• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Apr 16, 1996; 93(8): 3679–3683.

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


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 recently, neurotrophins have also been shown to regulate synaptic transmission. The synapsins are a family of neuron-specific phosphoproteins that play a role in regulation of neurotransmitter release, in axonal elongation, and in formation and maintenance of synaptic contacts. We report here that synapsin I is a downstream effector for the neurotrophin/Trk/MAP kinase cascade. Using purified components, we show that MAP kinase stoichiometrically phosphorylated synapsin I at three sites (Ser-62, Ser-67, and Ser-549). Phosphorylation of these sites was detected in rat brain homogenates, in cultured cerebrocortical neurons, and in isolated presynaptic terminals. Brain-derived neurotrophic factor and nerve growth factor upregulated phosphorylation of synapsin I at MAP kinase-dependent sites in intact cerebrocortical neurons and PC12 cells, respectively, while KCl- induced depolarization of cultured neurons decreased the phosphorylation state at these sites. MAP kinase-dependent phosphorylation of synapsin I significantly reduced its ability to promote G-actin polymerization and to bundle actin filaments. The results suggest that MAP kinase-dependent phosphorylation of synapsin I may contribute to the modulation of synaptic plasticity by neurotrophins and by other signaling pathways that converge at the level of MAP kinase activation.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.4M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Bading H, Greenberg ME. Stimulation of protein tyrosine phosphorylation by NMDA receptor activation. Science. 1991 Aug 23;253(5022):912–914. [PubMed]
  • Robbins DJ, Zhen E, Cheng M, Xu S, Ebert D, Cobb MH. MAP kinases ERK1 and ERK2: pleiotropic enzymes in a ubiquitous signaling network. Adv Cancer Res. 1994;63:93–116. [PubMed]
  • Campbell JS, Seger R, Graves JD, Graves LM, Jensen AM, Krebs EG. The MAP kinase cascade. Recent Prog Horm Res. 1995;50:131–159. [PubMed]
  • Pelech SL. Networking with proline-directed protein kinases implicated in tau phosphorylation. Neurobiol Aging. 1995 May-Jun;16(3):247–261. [PubMed]
  • Ghosh A, Greenberg ME. Calcium signaling in neurons: molecular mechanisms and cellular consequences. Science. 1995 Apr 14;268(5208):239–247. [PubMed]
  • Lev S, Moreno H, Martinez R, Canoll P, Peles E, Musacchio JM, Plowman GD, Rudy B, Schlessinger J. Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions. Nature. 1995 Aug 31;376(6543):737–745. [PubMed]
  • De Camilli P, Harris SM, Jr, Huttner WB, Greengard P. Synapsin I (Protein I), a nerve terminal-specific phosphoprotein. II. Its specific association with synaptic vesicles demonstrated by immunocytochemistry in agarose-embedded synaptosomes. J Cell Biol. 1983 May;96(5):1355–1373. [PMC free article] [PubMed]
  • Huttner WB, Schiebler W, Greengard P, De Camilli P. Synapsin I (protein I), a nerve terminal-specific phosphoprotein. III. Its association with synaptic vesicles studied in a highly purified synaptic vesicle preparation. J Cell Biol. 1983 May;96(5):1374–1388. [PMC free article] [PubMed]
  • Greengard P, Valtorta F, Czernik AJ, Benfenati F. Synaptic vesicle phosphoproteins and regulation of synaptic function. Science. 1993 Feb 5;259(5096):780–785. [PubMed]
  • Llinás R, Gruner JA, Sugimori M, McGuinness TL, Greengard P. Regulation by synapsin I and Ca(2+)-calmodulin-dependent protein kinase II of the transmitter release in squid giant synapse. J Physiol. 1991 May;436:257–282. [PMC free article] [PubMed]
  • Pieribone VA, Shupliakov O, Brodin L, Hilfiker-Rothenfluh S, Czernik AJ, Greengard P. Distinct pools of synaptic vesicles in neurotransmitter release. Nature. 1995 Jun 8;375(6531):493–497. [PubMed]
  • Li L, Chin LS, Shupliakov O, Brodin L, Sihra TS, Hvalby O, Jensen V, Zheng D, McNamara JO, Greengard P, et al. Impairment of synaptic vesicle clustering and of synaptic transmission, and increased seizure propensity, in synapsin I-deficient mice. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9235–9239. [PMC free article] [PubMed]
  • Han HQ, Nichols RA, Rubin MR, Bähler M, Greengard P. Induction of formation of presynaptic terminals in neuroblastoma cells by synapsin IIb. Nature. 1991 Feb 21;349(6311):697–700. [PubMed]
  • Lu B, Greengard P, Poo MM. Exogenous synapsin I promotes functional maturation of developing neuromuscular synapses. Neuron. 1992 Mar;8(3):521–529. [PubMed]
  • Ferreira A, Kosik KS, Greengard P, Han HQ. Aberrant neurites and synaptic vesicle protein deficiency in synapsin II-depleted neurons. Science. 1994 May 13;264(5161):977–979. [PubMed]
  • Chin LS, Li L, Ferreira A, Kosik KS, Greengard P. Impairment of axonal development and of synaptogenesis in hippocampal neurons of synapsin I-deficient mice. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9230–9234. [PMC free article] [PubMed]
  • Ferreira A, Han HQ, Greengard P, Kosik KS. Suppression of synapsin II inhibits the formation and maintenance of synapses in hippocampal culture. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9225–9229. [PMC free article] [PubMed]
  • Bähler M, Greengard P. Synapsin I bundles F-actin in a phosphorylation-dependent manner. Nature. 1987 Apr 16;326(6114):704–707. [PubMed]
  • Sanghera JS, Paddon HB, Bader SA, Pelech SL. Purification and characterization of a maturation-activated myelin basic protein kinase from sea star oocytes. J Biol Chem. 1990 Jan 5;265(1):52–57. [PubMed]
  • Labbé JC, Capony JP, Caput D, Cavadore JC, Derancourt J, Kaghad M, Lelias JM, Picard A, Dorée M. MPF from starfish oocytes at first meiotic metaphase is a heterodimer containing one molecule of cdc2 and one molecule of cyclin B. EMBO J. 1989 Oct;8(10):3053–3058. [PMC free article] [PubMed]
  • Nairn AC, Greengard P. Purification and characterization of Ca2+/calmodulin-dependent protein kinase I from bovine brain. J Biol Chem. 1987 May 25;262(15):7273–7281. [PubMed]
  • Pavlović-Surjancev B, Cahill AL, Perlman RL. Nicotinic agonists, phorbol esters, and growth factors activate two extracellular signal-regulated kinases, ERK1 and ERK2, in bovine chromaffin cells. J Neurochem. 1992 Dec;59(6):2134–2140. [PubMed]
  • Holmes CF. A new method for the selective isolation of phosphoserine-containing peptides. FEBS Lett. 1987 May 4;215(1):21–24. [PubMed]
  • Czernik AJ, Girault JA, Nairn AC, Chen J, Snyder G, Kebabian J, Greengard P. Production of phosphorylation state-specific antibodies. Methods Enzymol. 1991;201:264–283. [PubMed]
  • Czernik AJ, Pang DT, Greengard P. Amino acid sequences surrounding the cAMP-dependent and calcium/calmodulin-dependent phosphorylation sites in rat and bovine synapsin I. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7518–7522. [PMC free article] [PubMed]
  • Hall FL, Mitchell JP, Vulliet PR. Phosphorylation of synapsin I at a novel site by proline-directed protein kinase. J Biol Chem. 1990 Apr 25;265(12):6944–6948. [PubMed]
  • Dunkley PR, Jarvie PE, Heath JW, Kidd GJ, Rostas JA. A rapid method for isolation of synaptosomes on Percoll gradients. Brain Res. 1986 Apr 30;372(1):115–129. [PubMed]
  • Wang JK, Walaas SI, Sihra TS, Aderem A, Greengard P. Phosphorylation and associated translocation of the 87-kDa protein, a major protein kinase C substrate, in isolated nerve terminals. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2253–2256. [PMC free article] [PubMed]
  • Lu B, Yokoyama M, Dreyfus CF, Black IB. Depolarizing stimuli regulate nerve growth factor gene expression in cultured hippocampal neurons. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6289–6292. [PMC free article] [PubMed]
  • Benfenati F, Valtorta F, Chieregatti E, Greengard P. Interaction of free and synaptic vesicle-bound synapsin I with F-actin. Neuron. 1992 Feb;8(2):377–386. [PubMed]
  • Valtorta F, Greengard P, Fesce R, Chieregatti E, Benfenati F. Effects of the neuronal phosphoprotein synapsin I on actin polymerization. I. Evidence for a phosphorylation-dependent nucleating effect. J Biol Chem. 1992 Jun 5;267(16):11281–11288. [PubMed]
  • Romano C, Nichols RA, Greengard P. Synapsin I in PC12 cells. II. Evidence for regulation by NGF of phosphorylation at a novel site. J Neurosci. 1987 May;7(5):1300–1306. [PubMed]
  • Petrucci TC, Morrow JS. Synapsin I: an actin-bundling protein under phosphorylation control. J Cell Biol. 1987 Sep;105(3):1355–1363. [PMC free article] [PubMed]
  • Ceccaldi PE, Grohovaz F, Benfenati F, Chieregatti E, Greengard P, Valtorta F. Dephosphorylated synapsin I anchors synaptic vesicles to actin cytoskeleton: an analysis by videomicroscopy. J Cell Biol. 1995 Mar;128(5):905–912. [PMC free article] [PubMed]
  • Marsh HN, Scholz WK, Lamballe F, Klein R, Nanduri V, Barbacid M, Palfrey HC. Signal transduction events mediated by the BDNF receptor gp 145trkB in primary hippocampal pyramidal cell culture. J Neurosci. 1993 Oct;13(10):4281–4292. [PubMed]
  • Heumann R. Neurotrophin signalling. Curr Opin Neurobiol. 1994 Oct;4(5):668–679. [PubMed]
  • Snider WD. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell. 1994 Jun 3;77(5):627–638. [PubMed]
  • Marshall CJ. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995 Jan 27;80(2):179–185. [PubMed]
  • Lohof AM, Ip NY, Poo MM. Potentiation of developing neuromuscular synapses by the neurotrophins NT-3 and BDNF. Nature. 1993 May 27;363(6427):350–353. [PubMed]
  • Kim HG, Wang T, Olafsson P, Lu B. Neurotrophin 3 potentiates neuronal activity and inhibits gamma-aminobutyratergic synaptic transmission in cortical neurons. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12341–12345. [PMC free article] [PubMed]
  • Knipper M, da Penha Berzaghi M, Blöchl A, Breer H, Thoenen H, Lindholm D. Positive feedback between acetylcholine and the neurotrophins nerve growth factor and brain-derived neurotrophic factor in the rat hippocampus. Eur J Neurosci. 1994 Apr 1;6(4):668–671. [PubMed]
  • Knipper M, Leung LS, Zhao D, Rylett RJ. Short-term modulation of glutamatergic synapses in adult rat hippocampus by NGF. Neuroreport. 1994 Dec 20;5(18):2433–2436. [PubMed]
  • Kang H, Schuman EM. Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science. 1995 Mar 17;267(5204):1658–1662. [PubMed]
  • Stoop R, Poo MM. Potentiation of transmitter release by ciliary neurotrophic factor requires somatic signaling. Science. 1995 Feb 3;267(5198):695–699. [PubMed]
  • Levine ES, Dreyfus CF, Black IB, Plummer MR. Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8074–8077. [PMC free article] [PubMed]
  • Berninger B, García DE, Inagaki N, Hahnel C, Lindholm D. BDNF and NT-3 induce intracellular Ca2+ elevation in hippocampal neurones. Neuroreport. 1993 Sep 30;4(12):1303–1306. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...