Signaling from Synapse to Nucleus

  • Carrie L. Heusner
  • Kelsey C. Martin


Retrograde Transport CREB Phosphorylation Dendritic Spike Aplysia Neuron Nuclear Calcium 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Adams JP and Dudek SM. Late-phase long-term potentiation: getting to the nucleus. Nat Rev Neurosci6: 737–743, 2005.PubMedCrossRefGoogle Scholar
  2. 2.
    Alberini CM. Genes to remember. J Exp Biol202: 2887–2891, 1999.PubMedGoogle Scholar
  3. 3.
    Allan DW, St Pierre SE, Miguel-Aliaga I, and Thor S. Specification of neuropeptide cell identity by the integration of retrograde BMP signaling and a combinatorial transcription factor code. Cell113: 73–86, 2003.PubMedCrossRefGoogle Scholar
  4. 4.
    Ambron RT, Dulin MF, Zhang XP, Schmied R, and Walters ET. Axoplasm enriched in a protein mobilized by nerve injury induces memory-like alterations in Aplysianeurons. J Neurosci15: 3440–3446, 1995.PubMedGoogle Scholar
  5. 5.
    Ambron RT, Schmied R, Huang CC, and Smedman M. A signal sequence mediates the retrograde transport of proteins from the axon periphery to the cell body and then into the nucleus. J Neurosci12: 2813–2818, 1992.PubMedGoogle Scholar
  6. 6.
    Ambron RT and Walters ET. Priming events and retrograde injury signals. A new perspective on the cellular and molecular biology of nerve regeneration. Mol Neurobiol13: 61–79, 1996.PubMedCrossRefGoogle Scholar
  7. 7.
    Ataman B, Ashley J, Gorczyca D, Gorczyca M, Mathew D, Wichmann C, Sigrist SJ, and Budnik V. Nuclear trafficking of Drosophila Frizzled-2 during synapse development requires the PDZ protein dGRIP. Proc Natl Acad Sci U S A103: 7841–7846, 2006.PubMedCrossRefGoogle Scholar
  8. 8.
    Bading H. Transcription-dependent neuronal plasticity the nuclear calcium hypothesis. Eur J Biochem267: 5280–5283, 2000.PubMedCrossRefGoogle Scholar
  9. 9.
    Bardo S, Cavazzini MG, and Emptage N. The role of the endoplasmic reticulum Ca2+ store in the plasticity of central neurons. Trends Pharmacol Sci27: 78–84, 2006.PubMedCrossRefGoogle Scholar
  10. 10.
    Bean BP. The action potential in mammalian central neurons. Nat Rev Neurosci8: 451–465, 2007.PubMedCrossRefGoogle Scholar
  11. 11.
    Berninger B, Garcia DE, Inagaki N, Hahnel C, and Lindholm D. BDNF and NT-3 induce intracellular Ca2+ elevation in hippocampal neurones. Neuroreport4: 1303–1306, 1993.PubMedCrossRefGoogle Scholar
  12. 12.
    Berridge MJ. Neuronal calcium signaling. Neuron21: 13–26, 1998.PubMedCrossRefGoogle Scholar
  13. 13.
    Blumenfeld H, Spira ME, Kandel ER, and Siegelbaum SA. Facilitatory and inhibitory transmitters modulate calcium influx during action potentials in Aplysiasensory neurons. Neuron5: 487–499, 1990.PubMedCrossRefGoogle Scholar
  14. 14.
    Bulinski JC. Microtubule modification: acetylation speeds anterograde traffic flow. Curr Biol17: R18–20, 2007.PubMedCrossRefGoogle Scholar
  15. 15.
    Campenot RB. Local control of neurite development by nerve growth factor. Proc Natl Acad Sci U S A74: 4516–4519, 1977.PubMedCrossRefGoogle Scholar
  16. 16.
    Deisseroth K, Heist EK, and Tsien RW. Translocation of calmodulin to the nucleus supports CREB phosphorylation in hippocampal neurons. Nature392: 198–202, 1998.PubMedCrossRefGoogle Scholar
  17. 17.
    Dompierre JP, Godin JD, Charrin BC, Cordelieres FP, King SJ, Humbert S, and Saudou F. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington’s disease by increasing tubulin acetylation. J Neurosci27: 3571–3583, 2007.PubMedCrossRefGoogle Scholar
  18. 18.
    Dudek SM and Fields RD. Somatic action potentials are sufficient for late-phase LTPrelated cell signaling. Proc Natl Acad Sci U S A99: 3962–3967, 2002.PubMedCrossRefGoogle Scholar
  19. 19.
    Foskett JK, White C, Cheung KH, and Mak DO. Inositol trisphosphate receptor Ca2+ release channels. Physiol rev87: 593–658, 2007.PubMedCrossRefGoogle Scholar
  20. 20.
    Frey U and Morris RG. Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation. Trends Neurosci21: 181–188, 1998.PubMedCrossRefGoogle Scholar
  21. 21.
    Ginty DD, Kornhauser JM, Thompson MA, Bading H, Mayo KE, Takahashi JS, and Greenberg ME. Regulation of CREB phosphorylation in the suprachiasmatic nucleus by light and a circadian clock. Science260: 238–241, 1993.PubMedCrossRefGoogle Scholar
  22. 22.
    Ginty DD and Segal RA. Retrograde neurotrophin signaling: Trk-ing along the axon. Curr Opin Neurobiol12: 268–274, 2002.PubMedCrossRefGoogle Scholar
  23. 23.
    Giri DK, Ali-Seyed M, Li LY, Lee DF, Ling P, Bartholomeusz G, Wang SC, and Hung MC. Endosomal transport of ErbB-2: mechanism for nuclear entry of the cell surface receptor. Mol Cell Biol25: 11005–11018, 2005.PubMedCrossRefGoogle Scholar
  24. 24.
    Golding NL, Staff NP, and Spruston N. Dendritic spikes as a mechanism for cooperative long-term potentiation. Nature418: 326–331, 2002.PubMedCrossRefGoogle Scholar
  25. 25.
    Graef IA, Mermelstein PG, Stankunas K, Neilson JR, Deisseroth K, Tsien RW, and Crabtree GR. L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons. Nature401: 703–708, 1999.PubMedCrossRefGoogle Scholar
  26. 26.
    Groth RD and Mermelstein PG. Brain-derived neurotrophic factor activation of NFAT (nuclear factor of activated T-cells)-dependent transcription: a role for the transcription factor NFATc4 in neurotrophin-mediated gene expression. J Neurosci23: 8125–8134, 2003.PubMedGoogle Scholar
  27. 27.
    Guzik BW and Goldstein LS. Microtubule-dependent transport in neurons: steps towards an understanding of regulation, function and dysfunction. Curr Opin Cell Biol16: 443–450, 2004.PubMedCrossRefGoogle Scholar
  28. 28.
    Hanz S and Fainzilber M. Retrograde signaling in injured nerve–the axon reaction revisited. J Neurochem99: 13–19, 2006.PubMedCrossRefGoogle Scholar
  29. 29.
    Hanz S, Perlson E, Willis D, Zheng JQ, Massarwa R, Huerta JJ, Koltzenburg M, Kohler M, van-Minnen J, Twiss JL, and Fainzilber M. Axoplasmic importins enable retrograde injury signaling in lesioned nerve. Neuron40: 1095–1104, 2003.PubMedCrossRefGoogle Scholar
  30. 30.
    Hardingham GE, Arnold FJ, and Bading H. A calcium microdomain near NMDA receptors: on switch for ERK-dependent synapse-to-nucleus communication. Nat Neurosci4: 565–566, 2001.PubMedCrossRefGoogle Scholar
  31. 31.
    Hardingham GE, Arnold FJ, and Bading H. Nuclear calcium signaling controls CREBmediated gene expression triggered by synaptic activity. Nat Neurosci4: 261–267, 2001.PubMedCrossRefGoogle Scholar
  32. 32.
    Harel A and Forbes DJ. Importin beta: conducting a much larger cellular symphony. Mol Cell16: 319–330, 2004.PubMedGoogle Scholar
  33. 33.
    Heerssen HM and Segal RA. Location, location, location: a spatial view of neurotrophin signal transduction. Trends Neurosci25: 160–165, 2002.PubMedCrossRefGoogle Scholar
  34. 34.
    Hirokawa N and Takemura R. Molecular motors and mechanisms of directional transport in neurons. Nat Rev Neurosci6: 201–214, 2005.PubMedCrossRefGoogle Scholar
  35. 35.
    Howe CL. Modeling the signaling endosome hypothesis: why a drive to the nucleus is better than a (random) walk. Theor Biol Med Model2: 43, 2005.PubMedCrossRefGoogle Scholar
  36. 36.
    Howe CL and Mobley WC. Long-distance retrograde neurotrophic signaling. Curr Opin Neurobiol15: 40–48, 2005.PubMedCrossRefGoogle Scholar
  37. 37.
    Howe CL and Mobley WC. Signaling endosome hypothesis: A cellular mechanism for long distance communication. J Neurobiol58: 207–216, 2004.PubMedCrossRefGoogle Scholar
  38. 38.
    Jans DA, Xiao CY, and Lam MH. Nuclear targeting signal recognition: a key control point in nuclear transport? Bioessays22: 532–544, 2000.PubMedCrossRefGoogle Scholar
  39. 39.
    Jiang Y, McLennan IS, Koishi K, and Hendry IA. Transforming growth factor-beta 2 is anterogradely and retrogradely transported in motoneurons and up-regulated after nerve injury. Neuroscience97: 735–742, 2000.PubMedCrossRefGoogle Scholar
  40. 40.
    Kalderon D, Roberts BL, Richardson WD, and Smith AE. A short amino acid sequence able to specify nuclear location. Cell39: 499–509, 1984.PubMedCrossRefGoogle Scholar
  41. 41.
    Kalinovsky A and Scheiffele P. Transcriptional control of synaptic differentiation by retrograde signals. Curr Opin Neurobiol14: 272–279, 2004.PubMedCrossRefGoogle Scholar
  42. 42.
    Kandel ER. The molecular biology of memory storage: a dialog between genes and synapses. Biosci Rep21: 565–611, 2001.PubMedCrossRefGoogle Scholar
  43. 43.
    Kornhauser JM, Cowan CW, Shaywitz AJ, Dolmetsch RE, Griffith EC, Hu LS, Haddad C, Xia Z, and Greenberg ME. CREB transcriptional activity in neurons is regulated by multiple, calcium-specific phosphorylation events. Neuron34: 221–233, 2002.PubMedCrossRefGoogle Scholar
  44. 44.
    Korte M, Kang H, Bonhoeffer T, and Schuman E. A role for BDNF in the late-phase of hippocampal long-term potentiation. Neuropharmacology37: 553–559, 1998.PubMedCrossRefGoogle Scholar
  45. 45.
    Kumar JP, Wilkie GS, Tekotte H, Moses K, and Davis I. Perturbing nuclear transport in Drosophila eye imaginal discs causes specific cell adhesion and axon guidance defects. Dev Biol240: 315–325, 2001.PubMedCrossRefGoogle Scholar
  46. 46.
    Lee SH, Lim CS, Park H, Lee JA, Han JH, Kim H, Cheang YH, Lee SH, Lee YS, Ko HG, Jang DH, Kim H, Miniaci MC, Bartsch D, Kim E, Bailey CH, Kandel ER, and Kaang BK. Nuclear translocation of CAM-associated protein activates transcription for long-term facilitation in Aplysia. Cell129: 801–812, 2007.PubMedCrossRefGoogle Scholar
  47. 47.
    Levy JR and Holzbaur EL. Cytoplasmic dynein/dynactin function and dysfunction in motor neurons. Int J Dev Neurosci24: 103–111, 2006.PubMedCrossRefGoogle Scholar
  48. 48.
    Lim RY and Fahrenkrog B. The nuclear pore complex up close. Currt Opin Cell Biol18: 342–347, 2006.CrossRefGoogle Scholar
  49. 49.
    Lonze BE and Ginty DD. Function and regulation of CREB family transcription factors in the nervous system. Neuron35: 605–623, 2002.PubMedCrossRefGoogle Scholar
  50. 50.
    Martin KC, Casadio A, Zhu H, Yaping E, Rose JC, Chen M, Bailey CH, and Kandel ER. Synapse-specific, long-term facilitation of Aplysiasensory to motor synapses: a function for local protein synthesis in memory storage. Cell91: 927–938, 1997.PubMedCrossRefGoogle Scholar
  51. 51.
    Martin KC and Kosik KS. Synaptic tagging – who’s it? Nat Rev Neurosci3: 813–820, 2002.PubMedCrossRefGoogle Scholar
  52. 52.
    Mathew D, Ataman B, Chen J, Zhang Y, Cumberledge S, and Budnik V. Wingless signaling at synapses is through cleavage and nuclear import of receptor DFrizzled2. Science310: 1344–1347, 2005.PubMedCrossRefGoogle Scholar
  53. 53.
    McCabe BD, Hom S, Aberle H, Fetter RD, Marques G, Haerry TE, Wan H, O’Connor MB, Goodman CS, and Haghighi AP. Highwire regulates presynaptic BMP signaling essential for synaptic growth. Neuron41: 891–905, 2004.PubMedCrossRefGoogle Scholar
  54. 54.
    McCabe BD, Marques G, Haghighi AP, Fetter RD, Crotty ML, Haerry TE, Goodman CS, and O’Connor MB. The BMP homolog Gbb provides a retrograde signal that regulates synaptic growth at the Drosophila neuromuscular junction. Neuron39: 241–254, 2003.PubMedCrossRefGoogle Scholar
  55. 55.
    Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, and Baltimore D. NF-kappa B functions in synaptic signaling and behavior. Nat Neurosci6: 1072–1078, 2003.PubMedCrossRefGoogle Scholar
  56. 56.
    Meldolesi J. Rapidly exchanging Ca2+ stores in neurons: molecular, structural and functional properties. Prog Nneurobiol65: 309–338, 2001.CrossRefGoogle Scholar
  57. 57.
    Mikenberg I, Widera D, Kaus A, Kaltschmidt B, and Kaltschmidt C. Transcription Factor NF-kappaB Is Transported to the Nucleus via Cytoplasmic Dynein/Dynactin Motor Complex in Hippocampal Neurons. PLoS ONE2: e589, 2007.PubMedCrossRefGoogle Scholar
  58. 58.
    Otis KO, Thompson KR, and Martin KC. Importin-mediated nuclear transport in neurons. Curr Opin Neurobiol16: 329–335, 2006.PubMedCrossRefGoogle Scholar
  59. 59.
    Patterson SL, Pittenger C, Morozov A, Martin KC, Scanlin H, Drake C, and Kandel ER. Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. Neuron32: 123–140, 2001.PubMedCrossRefGoogle Scholar
  60. 60.
    Perlson E, Hanz S, Ben-Yaakov K, Segal-Ruder Y, Seger R, and Fainzilber M. Vimentin-dependent spatial translocation of an activated MAP kinase in injured nerve. Neuron45: 715–726, 2005.PubMedCrossRefGoogle Scholar
  61. 61.
    Perlson E, Hanz S, Medzihradszky KF, Burlingame AL, and Fainzilber M. From snails to sciatic nerve: Retrograde injury signaling from axon to soma in lesioned neurons. J Neurobiol58: 287–294, 2004.PubMedCrossRefGoogle Scholar
  62. 62.
    Pittenger C and Kandel ER. In search of general mechanisms for long-lasting plasticity: Aplysiaand the hippocampus. Philos Trans R Soc Lond B Biol Sci358: 757–763, 2003.PubMedCrossRefGoogle Scholar
  63. 63.
    Rawson JM, Lee M, Kennedy EL, and Selleck SB. Drosophila neuromuscular synapse assembly and function require the TGF-beta type I receptor saxophone and the transcription factor Mad. J Neurobiol55: 134–150, 2003.PubMedCrossRefGoogle Scholar
  64. 64.
    Reed NA, Cai D, Blasius TL, Jih GT, Meyhofer E, Gaertig J, and Verhey KJ. Microtubule acetylation promotes kinesin-1 binding and transport. Curr Biol16: 2166–2172, 2006.PubMedCrossRefGoogle Scholar
  65. 65.
    Robbins J, Dilworth SM, Laskey RA, and Dingwall C. Two interdependent basic domains in nucleoplasmin nuclear targeting sequence: identification of a class of bipartite nuclear targeting sequence. Cell64: 615–623, 1991.PubMedCrossRefGoogle Scholar
  66. 66.
    Sabatini BL, Maravall M, and Svoboda K. Ca(2+) signaling in dendritic spines. Curr Opin Neurobiol11: 349–356, 2001.PubMedCrossRefGoogle Scholar
  67. 67.
    Senger DL and Campenot RB. Rapid retrograde tyrosine phosphorylation of trkA and other proteins in rat sympathetic neurons in compartmented cultures. J Cell Biol138: 411–421, 1997.PubMedCrossRefGoogle Scholar
  68. 68.
    Setou M, Hayasaka T, and Yao I. Axonal transport versus dendritic transport. J Neurobiol 58: 201–206, 2004.PubMedCrossRefGoogle Scholar
  69. 69.
    Sherff CM and Carew TJ. Coincident induction of long-term facilitation in Aplysia: cooperativity between cell bodies and remote synapses. Science285: 1911–1914, 1999.PubMedCrossRefGoogle Scholar
  70. 70.
    Snider WD, Zhou FQ, Zhong J, and Markus A. Signaling the pathway to regeneration. Neuron35: 13–16, 2002.PubMedCrossRefGoogle Scholar
  71. 71.
    Spacek J and Harris KM. Three-dimensional organization of smooth endoplasmic reticulum in hippocampal CA1 dendrites and dendritic spines of the immature and mature rat. J Neurosci17: 190–203, 1997.PubMedGoogle Scholar
  72. 72.
    Sweatt JD. Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol14: 311–317, 2004.PubMedCrossRefGoogle Scholar
  73. 73.
    Thompson KR, Otis KO, Chen DY, Zhao Y, O’Dell TJ, and Martin KC. Synapse to nucleus signaling during long-term synaptic plasticity; a role for the classical active nuclear import pathway. Neuron44: 997–1009, 2004.PubMedGoogle Scholar
  74. 74.
    Verkhratsky A. The endoplasmic reticulum and neuronal calcium signaling. Cell Calcium 32: 393–404, 2002.PubMedCrossRefGoogle Scholar
  75. 75.
    Wellmann H, Kaltschmidt B, and Kaltschmidt C. Retrograde transport of transcription factor NF-kappa B in living neurons. J Biol Chem276: 11821–11829, 2001.PubMedCrossRefGoogle Scholar
  76. 76.
    Westermann S and Weber K. Post-translational modifications regulate microtubule function. Nat Rev Mol Cell Biol4: 938–947, 2003.PubMedCrossRefGoogle Scholar
  77. 77.
    White C, Yang J, Monteiro MJ, and Foskett JK. CIB1, a ubiquitously expressed Ca2+- binding protein ligand of the InsP3 receptor Ca2+ release channel. J Biol Chem281: 20825–20833, 2006.PubMedCrossRefGoogle Scholar
  78. 78.
    Whitehurst AW, Wilsbacher JL, You Y, Luby-Phelps K, Moore MS, and Cobb MH. ERK2 enters the nucleus by a carrier-independent mechanism. Proc Natl Acad Sci U S A 99: 7496–7501, 2002.PubMedCrossRefGoogle Scholar
  79. 79.
    Williams SR and Stuart GJ. Dependence of EPSP efficacy on synapse location in neocortical pyramidal neurons. Science295: 1907–1910, 2002.PubMedCrossRefGoogle Scholar
  80. 80.
    Williams SR and Stuart GJ. Role of dendritic synapse location in the control of action potential output. Trends Neurosci26: 147–154, 2003.PubMedCrossRefGoogle Scholar
  81. 81.
    Willingham AT, Orth AP, Batalov S, Peters EC, Wen BG, Aza-Blanc P, Hogenesch JB, and Schultz PG. A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science309: 1570–1573, 2005.PubMedCrossRefGoogle Scholar
  82. 82.
    Wu GY, Deisseroth K, and Tsien RW. Activity-dependent CREB phosphorylation: convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Proc Natl Acad Sci U S A98: 2808–2813, 2001.PubMedCrossRefGoogle Scholar
  83. 83.
    Yang J, McBride S, Mak DO, Vardi N, Palczewski K, Haeseleer F, and Foskett JK. Identification of a family of calcium sensors as protein ligands of inositol trisphosphate receptor Ca(2+) release channels. Proc Natl Acad Sci U S A99: 7711–7716, 2002.PubMedCrossRefGoogle Scholar
  84. 84.
    Zalk R, Lehnart SE, and Marks AR. Modulation of the Ryanodine Receptor and Intracellular Calcium. Annu Rev Biochem76: 367–385, 2007.PubMedCrossRefGoogle Scholar
  85. 85.
    Zhang XP and Ambron RT. Positive injury signals induce growth and prolong survival in Aplysianeurons. J Neurobiol45: 84–94, 2000.PubMedCrossRefGoogle Scholar
  86. 86.
    Zhou P, Porcionatto M, Pilapil M, Chen Y, Choi Y, Tolias KF, Bikoff JB, Hong EJ, Greenberg ME, and Segal RA. Polarized signaling endosomes coordinate BDNFInduced Chemotaxis of Cerebellar Precursors. Neuron55: 53–68, 2007.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Carrie L. Heusner
    • 1
  • Kelsey C. Martin
    • 1
  1. 1.Department of Biological Chemistry and Department of Psychiatry and Biobehavioral SciencesBrain Research Institute, Semel Institute for Neuroscience and Human behavior, UCLALos AngelesUSA

Personalised recommendations