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Visinin-like proteins (VSNLs): interaction partners and emerging functions in signal transduction of a subfamily of neuronal Ca2+-sensor proteins


The visinin-like protein (VSNL) subfamily, including VILIP-1 (the founder protein), VILIP-2, VILIP-3, hippocalcin, and neurocalcin δ, constitute a highly homologous subfamily of neuronal calcium sensor (NCS) proteins. Comparative studies have shown that VSNLs are expressed predominantly in the brain with restricted expression patterns in various subsets of neurons but are also found in peripheral organs. In addition, the proteins display differences in their calcium affinities, in their membrane-binding kinetics, and in the intracellular targets to which they associate after calcium binding. Even though the proteins use a similar calcium-myristoyl switch mechanism to translocate to cellular membranes, they show calcium-dependent localization to various subcellular compartments when expressed in the same neuron. These distinct calcium-myristoyl switch properties might be explained by specificity for defined phospholipids and membrane-bound targets; this enables VSNLs to modulate various cellular signal transduction pathways, including cyclic nucleotide and MAPK signaling. An emerging theme is the direct or indirect effect of VSNLs on gene expression and their interaction with components of membrane trafficking complexes, with a possible role in membrane trafficking of different receptors and ion channels, such as glutamate receptors of the kainate and AMPA subtype, nicotinic acetylcholine receptors, and Ca2+-channels. One hypothesis is that the highly homologous VSNLs have evolved to fulfil specialized functions in membrane trafficking and thereby affect neuronal signaling and differentiation in defined subsets of neurons. VSNLs are involved in differentiation processes showing a tumor-invasion-suppressor function in peripheral organs. Finally, VSNLs play neuroprotective and neurotoxic roles and have been implicated in neurodegenerative diseases.

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  1. Ames JB, Tanaka T, Stryer L, Ikura M (1996) Portrait of a myristoyl switch protein. Curr Opin Struct Biol 6:432–438

  2. Ames JB, Ishima R, Tanaka T, Gordon JI, Stryer L, Ikura M (1997) Molecular mechanics of calcium-myristoyl switches. Nature 389:198–202

  3. An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, Hinson JW, Mattsson KI, Strassle BW, Trimmer JS, Rhodes KJ (2000) Modulation of A-type potassium channels by a family of calcium sensors. Nature 403:553–556

  4. Bastianelli E, Polans AS, Hidaka H, Pochet R (1995) Differential distribution of six calcium-binding proteins in the rat olfactory epithelium during postnatal development and adulthood. J Comp Neurol 354:395–409

  5. Bernstein H-G, Baumann B, Danos P, Diekmann S, Bogerts B, Gundelfinger ED, Braunewell K-H (1999) Regional and cellular distribution of neural visinin-like protein immunoreactivities (VILIP-1 and VILIP-3) in human brain. J Neurocytol 28:655–662

  6. Blandini F, Braunewell K-H, Manahan-Vaughan D, Orzi F, Sarti P (2004) Neurodegeneration and energy metabolism: from chemistry and clinics. Cell Death Differ 11:479–484

  7. Blondeau F, Ritter B, Allaire PD, Wasiak S, Girard M, Hussain NK, Angers A, Legendre-Guillemin V, Roy L, Boismenu D, Kearney RE, Bell AW, Bergeron JJ, McPherson PS (2004) Tandem MS analysis of brain clathrin-coated vesicles reveals their critical involvement in synaptic vesicle recycling. Proc Natl Acad Sci USA 101:3833–3838

  8. Boekhoff I, Braunewell K-H, Andreini I, Breer H, Gundelfinger ED (1997) The calcium-binding protein VILIP in olfactory neurons: regulation of second messenger signaling. Eur J Cell Biol 72:151–158

  9. Brackmann M, Schuchmann S, Anand R, Braunewell K-H (2005) Neuronal Ca2+ sensor protein VILIP-1 affects cGMP signalling of guanylyl cyclase B by regulating clathrin-dependent receptor recycling in hippocampal neurons. J Cell Sci 118:2495–2505

  10. Braunewell K-H, Gundelfinger ED (1997) Low level expression of calcium-sensor protein VILIP induces cAMP- dependent differentiation in rat C6 glioma cells. Neurosci Lett 234:139–142

  11. Braunewell K-H, Gundelfinger ED (1999) Intracellular neuronal calcium sensor proteins: a family of EF-hand calcium-binding proteins in search of a function. Cell Tissue Res 299:1–12

  12. Braunewell K-H, Spilker C, Behnisch T, Gundelfinger ED (1997) The neuronal calcium-sensor protein VILIP modulates cyclic AMP accumulation in stably transfected C6 glioma cells: amino-terminal myristoylation determines functional activity. J Neurochem 68:2129–2139

  13. Braunewell K-H, Brackmann M, Schaupp M, Spilker C, Anand R, Gundelfinger ED (2001a) Intracellular neuronal calcium sensor (NCS) protein VILIP-1 modulates cGMP signalling pathways in transfected neural cells and cerebellar granule neurones. J Neurochem 78:1277–1286

  14. Braunewell K-H, Riederer P, Spilker C, Gundelfinger ED, Bogerts B, Bernstein HG (2001b) Abnormal localization of two neuronal calcium sensor proteins, visinin-like proteins (VILIPs)-1 and -3, in neocortical brain areas of Alzheimer disease patients. Dement Geriatr Cogn Disord 2:110–115

  15. Burgoyne RD (2007) Neuronal calcium sensor proteins: generating diversity in neuronal Ca2+ signalling. Nat Rev Neurosci 8:182–193

  16. Burgoyne RD, Weiss JL (2001) The neuronal calcium sensor family of Ca2+-binding proteins. Biochem J 353:1–12

  17. Burgoyne RD, O’Callaghan DW, Hasdemir B, Haynes LP, Tepikin AV (2004) Neuronal Ca2+-sensor proteins: multitalented regulators of neuronal function. Trends Neurosci 27:203–209

  18. Carrión AM, Link WA, Ledo F, Mellström B, Naranjo JR (1999) DREAM is a Ca2+-regulated transcriptional repressor. Nature 398:80–84

  19. Cheng HY, Pitcher GM, Laviolette SR, Whishaw IQ, Tong KI, Kockeritz LK, Wada T, Joza NA, Crackower M, Goncalves J, Sarosi I, Woodgett JR, Oliveira-dos-Santos AJ, Ikura M, Kooy D van der, Salter MW, Penninger JM (2002) DREAM is a critical transcriptional repressor for pain modulation. Cell 108:31–43

  20. Coussen F, Mulle C (2006) Kainate receptor-interacting proteins and membrane trafficking. Biochem Soc Trans 34:927–930

  21. Coussen F, Perrais D, Jaskolski F, Sachidhanandam S, Normand E, Bockaert J, Marin P, Mulle C (2006) Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex. Neuron 47:555–566

  22. Cox JA, Durussel I, Comte M, Nef S, Nef P, Lenz SE, Gundelfinger ED (1994) Cation binding and conformational changes in VILIP and NCS-1, two neuron-specific calcium-binding proteins. J Biol Chem 269:32807–32813

  23. Dai FF, Zhang Y, Kang Y, Wang Q, Gaisano HY, Braunewell KH, Chan CB, Wheeler MB (2006) The neuronal Ca2+ sensor protein visinin-like protein-1 is expressed in pancreatic islets and regulates insulin secretion. J Biol Chem 281:21942–21953

  24. De Raad S, Comte M, Nef P, Lenz SE, Gundelfinger ED, Cox JA (1995) Distribution pattern of three neural calcium-binding proteins (NCS-1, VILIP and recoverin) in chicken, bovine and rat retina. Histochem J 27:524–535

  25. Dizhoor AM, Ray S, Kumar S, Niemi G, Spencer M, Brolley D, Walsh KA, Philipov PP, Hurley JB, Stryer L (1991) Recoverin: a calcium sensitive activator of retinal rod guanylate cyclase. Science 251:915–918

  26. Duda T, Sharma RK (2008) ONE-GC membrane guanylate cyclase, a trimodal odorant signal transducer. Biochem Biophys Res Commun 367:440–445

  27. Duda T, Jankowska A, Venkataraman V, Nagele RG, Sharma RK (2001) A novel calcium-regulated membrane guanylate cyclase transduction system in the olfactory neuroepithelium. Biochemistry 40:12067–12077

  28. Duda T, Fik-Rymarkiewicz E, Venkataraman V, Krishnan A, Sharma RK (2004) Calcium-modulated ciliary membrane guanylate cyclase transduction machinery: constitution and operational principles. Mol Cell Biochem 267:107–122

  29. Few AP, Lautermilch NJ, Westenbroek RE, Scheuer T, Catterall WA (2005) Differential regulation of CaV2.1 channels by calcium-binding protein 1 and visinin-like protein-2 requires N-terminal myristoylation. J Neurosci 25:7071–7080

  30. Fu J, Fong K, Bellacosa A, Ross E, Apostolou S, Bassi DE, Jin F, Zhang J, Cairns P, Caceres II de, Braunewell KH, Klein-Szanto AJ (2008) VILIP-1 downregulation in non-small cell lung carcinomas: mechanisms and prediction of survival. PLoS ONE 3:e1698

  31. Gierke P, Zhao C, Linke B, Brackmann M, Heinemann U, Braunewell K-H (2004) Expression analysis of members of the neuronal calcium sensor protein family: combining bioinformatics and Western blot analysis. Biochem Biophys Res Commun 323:38–43

  32. Gierke P, Zhao C, Bernstein H-G, Noack C, Anand R, Heinemann U, Braunewell K-H (2008) Implication of neuronal Ca2+-sensor protein VILIP-1 in the glutamate hypothesis of schizophrenia. Neurobiol Dis 32:162–175

  33. Gonzalez Guerrico AM, Jaffer ZM, Page RE, Braunewell K-H, Chernoff J, Klein-Szanto AJP (2005) Visinin-like protein-1 is a potent inhibitor of cell adhesion and migration in squamous carcinoma cells. Oncogene 24:2307–2316

  34. Grant AL, Jones A, Thomas KL, Wisden W (1996) Characterization of the rat hippocalcin gene: the 5′ flanking region directs expression to the hippocampus. Neuroscience 75:1099–1115

  35. Hamashima H, Tamaru T, Noguchi H, Kobayashi M, Takamatsu K (2001) Immunochemical assessment of neural visinin-like calcium-binding protein 3 expression in rat brain. Neurosci Res 39:133–143

  36. Haynes LP, Thomas GM, Burgoyne RD (2005) Interaction of neuronal calcium sensor-1 and ADP-ribosylation factor 1 allows bidirectional control of phosphatidylinositol 4-kinase {beta} and trans-Golgi network-plasma membrane traffic. J Biol Chem 280:6047–6054

  37. Haynes LP, Fitzgerald DJ, Wareing B, O’Callaghan DW, Morgan A, Burgoyne RD (2006) Analysis of the interacting partners of the neuronal calcium-binding proteins L-CaBP1, hippocalcin, NCS-1 and neurocalcin delta. Proteomics 6:1822–1832

  38. Hyun JK, Yon C, Kim YS, Noh DY, Lee KH, Han JS (2000) Role of hippocalcin in Ca2+-induced activation of phospholipase D. Mol Cells 10:669–677

  39. Ivings L, Pennington SR, Jenkins R, Weiss JL, Burgoyne RD (2002) Identification of Ca2+-dependent binding partners for the neuronal calcium sensor protein neurocalcin delta: interaction with actin, clathrin and tubulin. Biochem J 363:599–608

  40. Jheng FF, Wang L, Lee L, Chang LS (2006) Functional contribution of Ca2+ and Mg2+ to the intermolecular interaction of visinin-like proteins. Protein J 25:250–256

  41. Kajimoto Y, Shirai Y, Mukai H, Kuno T, Tanaka C (1993) Molecular cloning of two additional members of the neural visinin-like Ca(2+)-binding protein gene family. J Neurochem 61:1091–1096

  42. Kamide K, Kokubo Y, Yang J, Tanaka C, Hanada H, Takiuchi S, Inamoto N, Banno M, Kawano Y, Okayama A, Tomoike H, Miyata T (2005) Hypertension susceptibility genes on chromosome 2p24-p25 in a general Japanese population. J Hypertens 23:955–960

  43. Kamiyama M, Kobayashi M, Araki S, Iida A, Tsunoda T, Kawai K, Imanishi M, Nomura M, Babazono T, Iwamoto Y, Kashiwagi A, Kaku K, Kawamori R, Ng DP, Hansen T, Gaede P, Pedersen O, Nakamura Y, Maeda S (2007) Polymorphisms in the 3′ UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy. Hum Genet 122:397–407

  44. Kato M, Watanabe Y, Iino S, Takaoka Y, Kobayashi S, Haga T, Hidaka H (1998) Cloning and expression of a cDNA encoding a new neurocalcin isoform (neurocalcin alpha) from bovine brain. Biochem J 331:871–876

  45. Kobayashi M, Takamatsu K, Saitoh S, Nogushi T (1993) Myristoylation of hippocalcin is linked to its membrane association properties. J Biol Chem 268:18898–18904

  46. Kobayashi M, Masaki T, Hori K, Masuo Y, Miyamoto M, Tsubokawa H, Noguchi H, Nomura M, Takamatsu K (2005) Hippocalcin-deficient mice display a defect in cAMP response element-binding protein activation associated with impaired spatial and associative memory. Neuroscience 133:471–484

  47. Korhonen L, Hansson I, Kukkonen JP, Brännvall K, Kobayashi M, Takamatsu K, Lindholm D (2005) Hippocalcin protects against caspase-12-induced and age-dependent neuronal degeneration. Mol Cell Neurosci 28:85–95

  48. Kraut N, Frampton J, Graf T (1995) Rem-1, a putative direct target gene of the Myb-Ets fusion oncoprotein in haematopoietic progenitors, is a member of the recoverin family. Oncogene 10:1027–1036

  49. Krishnan A, Venkataraman V, Fik-Rymarkiewicz E, Duda T, Sharma RK (2004) Structural, biochemical, and functional characterization of the calcium sensor neurocalcin delta in the inner retinal neurons and its linkage with the rod outer segment membrane guanylate cyclase transduction system. Biochemistry 43:2708–2723

  50. Kumar VD, Vijay-Kumar S, Krishnan A, Duda T, Sharma RK (1999) A second calcium regulator of rod outer segment membrane guanylate cyclase, ROS-GC1: neurocalcin. Biochemistry 38:12614–12620

  51. Kuno T, Kajimoto Y, Hashimoto T, Mukai H, Shirai Y, Saheki S, Tanaka C (1992) cDNA cloning of a neural visinin-like Ca(2+)-binding protein. Biochem Biophys Res Commun 184:1219–1225

  52. Ladant D (1995) Calcium and membrane binding properties of bovine neurocalcin delta expressed in Escherichia coli. J Biol Chem 270:3179–3185

  53. Laterza OF, Modur VR, Crimmins DL, Olander JV, Landt Y, Lee JM, Ladenson JH (2006) Identification of novel brain biomarkers. Clin Chem 52:1713–1721

  54. Lautermilch NJ, Few AP, Scheuer T, Catterall WA (2005) Modulation of CaV2.1 channels by the neuronal calcium-binding protein visinin-like protein-2. J Neurosci 25:7062–7070

  55. Lederer CW, Torrisi A, Pantelidou M, Santama N, Cavallaro S (2007) Pathways and genes differentially expressed in the motor cortex of patients with sporadic amyotrophic lateral sclerosis. BMC Genomics 8:26

  56. Ledo F, Carrion AM, Link WA, Mellström B, Naranjo JR (2000) DREAM-alphaCREM interaction via leucine-charged domains derepresses downstream regulatory element-dependent transcription. Mol Cell Biol 20:9120–9126

  57. Ledo F, Kremer L, Mellström B, Naranjo JR (2002) Ca2+-dependent block of CREB-CBP transcription by repressor DREAM. EMBO J 21:4583–4592

  58. Lenz SE, Henschel Y, Zopf D, Voss B, Gundelfinger ED (1992) VILIP, a cognate protein of the retinal calcium binding proteins visinin and recoverin, is expressed in the developing chicken brain. Brain Res Mol Brain Res 15:133–140

  59. Lenz SE, Braunewell KH, Weise C, Nedlina-Chittka A, Gundelfinger ED (1996a) The neuronal EF-hand Ca(2+)-binding protein VILIP: interaction with cell membrane and actin-based cytoskeleton. Biochem Biophys Res Commun 225:1078–1083

  60. Lenz SE, Jiang S, Braun K, Gundelfinger ED (1996b) Localization of the neural calcium-binding protein VILIP (visinin-like protein) in neurons of the chick visual system and cerebellum. Cell Tissue Res 283:413–424

  61. Lenz SE, Zuschratter W, Gundelfinger ED (1996c) Distribution of visinin-like protein (VILIP) immunoreactivity in the hippocampus of the Mongolian gerbil (Meriones unguiculatus). Neurosci Lett 206:133–136

  62. Lin L, Jeanclos EM, Treuil M, Braunewell KH, Gundelfinger ED, Anand R (2002a) The calcium sensor protein visinin-like protein-1 modulates the surface expression and agonist-sensitivity of the a4β2 nicotinic acetylcholine receptor. J Biol Chem 277:41872–41878

  63. Lin L, Braunewell KH, Gundelfinger ED, Anand R (2002b) Functional analysis of calcium-binding EF-hand motifs of visinin-like protein-1. Biochem Biophys Res Commun 296:827–832

  64. Lindholm D, Mercer EA, Yu LY, Chen Y, Kukkonen J, Korhonen L, Arumäe U (2002) Neuronal apoptosis inhibitory protein: structural requirements for hippocalcin binding and effects on survival of NGF-dependent sympathetic neurons. Biochim Biophys Acta 1600:138–147

  65. Link WA, Ledo F, Torres B, Palczewska M, Madsen TM, Savignac M, Albar JP, Mellström B, Naranjo JR (2004) Day-night changes in downstream regulatory element antagonist modulator/potassium channel interacting protein activity contribute to circadian gene expression in pineal gland. J Neurosci 24:5346–5355

  66. Mahloogi H, Gonzalez-Guerrico AM, De Cicco RL, Bassi DE, Goodrow T, Braunewell KH, Klein-Szanto AJP (2003) Graduate decrease of VILIP-1 expression during mouse skin tumor progression and its role in regulating tumor cell invasive behavior. Cancer Res 63:4997–5004

  67. Mammen A, Simpson PJ, Nighorn A, Imanishi Y, Palczewski K, Ronnett GV, Moon C (2004) Hippocalcin in the olfactory epithelium: a mediator of second messenger signaling. Biochem Biophys Res Commun 322:1131–1139

  68. Martinez-Guijarro FJ, Brinon JG, Blasco-Ibanez JM, Okazaki K, Hidaka H, Alonso JR (1998) Neurocalcin-immunoreactive cells in the rat hippocampus are GABAergic interneurons. Hippocampus 8:2–23

  69. Masuo Y, Ogura A, Kobayashi M, Masaki T, Furuta Y, Ono T, Takamatsu K (2007) Hippocalcin protects hippocampal neurons against excitotoxin damage by enhancing calcium extrusion. Neuroscience 145:495–504

  70. Mathisen PM, Johnson JM, Kawczak JA, Tuohy VK (1999) Visinin-like protein (VILIP) is a neuron-specific calcium-dependent double-stranded RNA-binding protein. J Biol Chem 274:31571–31576

  71. Mellström B, Savignac M, Gomez-Villafuertes R, Naranjo JR (2008) Ca2+-operated transcriptional networks: molecular mechanisms and in vivo models. Physiol Rev 88:421–449

  72. Mercer EA, Korhonen L, Skoglösa Y, Olsson PA, Kukkonen JP, Lindholm D (2000) NAIP interacts with hippocalcin and protects neurons against calcium-induced cell death through caspase-3-dependent and -independent pathways. EMBO J 19:3597–3607

  73. Monfort P, Munoz MD, Kosenko E, Felipo V (2002) Long-term potentiation in hippocampus involves sequential activation of soluble guanylate cyclase, cGMP-dependent protein kinase, and cGMP-degrading phosphodiesterase. J Neurosci 22:10116–10124

  74. Nagata K, Puls A, Futter C, Aspenstrom P, Schaefer E, Nakata T, Hirokawa N, Hall A (1998) The MAP kinase kinase kinase MLK2 co-localizes with activated JNK along microtubules and associates with kinesin superfamily motor KIF3. EMBO J 17:149–158

  75. Nakano A, Terasawa M, Watanabe M, Usuda N, Morita T, Hidaka H (1992) Neurocalcin, a novel calcium binding protein with three EF-hand domains, expressed in retinal amacrine cells and ganglion cells. Biochem Biophys Res Commun 186:1207–1211

  76. Nef P (1996) Neuron-specific calcium sensors (the NCS subfamily). In: Celio MR (ed) Guidebook to the calcium-binding proteins. Oxford University Press, New York, pp 94–98

  77. Noguchi H, Kobayashi M, Miwa N, Takamatsu K (2007) Lack of hippocalcin causes impairment in Ras/extracellular signal-regulated kinase cascade via a Raf-mediated activation process. J Neurosci Res 85:837–844

  78. O’Callaghan DW, Ivings L, Weiss JL, Ashby MC, Tepikin AV, Burgoyne RD (2002) Differential use of myristoyl groups on neuronal calcium sensor proteins as a determinant of spatio-temporal aspects of Ca2+ signal transduction. J Biol Chem 277:14227–14237

  79. O’Callaghan DW, Tepikin AV, Burgoyne RD (2003a) Dynamics and calcium sensitivity of the Ca2+-myristoyl switch protein hippocalcin in living cells. J Cell Biol 163:715–721

  80. O’Callaghan DW, Hasdemir B, Leighton M, Burgoyne RD (2003b) Residues within the myristoylation motif determine intracellular targeting of the neuronal Ca2+ sensor protein KChIP1 to post-ER transport vesicles and traffic of Kv4 K+ channels. J Cell Sci 116:4833–4845

  81. O’Callaghan DW, Haynes LP, Burgoyne RD (2005) High-affinity interaction of the N-terminal myristoylation motif of the neuronal calcium sensor protein hippocalcin with phosphatidylinositol 4,5-bisphosphate. Biochem J 391:231–238

  82. Oh DY, Yon C, Oh KJ, Lee KS, Han JS (2006) Hippocalcin increases phospholipase D2 expression through extracellular signal-regulated kinase activation and lysophosphatidic acid potentiates the hippocalcin-induced phospholipase D2 expression. J Cell Biochem 97:1052–1065

  83. Oh DY, Cho JH, Park SY, Kim YS, Yoon YJ, Yoon SH, Chung KC, Lee KS, Han JS (2008) A novel role of hippocalcin in bFGF-induced neurite outgrowth of H19–7 cells. J Neurosci Res 86:1557–1565

  84. Ohya S, Horowitz B (2002) Differential transcriptional expression of Ca2+ BP superfamilies in murine gastrointestinal smooth muscles. Am J Physiol Gastrointest Liver Physiol 283:1290–1297

  85. Oikawa K, Kimura S, Aoki N, Atsuta Y, Takiyama Y, Nagato T, Yanai M, Kobayashi H, Sato K, Sasajima T, Tateno M (2004) Neuronal calcium sensor protein visinin-like protein-3 interacts with microsomal cytochrome b5 in a Ca2+-dependent manner. J Biol Chem 279:15142–15152

  86. Palmer CL, Lim W, Hastie PG, Toward M, Korolchuk VI, Burbidge SA, Banting G, Collingridge GL, Isaac JT, Henley JM (2005) Hippocalcin functions as a calcium sensor in hippocampal LTD. Neuron 47:487–494

  87. Paterlini M, Revilla V, Grant AL, Wisden W (2000) Expression of the neuronal calcium sensor protein family in the rat brain. Neuroscience 99:205–216

  88. Pribanic S, Gisler S, Bacic D, Kocher O, Braunewell K-H, Nakadai T, Murer H, Biber J (2003) Expression of visinin-like protein 3 in mouse kidney. Nephron Physiol 95:76–82

  89. Rivas M, Mellström B, Naranjo JR, Santisteban P (2004) Transcriptional repressor DREAM interacts with thyroid transcription factor-1 and regulates thyroglobulin gene expression. J Biol Chem 279:33114–33122

  90. Saitoh S, Takamatsu K, Kobayashi M, Noguchi T (1993) Distribution of hippocalcin mRNA and immunoreactivity in rat brain. Neurosci Lett 157:107–110

  91. Saitoh S, Takamatsu K, Kobayashi M, Noguchi T (1994) Expression of hippocalcin in the developing rat brain. Brain Res Dev Brain Res 80:199–208

  92. Saitoh S, Kobayashi M, Kuroki T, Noguchi T, Takamatsu K (1995) The development of neural visinin-like Ca(2+)-binding protein 2 immunoreactivity in the rat neocortex and hippocampus. Neurosci Res 23:383–388

  93. Sanz C, Mellström B, Link WA, Naranjo JR, Fernandez-Luna JL (2001) Interleukin 3-dependent activation of DREAM is involved in transcriptional silencing of the apoptotic Hrk gene in hematopoietic progenitor cells. EMBO J 20:2286–2292

  94. Schnurra I, Bernstein HG, Riederer P, Braunewell KH (2001) The neuronal calcium sensor protein VILIP-1 is associated with amyloid plaques and extracellular tangles in Alzheimer’s disease and promotes cell death and tau phosphorylation in vitro: a link between calcium sensors and Alzheimer’s disease? Neurobiol Dis 8:900–909

  95. Schuman EM, Madison DV (1991) A requirement for the intercellular messenger nitric oxide in long-term potentiation. Science 254:1503–1506

  96. Spilker C, Braunewell K-H (2003) The calcium-myristoyl switch of neuronal calcium sensor (NCS) proteins: same biochemical principle but different calcium-dependent localization of VILIP-3 and -1 in hippocampal neurons. Mol Cell Neurosci 24:766–778

  97. Spilker C, Richter K, Smalla K-H, Manahan-Vaughan D, Gundelfinger ED, Braunewell K-H (2000) The neuronal EF-hand calcium-binding protein VILIP-3 is expressed in cerebellar Purkinje cells and shows a calcium-dependent membrane association. Neurosci 96:121–129

  98. Spilker C, Gundelfinger ED, Braunewell K-H (2002a) Evidence for different functional properties of the neuronal calcium sensor proteins VILIP-1 and VILIP-3: from subcellular localization to cellular function.Biochim Biophys Acta 1600:118–127

  99. Spilker C, Dresbach T, Braunewell K-H (2002b) Reversible translocation and activity-dependent localization of the calcium-myristoyl switch protein VILIP-1 to different membrane compartments in living hippocampal neurons. J Neurosci 22:7331–7339

  100. Tanaka T, Ames JB, Harvey TS, Stryer L, Ikura M (1995) Sequestration of the membrane-targeting myristoyl group of recoverin in the calcium-free state. Nature 376:444–447

  101. Telegdy G (1994) The action of ANP, BNP and related peptides on motivated behavior in rats. Rev Neurosci 5:309–315

  102. Teruel MN, Meyer T (2000) Translocation and reversible localization of signaling proteins: a dynamic future for signal transduction. Cell 103:181–184

  103. Tibbles LA, Woodgett JR (1999) The stress-activated protein kinase pathways. Cell Mol Life Sci 55:1230–1254

  104. Tzingounis AV, Kobayashi M, Takamatsu K, Nicoll RA (2007) Hippocalcin gates the calcium activation of the slow afterhyperpolarization in hippocampal pyramidal cells. Neuron 53:487–493

  105. Venkataraman V, Duda T, Ravichandran S, Sharma RK (2008) Neurocalcin delta modulation of ROS-GC1, a new model of Ca(2+) signaling. Biochemistry [Epub ahead of print]

  106. Wang JQ, Fibuch EE, Mao L (2007) Regulation of mitogen-activated protein kinases by glutamate receptors. J Neurochem 100:1–11

  107. Weiss JL, Archer DA, Burgoyne RD (2000) NCS-1/Frequenin functions in an autocrine pathway regulating Ca2+ channels in bovine adrenal chromaffin cells. J Biol Chem 275:40082–40087

  108. Wickborn C, Klein-Szanto AJ, Schlag PM, Braunewell KH (2006) Correlation of visinin-like-protein-1 expression with clinicopathological features in squamous cell carcinoma of the esophagus. Mol Carcinog 45:572–581

  109. Xie Y, Chan H, Fan J, Chen Y, Young J, Li W, Miao X, Yuan Z, Wang H, Tam PK, Ren Y (2007) Involvement of visinin-like protein-1 (VSNL-1) in regulating proliferative and invasive properties of neuroblastoma. Carcinogenesis 28:2122–2130

  110. Yamagata K, Goto K, Kuo CH, Kondo H, Miki N (1990) Visinin: a novel calcium binding protein expressed in retinal cone cells. Neuron 4:469–476

  111. Zaidi NF, Kuplast KG, Washicosky KJ, Kajiwara Y, Buxbaum JD, Wasco W (2006) Calsenilin interacts with transcriptional co-repressor C-terminal binding protein(s). J Neurochem 98:1290–1301

  112. Zhao C, Braunewell K-H (2008) Expression of the neuronal calcium sensor VILIP-1 in the rat hippocampus. Neuroscience 153:1202–1212

  113. Zhao X, Varnai P, Tuymetova G, Balla A, Toth ZE, Oker-Blom C, Roder J, Jeromin A, Balla T (2001) Interaction of neuronal calcium sensor-1 (NCS-1) with phosphatidylinositol 4-kinase beta stimulates lipid kinase activity and affects membrane trafficking in COS-7 cells. J Biol Chem 276:40183–40189

  114. Zozulya S, Stryer L (1992) Calcium-myristoyl protein switch. Proc Natl Acad Sci USA 89:11569–11573

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Correspondence to Karl-Heinz Braunewell.

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Work in the laboratories of K.H.B. has been supported by grants from DFG (Br1579/8–1 and Br1579/9–1, Priority Program of the German Research Foundation SPP1226), Deutsche Krebshilfe, Charité Berlin, and Kultusministerium des Landes Sachsen-Anhalt. Work in the laboratory A.J.K. has been supported by grants from the National Institutes of Health CA107257, CA06927, by an appropriation from the Commonwealth of Pennsylvania, and by a grant from the Pennsylvania Department of Health.

An erratum to this article can be found at http://dx.doi.org/10.1007/s00441-008-0745-y

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Braunewell, K., Szanto, A.J.K. Visinin-like proteins (VSNLs): interaction partners and emerging functions in signal transduction of a subfamily of neuronal Ca2+-sensor proteins. Cell Tissue Res 335, 301–316 (2009). https://doi.org/10.1007/s00441-008-0716-3

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  • Calcium-myristoyl switch
  • cAMP/cGMP signaling
  • Endocytosis
  • Exocytosis
  • MAPK pathways
  • Neurodegeneration
  • Neuronal calcium sensors