plasma membrane and synapses of hippocampal neurons from the PGS32 group.…”

Section: Discussionmentioning

confidence: 99%

Polygalasaponin XXXII from Polygala tenuifolia root improves hippocampal-dependent learning and memory

Xue

Yuan

et al. 2009

Acta Pharmacol Sin

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Aim: The aim of this study was to investigate the cognition-enhancing activity and underlying mechanisms of a triterpenoid saponin (polygalasaponin XXXII, PGS32) isolated from the roots of Polygala tenuifolia Willd. Methods: The Morris water maze was used to evaluate the spatial learning and memory of mice. To detect the basic properties of synaptic transmission and long-term potentiation (LTP) in the dentate gyrus of rats, electrophysiological recordings were made of evoked potentials. Western blotting analysis and immunofluorescence assays were used to determine the phosphorylation of extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), synapsin I and the expression of brain derived neurotrophic factor (BDNF). Results: When administered at 0.125, 0.5, or 2 mg/kg, PGS32 could significantly prevent scopolamine-induced cognitive impairments in mice. Intracerebroventricular (icv) administration of PGS32 greatly enhanced basic synaptic transmission in the dentate gyrus of rats and induced LTP. In primary hippocampal neurons, as well as in the hippocampus of maze-trained mice, PGS32 activated the mitogen-activated protein (MAP) kinase cascade by promoting phosphorylation of ERK, CREB and synapsin I. The expression of BDNF was also greatly enhanced in the hippocampus. Conclusion: Our findings suggest that PGS32 can improve hippocampus-dependent learning and memory, possibly through improvement of synaptic transmission, activation of the MAP kinase cascade and enhancement of the level of BDNF. Therefore, PGS32 shows promise as a potential cognition-enhancing therapeutic drug.

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“…Synapsin I was purified from bovine brain as described (12). Purified synapsin I was stoichiometrically phosphorylated in vitro using purified protein kinases (13)(14)(15) or was subjected to cysteine-specific chemical cleavage with NTCB as described (15). Subcellular fractions were prepared from rat forebrain, and synaptic vesicles were purified through the step of controlled-pore glass chromatography as described (16).…”

Section: Methodsmentioning

confidence: 99%

Synapsin I interacts with c-Src and stimulates its tyrosine kinase activity

Onofri

Giovedì

Vaccaro

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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Synapsin I is a synaptic vesicle-associated phosphoprotein that has been implicated in the formation of presynaptic specializations and in the regulation of neurotransmitter release. The nonreceptor tyrosine kinase c-Src is enriched on synaptic vesicles, where it accounts for most of the vesicle-associated tyrosine kinase activity. Using overlay, affinity chromatography, and coprecipitation assays, we have now shown that synapsin I is the major binding protein for the Src homology 3 (SH3) domain of c-Src in highly purified synaptic vesicle preparations. The interaction was mediated by the proline-rich domain D of synapsin I and was not significantly affected by stoichiometric phosphorylation of synapsin I at any of the known regulatory sites. The interaction of purified c-Src and synapsin I resulted in a severalfold stimulation of tyrosine kinase activity and was antagonized by the purified c-Src-SH3 domain. Depletion of synapsin I from purified synaptic vesicles resulted in a decrease of endogenous tyrosine kinase activity. Portions of the total cellular pools of synapsin I and Src were coprecipitated from detergent extracts of rat brain synaptosomal fractions using antibodies to either protein species. The interaction between synapsin I and c-Src, as well as the synapsin I-induced stimulation of tyrosine kinase activity, may be physiologically important in signal transduction and in the modulation of the function of axon terminals, both during synaptogenesis and at mature synapses.Synapsin I is the major synaptic vesicle protein that binds to the Src homology 3 (SH3) domains of the adapter protein Grb2 in vitro (1). This interaction is mediated by domain D of synapsin I, a 23-kDa proline-rich, strongly basic domain located in the COOH-terminal portion of synapsin I (2). It seemed possible that domain D or other proline-rich regions in synapsin I might interact with other SH3 domain-containing proteins within the nerve terminal and that these interactions might have a physiological role in presynaptic function. One such candidate, the SH3 domain-containing nonreceptor tyrosine kinase c-Src, is expressed at high levels in postmitotic neurons and is enriched on synaptic vesicles, where it accounts for most of the vesicle-associated tyrosine kinase activity (3-6). Using purified components in vitro, we now report that a domain Dmediated interaction of synapsin I with the SH3 domain of c-Src results in a 5-fold activation of the catalytic activity of c-Src. We also present studies employing a variety of biochemical techniques that serve to further characterize the specificity, subcellular location, regulation, and potential functional consequences of the c-Src͞synapsin I interaction.

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Neurotrophins stimulate phosphorylation of synapsin I by MAP kinase and regulate synapsin I-actin interactions.

Abstract: The ability of neurotrophins to modulate the survival and differentiation of neuronal populations involves the Trk/MAP (mitogen-activated protein kinase) kinase signaling pathway. More

Cited by 373 publications

References 47 publications

Selective Regulation of Agrin mRNA Induction and Alternative Splicing in PC12 Cells by Ras-dependent Actions of Nerve Growth Factor

Selective Regulation of Agrin mRNA Induction and Alternative Splicing in PC12 Cells by Ras-dependent Actions of Nerve Growth Factor

Polygalasaponin XXXII from Polygala tenuifolia root improves hippocampal-dependent learning and memory

Synapsin I interacts with c-Src and stimulates its tyrosine kinase activity

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