Molecular Neurobiology

, Volume 53, Issue 3, pp 1959–1976 | Cite as

(S)-Lacosamide Binding to Collapsin Response Mediator Protein 2 (CRMP2) Regulates CaV2.2 Activity by Subverting Its Phosphorylation by Cdk5

  • Aubin Moutal
  • Liberty François-Moutal
  • Samantha Perez-Miller
  • Karissa Cottier
  • Lindsey Anne Chew
  • Seul Ki Yeon
  • Jixun Dai
  • Ki Duk Park
  • May KhannaEmail author
  • Rajesh KhannaEmail author


The neuronal circuit remodels during development as well as in human neuropathologies such as epilepsy. Neurite outgrowth is an obligatory step in these events. We recently reported that alterations in the phosphorylation state of an axon specification/guidance protein, the collapsin response mediator protein 2 (CRMP2), play a major role in the activity-dependent regulation of neurite outgrowth. We also identified (S)-LCM, an inactive stereoisomer of the clinically used antiepileptic drug (R)-LCM (Vimpat®), as a novel tool for preferentially targeting CRMP2-mediated neurite outgrowth. Here, we investigated the mechanism by which (S)-LCM affects CRMP2 phosphorylation by two key kinases, cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3β (GSK-3β). (S)-LCM application to embryonic cortical neurons resulted in reduced levels of Cdk5- and GSK-3β-phosphorylated CRMP2. Mechanistically, (S)-LCM increased CRMP2 binding to both Cdk5- and GSK-3β without affecting binding of CRMP2 to its canonical partner tubulin. Saturation transfer difference nuclear magnetic resonance (STD NMR) and differential scanning fluorimetry (DSF) experiments demonstrated direct binding of (S)-LCM to CRMP2. Using an in vitro luminescent kinase assay, we observed that (S)-LCM specifically inhibited Cdk5-mediated phosphorylation of CRMP2. Cross-linking experiments and analytical ultracentrifugation showed no effect of (S)-LCM on the oligomerization state of CRMP2. The increased association between Cdk5-phosphorylated CRMP2 and CaV2.2 was reduced by (S)-LCM in vitro and in vivo. This reduction translated into a decrease of calcium influx via CaV2.2 in (S)-LCM-treated neurons compared to controls. (S)-LCM, to our knowledge, is the first molecule described to directly inhibit CRMP2 phosphorylation and may be useful for delineating CRMP2-facilitated functions.


CRMP2 (S)-Lacosamide STD NMR DSF Cdk5 GSK-3β CaV2.2 



This work was supported by a Korea Institute of Science and Technology (KIST) institutional program grant 2E25240 to K.D.P., a Career Development Award from the Arizona Health Science Center to M.K., a National Scientist Development grant SDG5280023 from the American Heart Association, and a Neurofibromatosis New Investigator Award NF1000099 from the Department of Defense Congressionally Directed Military Medical Research and Development Program to R.K. We thank Dr. Harold Kohn for providing (S)-Lacosamide, Dr. Karl J. Dria (Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis) for mass spectrometry analysis of purified CRMP2, and Dr. Chad K. Park (Analytical Biophysics Facility, Department of Chemistry and Biochemistry, University of Arizona) for analytical density ultracentrifugation. We also thank Marissa Posada and Daniel J. Carlson for technical assistance, Erik T. Dustrude and Dr. Nickolay Brustovetsky (Indiana University School of Medicine) and Dr. Sarah M. Wilson for helpful comments on the manuscript.

Supplementary material


(MP4 62794 kb)


  1. 1.
    Charrier E, Reibel S, Rogemond V, Aguera M, Thomasset N, Honnorat J (2003) Collapsin response mediator proteins (CRMPs): involvement in nervous system development and adult neurodegenerative disorders. Mol Neurobiol 28(1):51–64. doi: 10.1385/MN:28:1:51 CrossRefPubMedGoogle Scholar
  2. 2.
    Quach TT, Wilson SM, Rogemond V, Chounlamountri N, Kolattukudy PE, Martinez S, Khanna M, Belin MF et al (2013) Mapping CRMP3 domains involved in dendrite morphogenesis and voltage-gated calcium channel regulation. J Cell Sci 126(Pt 18):4262–4273. doi: 10.1242/jcs.131409 CrossRefPubMedGoogle Scholar
  3. 3.
    Brot S, Rogemond V, Perrot V, Chounlamountri N, Auger C, Honnorat J, Moradi-Ameli M (2010) CRMP5 interacts with tubulin to inhibit neurite outgrowth, thereby modulating the function of CRMP2. J Neurosci Off J Soc Neurosci 30(32):10639–10654. doi: 10.1523/JNEUROSCI. 0059-10.2010 CrossRefGoogle Scholar
  4. 4.
    Hotta A, Inatome R, Yuasa-Kawada J, Qin Q, Yamamura H, Yanagi S (2005) Critical role of collapsin response mediator protein-associated molecule CRAM for filopodia and growth cone development in neurons. Mol Biol Cell 16(1):32–39. doi: 10.1091/mbc.E04-08-0679 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Aylsworth A, Jiang SX, Desbois A, Hou ST (2009) Characterization of the role of full-length CRMP3 and its calpain-cleaved product in inhibiting microtubule polymerization and neurite outgrowth. Exp Cell Res 315(16):2856–2868. doi: 10.1016/j.yexcr.2009.06.014 CrossRefPubMedGoogle Scholar
  6. 6.
    Goshima Y, Nakamura F, Strittmatter P, Strittmatter SM (1995) Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33. Nature 376(6540):509–514. doi: 10.1038/376509a0 CrossRefPubMedGoogle Scholar
  7. 7.
    Fukata Y, Itoh TJ, Kimura T, Menager C, Nishimura T, Shiromizu T, Watanabe H, Inagaki N et al (2002) CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nat Cell Biol 4(8):583–591. doi: 10.1038/ncb825 PubMedGoogle Scholar
  8. 8.
    Inagaki N, Chihara K, Arimura N, Menager C, Kawano Y, Matsuo N, Nishimura T, Amano M et al (2001) CRMP-2 induces axons in cultured hippocampal neurons. Nat Neurosci 4(8):781–782. doi: 10.1038/90476 CrossRefPubMedGoogle Scholar
  9. 9.
    Kawano Y, Yoshimura T, Tsuboi D, Kawabata S, Kaneko-Kawano T, Shirataki H, Takenawa T, Kaibuchi K (2005) CRMP-2 is involved in kinesin-1-dependent transport of the Sra-1/WAVE1 complex and axon formation. Mol Cell Biol 25(22):9920–9935. doi: 10.1128/MCB. 25.22.9920-9935.2005 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Chae YC, Lee S, Heo K, Ha SH, Jung Y, Kim JH, Ihara Y, Suh PG et al (2009) Collapsin response mediator protein-2 regulates neurite formation by modulating tubulin GTPase activity. Cell Signal 21(12):1818–1826. doi: 10.1016/j.cellsig.2009.07.017 CrossRefPubMedGoogle Scholar
  11. 11.
    Kimura T, Watanabe H, Iwamatsu A, Kaibuchi K (2005) Tubulin and CRMP-2 complex is transported via Kinesin-1. J Neurochem 93(6):1371–1382. doi: 10.1111/j.1471-4159.2005.03063.x CrossRefPubMedGoogle Scholar
  12. 12.
    Brown M, Jacobs T, Eickholt B, Ferrari G, Teo M, Monfries C, Qi RZ, Leung T et al (2004) Alpha2-chimaerin, cyclin-dependent kinase 5/p35, and its target collapsin response mediator protein-2 are essential components in semaphorin 3A-induced growth-cone collapse. J Neurosci Off J Soc Neurosci 24(41):8994–9004. doi: 10.1523/JNEUROSCI. 3184-04.2004 CrossRefGoogle Scholar
  13. 13.
    Cole AR, Knebel A, Morrice NA, Robertson LA, Irving AJ, Connolly CN, Sutherland C (2004) GSK-3 phosphorylation of the Alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons. J Biol Chem 279(48):50176–50180. doi: 10.1074/jbc.C400412200 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Cole AR, Causeret F, Yadirgi G, Hastie CJ, McLauchlan H, McManus EJ, Hernandez F, Eickholt BJ et al (2006) Distinct priming kinases contribute to differential regulation of collapsin response mediator proteins by glycogen synthase kinase-3 in vivo. J Biol Chem 281(24):16591–16598. doi: 10.1074/jbc.M513344200 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K (2005) GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120(1):137–149. doi: 10.1016/j.cell.2004.11.012 CrossRefPubMedGoogle Scholar
  16. 16.
    Brittain JM, Wang Y, Eruvwetere O, Khanna R (2012) Cdk5-mediated phosphorylation of CRMP-2 enhances its interaction with CaV2.2. FEBS Lett 586(21):3813–3818. doi: 10.1016/j.febslet.2012.09.022 CrossRefPubMedGoogle Scholar
  17. 17.
    Brittain JM, Piekarz AD, Wang Y, Kondo T, Cummins TR, Khanna R (2009) An atypical role for collapsin response mediator protein 2 (CRMP-2) in neurotransmitter release via interaction with presynaptic voltage-gated calcium channels. J Biol Chem 284(45):31375–31390. doi: 10.1074/jbc.M109.009951 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Chi XX, Schmutzler BS, Brittain JM, Wang Y, Hingtgen CM, Nicol GD, Khanna R (2009) Regulation of N-type voltage-gated calcium channels (Cav2.2) and transmitter release by collapsin response mediator protein-2 (CRMP-2) in sensory neurons. J Cell Sci 122(Pt 23):4351–4362. doi: 10.1242/jcs.053280 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Brittain JM, Duarte DB, Wilson SM, Zhu W, Ballard C, Johnson PL, Liu N, Xiong W et al (2011) Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca(2)(+) channel complex. Nat Med 17(7):822–829. doi: 10.1038/nm.2345 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Tan M, Ma S, Huang Q, Hu K, Song B, Li M (2013) GSK-3alpha/beta-mediated phosphorylation of CRMP-2 regulates activity-dependent dendritic growth. J Neurochem 125(5):685–697. doi: 10.1111/jnc.12230 CrossRefPubMedGoogle Scholar
  21. 21.
    Lu CB, Fu W, Xu X, Mattson MP (2009) Numb-mediated neurite outgrowth is isoform-dependent, and requires activation of voltage-dependent calcium channels. Neuroscience 161(2):403–412. doi: 10.1016/j.neuroscience.2009.03.063 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Sann SB, Xu L, Nishimune H, Sanes JR, Spitzer NC (2008) Neurite outgrowth and in vivo sensory innervation mediated by a Ca(V)2.2-laminin beta 2 stop signal. J Neurosci Off J Soc Neurosci 28(10):2366–2374. doi: 10.1523/JNEUROSCI. 3828-07.2008 CrossRefGoogle Scholar
  23. 23.
    Cohan CS, Kater SB (1986) Suppression of neurite elongation and growth cone motility by electrical activity. Science 232(4758):1638–1640CrossRefPubMedGoogle Scholar
  24. 24.
    Kater SB, Mattson MP, Cohan C, Connor J (1988) Calcium regulation of the neuronal growth cone. Trends Neurosci 11(7):315–321. doi: 10.1016/0166-2236(88)90094-x CrossRefPubMedGoogle Scholar
  25. 25.
    van Pelt J, van Ooyen A, Corner MA (1996) Growth cone dynamics and activity-dependent processes in neuronal network development. Prog Brain Res 108:333–346CrossRefPubMedGoogle Scholar
  26. 26.
    Khanna R, Wilson SM, Brittain JM, Weimer J, Sultana R, Butterfield A, Hensley K (2012) Opening Pandora’s jar: a primer on the putative roles of CRMP2 in a panoply of neurodegenerative, sensory and motor neuron, and central disorders. Future Neurol 7(6):749–771. doi: 10.2217/fnl.12.68 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ip JP, Fu AK, Ip NY (2014) CRMP2: functional roles in neural development and therapeutic potential in neurological diseases. Neuroscientist Rev J Bringing Neurobiol Neurol Psychiatr. doi: 10.1177/1073858413514278 Google Scholar
  28. 28.
    Cole AR, Noble W, van Aalten L, Plattner F, Meimaridou R, Hogan D, Taylor M, LaFrancois J et al (2007) Collapsin response mediator protein-2 hyperphosphorylation is an early event in Alzheimer’s disease progression. J Neurochem 103(3):1132–1144. doi: 10.1111/j.1471-4159.2007.04829.x CrossRefPubMedGoogle Scholar
  29. 29.
    Isono T, Yamashita N, Obara M, Araki T, Nakamura F, Kamiya Y, Alkam T, Nitta A et al (2013) Amyloid-beta(2)(5)(−)(3)(5) induces impairment of cognitive function and long-term potentiation through phosphorylation of collapsin response mediator protein 2. Neurosci Res 77(3):180–185. doi: 10.1016/j.neures.2013.08.005S0168-0102(13)00190-9 CrossRefPubMedGoogle Scholar
  30. 30.
    Lim NK, Hung LW, Pang TY, McLean CA, Liddell JR, Hilton JB, Li QX, White AR et al (2014) Localized changes to glycogen synthase kinase-3 and collapsin response mediator protein-2 in the Huntington’s disease affected brain. Hum Mol Genet 23(15):4051–4063. doi: 10.1093/hmg/ddu119ddu119 CrossRefPubMedGoogle Scholar
  31. 31.
    Shimada K, Ishikawa T, Nakamura F, Shimizu D, Chishima T, Ichikawa Y, Sasaki T, Endo I et al (2013) Collapsin response mediator protein 2 is involved in regulating breast cancer progression. Breast Cancer. doi: 10.1007/s12282-013-0447-5 Google Scholar
  32. 32.
    Oliemuller E, Pelaez R, Garasa S, Pajares MJ, Agorreta J, Pio R, Montuenga LM, Teijeira A et al (2013) Phosphorylated tubulin adaptor protein CRMP-2 as prognostic marker and candidate therapeutic target for NSCLC. Int J Cancer 132(9):1986–1995. doi: 10.1002/ijc.27881 CrossRefPubMedGoogle Scholar
  33. 33.
    Kamiya YS K, Takiguchi M, Funakoshi K (2013) CDK5, CRMP2 and NR2B in spinal dorsal horn and dorsal root ganglion have different role in pain signaling between neuropathic pain model and inflammatory pain model: 14AP4 5. Eur J Anaesthesiol 30:214CrossRefGoogle Scholar
  34. 34.
    Wilson SM, Ki Yeon S, Yang XF, Park KD, Khanna R (2014) Differential regulation of collapsin response mediator protein 2 (CRMP2) phosphorylation by GSK3ss and CDK5 following traumatic brain injury. Front Cell Neurosci 8:135. doi: 10.3389/fncel.2014.00135 PubMedPubMedCentralGoogle Scholar
  35. 35.
    Wilson SM, Moutal A, Melemedjian OK, Wang Y, Ju W, Francois-Moutal L, Khanna M, Khanna R (2014) The functionalized amino acid (S)-Lacosamide subverts CRMP2-mediated tubulin polymerization to prevent constitutive and activity-dependent increase in neurite outgrowth. Front Cell Neurosci 8:196. doi: 10.3389/fncel.2014.00196 PubMedPubMedCentralGoogle Scholar
  36. 36.
    Wilson SM, Xiong W, Wang Y, Ping X, Head JD, Brittain JM, Gagare PD, Ramachandran PV et al (2012) Prevention of posttraumatic axon sprouting by blocking collapsin response mediator protein 2-mediated neurite outgrowth and tubulin polymerization. Neuroscience 210:451–466. doi: 10.1016/j.neuroscience.2012.02.038 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Wilson SM, Khanna R (2014) Specific binding of lacosamide to collapsin response mediator protein 2 (CRMP2) and direct impairment of its canonical function: implications for the therapeutic potential of lacosamide. Mol Neurobiol. doi: 10.1007/s12035-014-8775-9 PubMedPubMedCentralGoogle Scholar
  38. 38.
    Sheets PL, Heers C, Stoehr T, Cummins TR (2008) Differential block of sensory neuronal voltage-gated sodium channels by lacosamide [(2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide], lidocaine, and carbamazepine. J Pharmacol Exp Ther 326(1):89–99. doi: 10.1124/jpet.107.133413 CrossRefPubMedGoogle Scholar
  39. 39.
    Wang Y, Brittain JM, Jarecki BW, Park KD, Wilson SM, Wang B, Hale R, Meroueh SO et al (2010) In silico docking and electrophysiological characterization of lacosamide binding sites on collapsin response mediator protein-2 identifies a pocket important in modulating sodium channel slow inactivation. J Biol Chem 285(33):25296–25307. doi: 10.1074/jbc.M110.128801 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Choi D, Stables JP, Kohn H (1996) Synthesis and anticonvulsant activities of N-benzyl-2-acetamidopropionamide derivatives. J Med Chem 39(9):1907–1916CrossRefPubMedGoogle Scholar
  41. 41.
    Greenaway C, Ratnaraj N, Sander JW, Patsalos PN (2010) A high-performance liquid chromatography assay to monitor the new antiepileptic drug lacosamide in patients with epilepsy. Ther Drug Monit 32(4):448–452. doi: 10.1097/FTD.0b013e3181dcc5fb CrossRefPubMedGoogle Scholar
  42. 42.
    Moutal A, Francois-Moutal L, Brittain JM, Khanna M, Khanna R (2014) Differential neuroprotective potential of CRMP2 peptide aptamers conjugated to cationic, hydrophobic, and amphipathic cell penetrating peptides. Front Cell Neurosci 8:471. doi: 10.3389/fncel.2014.00471 PubMedGoogle Scholar
  43. 43.
    Koo TS, Kim SJ, Ha DJ, Baek M, Moon H (2011) Pharmacokinetics, brain distribution, and plasma protein binding of the antiepileptic drug lacosamide in rats. Arch Pharm Res 34(12):2059–2064. doi: 10.1007/s12272-011-1208-7 CrossRefPubMedGoogle Scholar
  44. 44.
    Shandra A, Shandra P, Kaschenko O, Matagne A, Stohr T (2013) Synergism of lacosamide with established antiepileptic drugs in the 6-Hz seizure model in mice. Epilepsia 54(7):1167–1175. doi: 10.1111/epi.12237 CrossRefPubMedGoogle Scholar
  45. 45.
    Wilson SM, Schmutzler BS, Brittain JM, Dustrude ET, Ripsch MS, Pellman JJ, Yeum TS, Hurley JH et al (2012) Inhibition of transmitter release and attenuation of AIDS therapy-induced and tibial nerve injury-related painful peripheral neuropathy by novel synthetic Ca2+ channel peptides. J Biol Chem 287(42):35065–35077. doi: 10.1074/jbc.M112.378695 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Stenmark P, Ogg D, Flodin S, Flores A, Kotenyova T, Nyman T, Nordlund P, Kursula P (2007) The structure of human collapsin response mediator protein 2, a regulator of axonal growth. J Neurochem 101(4):906–917CrossRefPubMedGoogle Scholar
  47. 47.
    Banks JL, Beard HS, Cao Y, Cho AE, Damm W, Farid R, Felts AK, Halgren TA et al (2005) Integrated modeling program, applied chemical theory (IMPACT). J Comput Chem 26(16):1752–1780. doi: 10.1002/jcc.20292 CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Schuttelkopf AW, van Aalten DM (2004) PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr Sect D: Biol Crystallogr 60(Pt 8):1355–1363. doi: 10.1107/S0907444904011679 CrossRefGoogle Scholar
  49. 49.
    Sanner MF (1999) Python: a programming language for software integration and development. J Mol Graph Model 17(1):57–61PubMedGoogle Scholar
  50. 50.
    Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455–461. doi: 10.1002/jcc.21334 PubMedPubMedCentralGoogle Scholar
  51. 51.
    Winn MD, Ballard CC, Cowtan KD, Dodson EJ, Emsley P, Evans PR, Keegan RM, Krissinel EB et al (2011) Overview of the CCP4 suite and current developments. Acta Crystallogr Sect D: Biol Crystallogr 67(Pt 4):235–242. doi: 10.1107/S0907444910045749 CrossRefGoogle Scholar
  52. 52.
    Meyer B, Peters T (2003) NMR spectroscopy techniques for screening and identifying ligand binding to protein receptors. Angew Chem 42(8):864–890. doi: 10.1002/anie.200390233 CrossRefGoogle Scholar
  53. 53.
    Meyer B, Klein J, Mayer M, Meinecke R, Moller H, Neffe A, Schuster O, Wulfken J et al (2004) Saturation transfer difference NMR spectroscopy for identifying ligand epitopes and binding specificities. Ernst Schering Res Found Work 44:149–167Google Scholar
  54. 54.
    Ericsson UB, Hallberg BM, Detitta GT, Dekker N, Nordlund P (2006) Thermofluor-based high-throughput stability optimization of proteins for structural studies. Anal Biochem 357(2):289–298. doi: 10.1016/j.ab.2006.07.027 CrossRefPubMedGoogle Scholar
  55. 55.
    Schuck P (2000) Size-distribution analysis of macromolecules by sedimentation velocity ultracentrifugation and lamm equation modeling. Biophys J 78(3):1606–1619. doi: 10.1016/S0006-3495(00)76713-0 CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Waxman E, Ross JB, Laue TM, Guha A, Thiruvikraman SV, Lin TC, Konigsberg WH, Nemerson Y (1992) Tissue factor and its extracellular soluble domain: the relationship between intermolecular association with factor VIIa and enzymatic activity of the complex. Biochemistry 31(16):3998–4003CrossRefPubMedGoogle Scholar
  57. 57.
    Ju W, Li Q, Wilson SM, Brittain JM, Meroueh L, Khanna R (2013) SUMOylation alters CRMP2 regulation of calcium influx in sensory neurons. Channels 3 (7)Google Scholar
  58. 58.
    Ju W, Li Q, Allette YM, Ripsch MS, White FA, Khanna R (2012) Suppression of pain-related behavior in two distinct rodent models of peripheral neuropathy by a homopolyarginine-conjugated CRMP2 peptide. J Neurochem 124(6):869–879. doi: 10.1111/jnc.12070 CrossRefGoogle Scholar
  59. 59.
    Konietschke F, Libiger O, Hothorn LA (2012) Nonparametric evaluation of quantitative traits in population-based association studies when the genetic model is unknown. PLoS ONE 7(2):e31242. doi: 10.1371/journal.pone.0031242 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Wayman GA, Impey S, Marks D, Saneyoshi T, Grant WF, Derkach V, Soderling TR (2006) Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependent transcription of Wnt-2. Neuron 50(6):897–909. doi: 10.1016/j.neuron.2006.05.008 CrossRefPubMedGoogle Scholar
  61. 61.
    Zhu YS, Saito T, Asada A, Maekawa S, Hisanaga S (2005) Activation of latent cyclin-dependent kinase 5 (Cdk5)-p35 complexes by membrane dissociation. J Neurochem 94(6):1535–1545. doi: 10.1111/j.1471-4159.2005.03301.x CrossRefPubMedGoogle Scholar
  62. 62.
    Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378(6559):785–789. doi: 10.1038/378785a0 CrossRefPubMedGoogle Scholar
  63. 63.
    Wakatsuki S, Saitoh F, Araki T (2011) ZNRF1 promotes Wallerian degeneration by degrading AKT to induce GSK3B-dependent CRMP2 phosphorylation. Nat Cell Biol 13(12):1415–1423. doi: 10.1038/ncb2373 CrossRefPubMedGoogle Scholar
  64. 64.
    Majava V, Loytynoja N, Chen WQ, Lubec G, Kursula P (2008) Crystal and solution structure, stability and post-translational modifications of collapsin response mediator protein 2. FEBS J 275(18):4583–4596CrossRefPubMedGoogle Scholar
  65. 65.
    Wang LH, Strittmatter SM (1997) Brain CRMP forms heterotetramers similar to liver dihydropyrimidinase. J Neurochem 69(6):2261–2269CrossRefPubMedGoogle Scholar
  66. 66.
    Laue TM, Shah BD, Ridgeway TM, Peleltier SL (1992) Computer-aided interpretation of analytical sedimentation data for proteins. In: Harding SE (ed) Analytical ultracentrifugation in biochemistry and polymer science. The Royal Society of Chemistry, Cambridge, pp 90–125Google Scholar
  67. 67.
    Stenmark P, Ogg D, Flodin S, Flores A, Kotenyova T, Nyman T, Nordlund P, Kursula P (2007) The structure of human collapsin response mediator protein 2, a regulator of axonal growth. J Neurochem 101(4):906–917. doi: 10.1111/j.1471-4159.2006.04401.x CrossRefPubMedGoogle Scholar
  68. 68.
    Connor JA (1986) Digital imaging of free calcium changes and of spatial gradients in growing processes in single, mammalian central nervous system cells. Proc Natl Acad Sci U S A 83(16):6179–6183CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Pravettoni E, Bacci A, Coco S, Forbicini P, Matteoli M, Verderio C (2000) Different localizations and functions of L-type and N-type calcium channels during development of hippocampal neurons. Dev Biol 227(2):581–594. doi: 10.1006/dbio.2000.9872 CrossRefPubMedGoogle Scholar
  70. 70.
    Wheeler DG, Groth RD, Ma H, Barrett CF, Owen SF, Safa P, Tsien RW (2012) Ca(V)1 and Ca(V)2 channels engage distinct modes of Ca(2+) signaling to control CREB-dependent gene expression. Cell 149(5):1112–1124CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Uchida Y, Ohshima T, Sasaki Y, Suzuki H, Yanai S, Yamashita N, Nakamura F, Takei K et al (2005) Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3beta phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer’s disease. Genes Cells Devoted Mol Cell Mech 10(2):165–179. doi: 10.1111/j.1365-2443.2005.00827.x CrossRefGoogle Scholar
  72. 72.
    Nikolic M, Dudek H, Kwon YT, Ramos YF, Tsai LH (1996) The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation. Genes Dev 10(7):816–825CrossRefPubMedGoogle Scholar
  73. 73.
    Rochlin MW, Wickline KM, Bridgman PC (1996) Microtubule stability decreases axon elongation but not axoplasm production. J Neurosci Off J Soc Neurosci 16(10):3236–3246Google Scholar
  74. 74.
    Cole AR, Soutar MP, Rembutsu M, van Aalten L, Hastie CJ, McLauchlan H, Peggie M, Balastik M et al (2008) Relative resistance of Cdk5-phosphorylated CRMP2 to dephosphorylation. J Biol Chem 283(26):18227–18237. doi: 10.1074/jbc.M801645200 CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Marques JM, Rodrigues RJ, Valbuena S, Rozas JL, Selak S, Marin P, Aller MI, Lerma J (2013) CRMP2 tethers kainate receptor activity to cytoskeleton dynamics during neuronal maturation. J Neurosci Off J Soc Neurosci 33(46):18298–18310. doi: 10.1523/JNEUROSCI. 3136-13.2013 CrossRefGoogle Scholar
  76. 76.
    Hernandez P, Lee G, Sjoberg M, Maccioni RB (2009) Tau phosphorylation by cdk5 and Fyn in response to amyloid peptide Abeta (25–35): involvement of lipid rafts. J Alzheimer’s Dis JAD 16(1):149–156. doi: 10.3233/JAD-2009-0933 CrossRefPubMedGoogle Scholar
  77. 77.
    Rosslenbroich V, Dai L, Franken S, Gehrke M, Junghans U, Gieselmann V, Kappler J (2003) Subcellular localization of collapsin response mediator proteins to lipid rafts. Biochem Biophys Res Commun 305(2):392–399CrossRefPubMedGoogle Scholar
  78. 78.
    Robinson P, Etheridge S, Song L, Armenise P, Jones OT, Fitzgerald EM (2010) Formation of N-type (Cav2.2) voltage-gated calcium channel membrane microdomains: lipid raft association and clustering. Cell Calcium 48(4):183–194. doi: 10.1016/j.ceca.2010.08.006 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Pharmacology, College of MedicineUniversity of ArizonaTucsonUSA
  2. 2.Neuroscience Graduate Interdisciplinary Program, College of MedicineUniversity of ArizonaTucsonUSA
  3. 3.Nuclear Magnetic Resonance Facility, Department of Chemistry and Biochemistry, College of MedicineUniversity of ArizonaTucsonUSA
  4. 4.Center for Neuro-Medicine, Brain Science InstituteKorea Institute of Science and TechnologySeoulRepublic of Korea

Personalised recommendations