Neuroscience Bulletin

, Volume 30, Issue 4, pp 627–644 | Cite as

Mechanisms of neuronal membrane sealing following mechanical trauma

  • Benjamin K. Hendricks
  • Riyi ShiEmail author


Membrane integrity is crucial for maintaining the intricate signaling and chemically-isolated intracellular environment of neurons; disruption risks deleterious effects, such as unregulated ionic flux, neuronal apoptosis, and oxidative radical damage as observed in spinal cord injury and traumatic brain injury. This paper, in addition to a discussion of the current understanding of cellular tactics to seal membranes, describes two major factors involved in membrane repair. These are line tension, the hydrophobic attractive force between two lipid free-edges, and membrane tension, the rigidity of the lipid bilayer with respect to the tethered cortical cytoskeleton. Ca2+, a major mechanistic trigger for repair processes, increases following flux through a membrane injury site, and activates phospholipase enzymes, calpain-mediated cortical cytoskeletal proteolysis, protein kinase cascades, and lipid bilayer microdomain modification. The membrane tension appears to be largely modulated through vesicle dynamics, cytoskeletal organization, membrane curvature, and phospholipase manipulation. Dehydration of the phospholipid gap edge and modification of membrane packaging, as in temperature variation, experimentally impact line tension. Due to the time-sensitive nature of axonal sealing, increasing the efficacy of axolemmal sealing through therapeutic modification would be of great clinical value, to deter secondary neurodegenerative effects. Better therapeutic enhancement of membrane sealing requires a complete understanding of its intricate underlying neuronal mechanism.


axolemmal sealing membrane tension line tension phospholipase calpain poly-ethylene glycol patch model 


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  1. [1]
    Nguyen MP, Bittner GD, Fishman HM. Critical interval of somal calcium transient after neurite transection determines B 104 cell survival. J Neurosci Res 2005, 81: 805–816.PubMedCentralPubMedGoogle Scholar
  2. [2]
    Kilinc D, Gallo G, Barbee KA. Mechanical membrane injury induces axonal beading through localized activation of calpain. Exp Neurol 2009, 219: 553–561.PubMedCentralPubMedGoogle Scholar
  3. [3]
    Farkas O, Lifshitz J, Povlishock JT. Mechanoporation induced by diffuse traumatic brain injury: an irreversible or reversible response to injury? J Neurosci 2006, 26: 3130–3140.PubMedGoogle Scholar
  4. [4]
    Buki A, Koizumi H, Povlishock JT. Moderate posttraumatic hypothermia decreases early calpain-mediated proteolysis and concomitant cytoskeletal compromise in traumatic axonal injury. Exp Neurol 1999, 159: 319–328.PubMedGoogle Scholar
  5. [5]
    Shi R, Asano T, Vining NC, Blight AR. Control of membrane sealing in injured mammalian spinal cord axons. J Neurophysiol 2000, 84: 1763–1769.PubMedGoogle Scholar
  6. [6]
    Borgens RB, Shi R. Immediate recovery from spinal cord injury through molecular repair of nerve membranes with polyethylene glycol. FASEB J 2000, 14: 27–35.PubMedGoogle Scholar
  7. [7]
    Gitler D, Spira ME. Real time imaging of calcium-induced localized proteolytic activity after axotomy and its relation to growth cone formation. Neuron 1998, 20: 1123–1135.PubMedGoogle Scholar
  8. [8]
    Yawo H, Kuno M. Calcium dependence of membrane sealing at the cut end of the cockroach giant axon. J Neurosci 1985, 5: 1626–1632.PubMedGoogle Scholar
  9. [9]
    Ballinger ML, Blanchette AR, Krause TL, Smyers ME, Fishman HM, Bittner GD. Delaminating myelin membranes help seal the cut ends of severed earthworm giant axons. J Neurobiol 1997, 33: 945–960.PubMedGoogle Scholar
  10. [10]
    Detrait E, Eddleman CS, Yoo S, Fukuda M, Nguyen MP, Bittner GD, et al. Axolemmal repair requires proteins that mediate synaptic vesicle fusion. J Neurobiol 2000, 44: 382–391.PubMedGoogle Scholar
  11. [11]
    Howard MJ, David G, Barrett JN. Resealing of transected myelinated mammalian axons in vivo: evidence for involvement of calpain. Neuroscience 1999, 93: 807–815.PubMedGoogle Scholar
  12. [12]
    Rehder V, Jensen JR, Kater SB. The initial stages of neural regeneration are dependent upon intracellular calcium levels. Neuroscience 1992, 51: 565–574.PubMedGoogle Scholar
  13. [13]
    Shi R, Pryor JD. Temperature dependence of membrane sealing following transection in mammalian spinal cord axons. Neuroscience 2000, 98: 157–166.PubMedGoogle Scholar
  14. [14]
    Sun W, Fu Y, Shi Y, Cheng JX, Cao P, Shi R. Paranodal myelin damage after acute stretch in Guinea pig spinal cord. J Neurotrauma 2012, 29: 611–619.PubMedCentralPubMedGoogle Scholar
  15. [15]
    Ouyang H, Galle B, Li J, Nauman E, Shi R. Critical roles of decompression in functional recovery of ex vivo spinal cord white matter. J Neurosurg Spine 2009, 10: 161–170.PubMedGoogle Scholar
  16. [16]
    Ouyang H, Sun W, Fu Y, Li J, Cheng JX, Nauman E, et al. Compression induces acute demyelination and potassium channel exposure in spinal cord. J Neurotrauma 2010, 27: 1109–1120.PubMedCentralPubMedGoogle Scholar
  17. [17]
    Nehrt A, Hamann K, Ouyang H, Shi R. Polyethylene glycol enhances axolemmal resealing following transection in cultured cells and in ex vivo spinal cord. J Neurotrauma 2010, 27: 151–161.PubMedGoogle Scholar
  18. [18]
    Geddis MS, Rehder V. Initial stages of neural regeneration in Helisoma trivolvis are dependent upon PLA2 activity. J Neurobiol 2003, 54: 555–565.PubMedGoogle Scholar
  19. [19]
    McNeil PL, Terasaki M. Coping with the inevitable: how cells repair a torn surface membrane. Nat Cell Biol 2001, 3: E124–129.PubMedGoogle Scholar
  20. [20]
    Swanson JA, McNeil PL. Nuclear reassembly excludes large macromolecules. Science 1987, 238: 548–550.PubMedGoogle Scholar
  21. [21]
    Togo T, Krasieva TB, Steinhardt RA. A decrease in membrane tension precedes successful cell-membrane repair. Mol Biol Cell 2000, 11: 4339–4346.PubMedCentralPubMedGoogle Scholar
  22. [22]
    McNeil PL, Khakee R. Disruptions of muscle fiber plasma membranes. Role in exercise-induced damage. Am J Pathol 1992, 140: 1097–1109.PubMedCentralPubMedGoogle Scholar
  23. [23]
    Togo T, Alderton JM, Steinhardt RA. Long-term potentiation of exocytosis and cell membrane repair in fibroblasts. Mol Biol Cell 2003, 14: 93–106.PubMedCentralPubMedGoogle Scholar
  24. [24]
    Terasaki M, Miyake K, McNeil PL. Large plasma membrane disruptions are rapidly resealed by Ca2+-dependent vesiclevesicle fusion events. J Cell Biol 1997, 139: 63–74.PubMedCentralPubMedGoogle Scholar
  25. [25]
    Mellgren RL, Zhang W, Miyake K, McNeil PL. Calpain is required for the rapid, calcium-dependent repair of wounded plasma membrane. J Biol Chem 2007, 282: 2567–2575.PubMedGoogle Scholar
  26. [26]
    Sheetz MP. Cell control by membrane-cytoskeleton adhesion. Nat Rev Mol Cell Biol 2001, 2: 392–396.PubMedGoogle Scholar
  27. [27]
    Togo T, Alderton JM, Bi GQ, Steinhardt RA. The mechanism of facilitated cell membrane resealing. J Cell Sci 1999, 112: 719–731.PubMedGoogle Scholar
  28. [28]
    McNeil PL, Vogel SS, Miyake K, Terasaki M. Patching plasma membrane disruptions with cytoplasmic membrane. J Cell Sci 2000, 113: 1891–1902.PubMedGoogle Scholar
  29. [29]
    McNeil PL, Baker MM. Cell surface events during resealing visualized by scanning-electron microscopy. Cell Tissue Res 2001, 304: 141–146.PubMedGoogle Scholar
  30. [30]
    Yoo S, Nguyen MP, Fukuda M, Bittner GD, Fishman HM. Plasmalemmal sealing of transected mammalian neurites is a gradual process mediated by Ca(2+)-regulated proteins. J Neurosci Res 2003, 74: 541–551.PubMedGoogle Scholar
  31. [31]
    Idone V, Tam C, Andrews N W. Two-way traffic on the road to plasma membrane repair. Trends Cell Biol 2008, 18: 552–559.PubMedCentralPubMedGoogle Scholar
  32. [32]
    Nicholas B, Smethurst P, Verderio E, Jones R, Griffin M. Cross-linking of cellular proteins by tissue transglutaminase during necrotic cell death: a mechanism for maintaining tissue integrity. Biochem J 2003, 371: 413–422.PubMedCentralPubMedGoogle Scholar
  33. [33]
    Idone V, Tam C, Goss JW, Toomre D, Pypaert M, Andrews NW. Repair of injured plasma membrane by rapid Ca2+-dependent endocytosis. J Cell Biol 2008, 180: 905–914.PubMedCentralPubMedGoogle Scholar
  34. [34]
    Hai A, Spira ME. On-chip electroporation, membrane repair dynamics and transient in-cell recordings by arrays of gold mushroom-shaped microelectrodes. Lab Chip 2012, 12: 2865–2873.PubMedGoogle Scholar
  35. [35]
    Chernomordik LV, Melikyan GB, Chizmadzhev YA. Biomembrane fusion: a new concept derived from model studies using two interacting planar lipid bilayers. Biochim Biophys Acta 1987, 906: 309–352.PubMedGoogle Scholar
  36. [36]
    Zhelev DV, Needham D. Tension-stabilized pores in giant vesicles: determination of pore size and pore line tension. Biochim Biophys Acta 1993, 1147: 89–104.PubMedGoogle Scholar
  37. [37]
    Matsushita Y, Bramlett HM, Alonso O, Dietrich WD. Posttraumatic hypothermia is neuroprotective in a model of traumatic brain injury complicated by a secondary hypoxic insult. Crit Care Med 2001, 29: 2060–2066.PubMedGoogle Scholar
  38. [38]
    Biagas KV, Gaeta ML. Treatment of traumatic brain injury with hypothermia. Curr Opin Pediatr 1998, 10: 271–277.PubMedGoogle Scholar
  39. [39]
    Chernomordik LV, Kozlov MM. Prote in-lipid interplay in fusion and fission of biological membranes. Annu Rev Biochem 2003, 72: 175–207.PubMedGoogle Scholar
  40. [40]
    Goni FM, Montes LR, Alonso A. Phos pholipases C and sphingomyelinases: Lipids as substrates and modulators of enzyme activity. Prog Lipid Res 2012, 51: 238–266.PubMedGoogle Scholar
  41. [41]
    Moroz JD, Nelson P. Dynamically stabilized pores in bilayer membranes. Biophys J 1997, 72: 2211–2216.PubMedCentralPubMedGoogle Scholar
  42. [42]
    Dai J, Sheetz MP. Regulation of end ocytosis, exocytosis, and shape by membrane tension. Cold Spring Harb Symp Quant Biol 1995, 60: 567–571.PubMedGoogle Scholar
  43. [43]
    Sheetz MP, Dai J. Modulation of membrane dynamics and cell motility by membrane tension. Trends Cell Biol 1996, 6: 85–89.PubMedGoogle Scholar
  44. [44]
    Dai J, Sheetz MP. Membrane tether for mation from blebbing cells. Biophys J 1999, 77: 3363–3370.PubMedCentralPubMedGoogle Scholar
  45. [45]
    Xie XY, Barrett JN. Membrane resealing in cultured rat septal neurons after neurite transection: evidence for enhancement by Ca(2+)-triggered protease activity and cytoskeletal disassembly. J Neurosci 1991, 11: 3257–3267.PubMedGoogle Scholar
  46. [46]
    Gitler D, Spira ME. Short window of opportunity for calpain induced growth cone formation after axotomy of Aplysia neurons. J Neurobiol 2002, 52: 267–279.PubMedGoogle Scholar
  47. [47]
    Czogalla A, Sikorski AF. Spectrin and calpain: a ‘target’ and a ‘sniper’ in the pathology of neuronal cells. Cell Mol Life Sci 2005, 62: 1913–1924.PubMedGoogle Scholar
  48. [48]
    Johnson GV, Litersky JM, Jope RS. Degradation of microtubule-associated protein 2 and brain spectrin by calpain: a comparative study. J Neurochem 1991, 56: 1630–1638.PubMedGoogle Scholar
  49. [49]
    Kopil CM, Siebert AP, Foskett JK, Neumar R W. Calpaincleaved type 1 inositol 1,4,5-trisphosphate receptor impairs ER Ca(2+) buffering and causes neurodegeneration in primary cortical neurons. J Neurochem 2012, 123: 147–158.PubMedGoogle Scholar
  50. [50]
    Siman R, Noszek JC. Excitatory amino acids activate calpain I and induce structural protein breakdown in vivo. Neuron 1988, 1: 279–287.PubMedGoogle Scholar
  51. [51]
    Kamber D, Erez H, Spira ME. Local calcium-de pendent mechanisms determine whether a cut axonal end assembles a retarded endbulb or competent growth cone. Exp Neurol 2009, 219: 112–125.PubMedGoogle Scholar
  52. [52]
    Khoutorsky A, Spira ME. Calcium-activated pro teases are critical for refilling depleted vesicle stores in cultured sensorymotor synapses of Aplysia. Learn Mem 2005, 12: 414–422.PubMedCentralPubMedGoogle Scholar
  53. [53]
    Xu K, Zhong G, Zhuang X. Actin, spectrin, and associated proteins form a periodic cytoskeletal structure in axons. Science 2013, 339: 452–456.PubMedGoogle Scholar
  54. [54]
    Kontrogianni-Konstantopoulos A, Frye CS, Benz EJ, Jr., Huang SC. The prototypical 4. 1R-10-kDa domain and the 4.1g-10-kDa paralog mediate fodrin-actin complex formation. J Biol Chem 2001, 276: 20679–20687.PubMedGoogle Scholar
  55. [55]
    Croall DE, Morrow JS, DeMartino GN. Limited proteolysis of the erythrocyte membrane skeleton by calcium-dependent proteinases. Biochim Biophys Acta 1986, 882: 287–296.PubMedGoogle Scholar
  56. [56]
    Boivin P, Galand C, Dhermy D. In vitro digestion of spectrin, protein 4.1 and ankyrin by erythrocyte calcium dependent neutral protease (calpain I). Int J Biochem 1990, 22: 1479–1489.PubMedGoogle Scholar
  57. [57]
    Prager-Khoutorsky M, Spira ME. Neurite retraction and regrowth regulated by membrane retrieval, membrane supply, and actin dynamics. Brain Res 2009, 1251: 65–79.PubMedGoogle Scholar
  58. [58]
    Dourdin N, Bhatt AK, Dutt P, Greer PA, Arthur JS, Elce JS, et al. Reduced cell migration and disruption of the actin cytoskeleton in calpain-deficient embryonic fibroblasts. J Biol Chem 2001, 276: 48382–48388.PubMedGoogle Scholar
  59. [59]
    Diz-Munoz A, Fletcher DA, Weiner OD. Use the force: membrane tension as an organizer of cell shape and motility. Trends Cell Biol 2013, 23: 47–53.PubMedCentralPubMedGoogle Scholar
  60. [60]
    Gauthier NC, Rossier OM, Mathur A, Hone JC, Sheetz MP. Plasma membrane area increases with spread area by exocytosis of a GPI-anchored protein compartment. Mol Biol Cell 2009, 20: 3261–3272.PubMedCentralPubMedGoogle Scholar
  61. [61]
    Jaiswal JK, Andrews NW, Simon SM. Membrane proximally sosomes are the major vesicles responsible for calciumdependent exocytosis in nonsecretory cells. J Cell Biol 2002, 159: 625–635.PubMedCentralPubMedGoogle Scholar
  62. [62]
    Reddy A, Caler EV, Andrews NW. Plasma membrane repair is mediated by Ca(2+)-regulated exocytosis of lysosomes. Cell 2001, 106: 157–169.PubMedGoogle Scholar
  63. [63]
    Eddleman CS, Ballinger ML, Smyers ME, Fishman HM, Bittner GD. Endocytotic formation of vesicles and other membranous structures induced by Ca2+ and axolemmal injury. J Neurosci 1998, 18: 4029–4041.PubMedGoogle Scholar
  64. [64]
    Langford GM. Myosin-V, a versatile motor for short-range vesicle transport. Traffic 2002, 3: 859–865.PubMedGoogle Scholar
  65. [65]
    Bi GQ, Morris RL, Liao G, Alderton JM, Scholey JM, Steinhardt RA. Kinesin- and myosin-driven steps of vesicle recruitment for Ca2+-regulated exocytosis. J Cell Biol 1997, 138: 999–1008.PubMedCentralPubMedGoogle Scholar
  66. [66]
    Coorssen JR. Phospholipase activation and secretion: evidence that PLA2, PLC, and PLD are not essential to exocytosis. Am J Physiol 1996, 270: C1153–1163.PubMedGoogle Scholar
  67. [67]
    Yawo H, Kuno M. How a nerve fiber repairs its cut end: involvement of phospholipase A2. Science 1983, 222: 1351–1353.PubMedGoogle Scholar
  68. [68]
    Edstrom A, Briggman M, Ekstrom PA. Phospholipase A2 activity is required for regeneration of sensory axons in cultured adult sciatic nerves. J Neurosci Res 1996, 43: 183–189.PubMedGoogle Scholar
  69. [69]
    Hornfelt M, Ekstrom PA, Edstrom A. Involvement of axonal phospholipase A2 activity in the outgrowth of adult mouse sensory axons in vitro. Neuroscience 1999, 91: 1539–1547.PubMedGoogle Scholar
  70. [70]
    Clark JD, Lin LL, Kriz RW, Ramesha CS, Sultzman LA, Lin AY, et al. A novel arachidonic acid-selective cytosolic PLA2 contains a Ca(2+)-dependent translocation domain with homology to PKC and GAP. Cell 1991, 65: 1043–1051.PubMedGoogle Scholar
  71. [71]
    Channon JY, Leslie CC. A calcium-dependent mechanism for associa ting a soluble arachidonoyl-hydrolyzing phospholipase A2 with membrane in the macrophage cell line RAW 264.7. J Biol Chem 1990, 265: 5409–5413.PubMedGoogle Scholar
  72. [72]
    Khan WA, Blobe GC, Hannun YA. Arachidonic acid and free fatty acids as second messengers and the role of protein kinase C. Cell Signal 1995, 7: 171–184.PubMedGoogle Scholar
  73. [73]
    Okada M, Taguchi K, Maekawa S, Fukami K, Yagisawa H. Calcium fluxes cause nuclear shrinkage and the translocation of phospholipase C-delta1 into the nucleus. Neurosci Lett 2010, 472: 188–193.PubMedGoogle Scholar
  74. [74]
    Hwang JI, Oh YS, Shin KJ, Kim H, Ryu SH, Suh PG. Molecular cloning and characterization of a novel phospholipase C, PLC-eta. Biochem J 2005, 389: 181–186.PubMedCentralPubMedGoogle Scholar
  75. [75]
    Liu WS, Heckman CA. The sevenfold way of PKC regulation. Cell Signal 1998, 10: 529–542.PubMedGoogle Scholar
  76. [76]
    Cockcroft S. The latest phospholipase C, PLCeta, is implicated in neuronal function. Trends Biochem Sci 2006, 31: 4–7.PubMedGoogle Scholar
  77. [77]
    Gijon MA, Leslie CC. Regulation of arachidonic acid release and cytosolic phospholipase A2 activation. J Leukoc Biol 1999, 65: 330–336.PubMedGoogle Scholar
  78. [78]
    Essen LO, Perisic O, Lynch DE, Katan M, Williams RL. A ternary metal binding site in the C2 domain of phosphoinositide-specific phospholipase C-delta1. Biochemistry 1997, 36: 2753–2762.PubMedGoogle Scholar
  79. [79]
    Negre-Aminou P, Pfenninger KH. Arachidonic acid turnover and phospholipa se A2 activity in neuronal growth cones. J Neurochem 1993, 60: 1126–1136.PubMedGoogle Scholar
  80. [80]
    Gresset A, Sondek J, Harden TK. The phospholipase Cisozymes and their re gulation. Subcell Biochem 2012, 58: 61–94.PubMedCentralPubMedGoogle Scholar
  81. [81]
    Mansfeld J, Ulbrich-Hofmann R. Modulation of phospholipase D activity in v itro. Biochim Biophys Acta 2009, 1791: 913–926.PubMedGoogle Scholar
  82. [82]
    Hodgkin MN, Clark JM, Rose S, Saqib K, Wakelam MJ. Characterization of the regulation of phospholipase D activity in the detergent-insoluble fraction of HL60 cells by protein kinase C and small G-proteins. Biochem J 1999, 339(Pt 1): 87–93.PubMedCentralPubMedGoogle Scholar
  83. [83]
    Han JM, Kim JH, Lee BD, Lee SD, Kim Y, Jung YW, et al. Phosphorylation-depen dent regulation of phospholipase D2 by protein kinase C delta in rat Pheochromocytoma PC12 cells. J Biol Chem 2002, 277: 8290–8297.PubMedGoogle Scholar
  84. [84]
    Merchenthaler I, Liposits Z, Reid JJ, Wetsel WC. Light and electron microscopic immunocytochemical localization of PKC delta immunoreactivity in the rat central nervous system. J Comp Neurol 1993, 336: 378–399.PubMedGoogle Scholar
  85. [85]
    Masutani M, Mizoguchi A, Arii T, Iwasaki T, Ide C. Localization of protein kinase C alpha, beta and gamma subspecies in sensory axon terminals of the rat muscle spindle. J Neurocytol 1994, 23: 811–819.PubMedGoogle Scholar
  86. [86]
    Spaeth CS, Boydston EA, Figard LR, Zuzek A, Bittner GD. A model for sealing plasmalemmal damage in neurons and other eukaryotic cells. J Neurosci 2010, 30: 15790–15800.PubMedGoogle Scholar
  87. [87]
    Zuzek A, Fan JD, Spaeth CS, Bittner GD. Sealing of transected neurites of rat B104 cells requires a diacylglycerol PKC-dependent pathway and a PKA-dependent pathway. Cell Mol Neurobiol 2013, 33: 31–46.PubMedGoogle Scholar
  88. [88]
    Laux T, Fukami K, Thelen M, Golub T, Frey D, Caroni P. GAP43, MARCKS, and CAP23 m odulate PI(4,5)P(2) at plasmalemmal rafts, and regulate cell cortex actin dynamics through a common mechanism. J Cell Biol 2000, 149: 1455–1472.PubMedCentralPubMedGoogle Scholar
  89. [89]
    Hodgkin MN, Pettitt TR, Martin A, Michell RH, Pemberton AJ, Wakelam MJ. Diacylglycerols and phosphatidates: which molecular species are intracellular messengers? Trends Biochem Sci 1998, 23: 200–204.PubMedGoogle Scholar
  90. [90]
    Roth MG, Bi K, Ktistakis NT, Yu S. Phospholipase D as an effector for ADP-ribosylat ion factor in the regulation of vesicular traffic. Chem Phys Lipids 1999, 98: 141–152.PubMedGoogle Scholar
  91. [91]
    Pettitt TR, Martin A, Horton T, Liossis C, Lord JM, Wakelam MJ. Diacylglycerol and p hosphatidate generated by phospholipases C and D, respectively, have distinct fatty acid compositions and functions. Phospholipase D-derived diacylglycerol does not activate protein kinase C in porcine aortic endothelial cells. J Biol Chem 1997, 272: 17354–17359.PubMedGoogle Scholar
  92. [92]
    Lee JC, Simonyi A, Sun AY, Sun GY. Phospholipases A2 and neural membrane dynamics: implications for Alzheimer’s disease. J Neurochem 2011, 116: 813–819.PubMedCentralPubMedGoogle Scholar
  93. [93]
    Jenkins GM, Frohman MA. Phospholipase D: a lipid centric review. Cell Mol Life Sci 2005, 62: 2305–2316.PubMedGoogle Scholar
  94. [94]
    Rivera R, Chun J. Biological effects of lysophospholipids. Rev Physiol Biochem Pharmaco l 2008, 160: 25–46.Google Scholar
  95. [95]
    van Dijk MC, Postma F, Hilkmann H, Jalink K, van Blitterswijk WJ, Moolenaar WH. Exogenou s phospholipase D generates lysophosphatidic acid and activates Ras, Rho and Ca2+ signaling pathways. Curr Biol 1998, 8: 386–392.PubMedGoogle Scholar
  96. [96]
    Swarthout JT, Walling HW. Lysophosphatidic acid: receptors, signaling and survival. Cell Mol Life Sci 2000, 57: 1978–1985.PubMedGoogle Scholar
  97. [97]
    Lamaze C, Chuang TH, Terlecky LJ, Bokoch GM, Schmid SL. Regulation of receptor-mediated en docytosis by Rho and Rac. Nature 1996, 382: 177–179.PubMedGoogle Scholar
  98. [98]
    Jalink K, van Corven EJ, Hengeveld T, Morii N, Narumiya S, Moolenaar WH. Inhibition of lysophosphatidate- and thrombin-induced neurite retraction and neuronal cell rounding by ADP ribosylation of the small GTP-binding protein Rho. J Cell Biol 1994, 126: 801–810.PubMedGoogle Scholar
  99. [99]
    Horn KP, Busch SA, Hawthorne AL, van Rooijen N, Silver J. Another barrier to regeneration in the CNS: activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions. J Neurosci 2008, 28: 9330–9341.PubMedCentralPubMedGoogle Scholar
  100. [100]
    Raucher D, Stauffer T, Chen W, Shen K, Guo S, York JD, et al. Phosphatidylinositol 4,5-bisph osphate functions as a second messenger that regulates cytoskeleton-plasma membrane adhesion. Cell 2000, 100: 221–228.PubMedGoogle Scholar
  101. [101]
    Sechi AS, Wehland J. The actin cytoskeleton and plasma membrane connection: PtdIns(4,5)P(2) i nfluences cytoskeletal protein activity at the plasma membrane. J Cell Sci 2000, 113 Pt 21: 3685–3695.Google Scholar
  102. [102]
    Gilmore AP, Burridge K. Regulation of vinculin binding to talin and actin by phosphatidyl-inositol-4–5-bisphosphate. Nature 1996, 381: 531–535.PubMedGoogle Scholar
  103. [103]
    Apgar JR. Activation of protein kinase C in rat basophilic leukemia cells stimulates increased production of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate: correlation with actin polymerization. Mol Biol Cell 1995, 6: 97–108.PubMedCentralPubMedGoogle Scholar
  104. [104]
    Tolbert CE, Burridge K, Campbell SL. Vinculin regulation of F-actin bundle formation: what does it mean for the cell? Cell Adh Migr 2013, 7: 219–225.PubMedCentralPubMedGoogle Scholar
  105. [105]
    Weber H, Huhns S, Luthen F, Jonas L. Calpain-mediated breakdown of cytoskeletal proteins contributes to cholecystokinin-induced damage of rat pancreatic acini. Int J Exp Pathol 2009, 90: 387–399.PubMedCentralPubMedGoogle Scholar
  106. [106]
    Goni FM, Alonso A. Structure and functional properties of diacylglycerols in membranes. Prog Lipid Res 1999, 38: 1–48.PubMedGoogle Scholar
  107. [107]
    Churchward MA, Rogasevskaia T, Brandman DM, Khosravani H, Nava P, Atkinson JK, et al. Specific lipids supply critical negative spontaneous curvature—an essential component of native Ca2+-triggered membrane fusion. Biophys J 2008, 94: 3976–3986.PubMedCentralPubMedGoogle Scholar
  108. [108]
    Mochida S, Orita S, Sakaguchi G, Sasaki T, Takai Y. Role of the Doc2 alpha-Munc13-1 interaction in t he neurotransmitter release process. Proc Natl Acad Sci U S A 1998, 95: 11418–11422.PubMedCentralPubMedGoogle Scholar
  109. [109]
    Steinhardt RA, Bi G, Alderton JM. Cell membrane resealing by a vesicular mechanism similar to neurotr ansmitter release. Science 1994, 263: 390–393.PubMedGoogle Scholar
  110. [110]
    Bi GQ, Alderton JM, Steinhardt RA. Calcium-regulated exocytosis is required for cell membrane resealing. J Cell Biol 1995, 131: 1747–1758.PubMedGoogle Scholar
  111. [111]
    Tuck E, Cavalli V. Roles of membrane trafficking in nerve repair and regeneration. Commun Integr Biol 2010, 3: 209–214.PubMedCentralPubMedGoogle Scholar
  112. [112]
    Chapman ER. Synaptotagmin: a Ca(2+) sensor that triggers exocytosis? Nat Rev Mol Cell Biol 2002, 3: 498–508.PubMedGoogle Scholar
  113. [113]
    Kee Y, Scheller RH. Localization of synaptotagmin-binding domains on syntaxin. J Neurosci 1996, 16: 1975–1981.PubMedGoogle Scholar
  114. [114]
    Shao X, Li C, Fernandez I, Zhang X, Sudhof TC, Rizo J. Synaptotagmin-syntaxin interaction: the C2 domain a s a Ca2+-dependent electrostatic switch. Neuron 1997, 18: 133–142.PubMedGoogle Scholar
  115. [115]
    Sudhof TC, Rizo J. Synaptotagmins: C2-domain proteins that regulate membrane traffic. Neuron 1996, 17: 379–388.PubMedGoogle Scholar
  116. [116]
    Bloom OE, Morgan JR. Membrane trafficking events underlying axon repair, growth, and regeneration. Mol Cell Neurosci 2011, 48: 339–348.PubMedGoogle Scholar
  117. [117]
    Bloom O, Evergren E, Tomilin N, Kjaerulff O, Low P, Brodin L, et al. Colocalization of synapsin and actin during synaptic vesicle recycling. J Cell Biol 2003, 161: 737–747.PubMedCentralPubMedGoogle Scholar
  118. [118]
    Hirokawa N, Sobue K, Kanda K, Harada A, Yorifuji H. The cytoskeletal architecture of the presynaptic terminal and molecular structure of synapsin 1. J Cell Biol 1989, 108: 111–126.PubMedGoogle Scholar
  119. [119]
    Mason CA. Axon development in mouse cerebellum: embryonic axon forms and expression of synapsin I. Neuroscience 1986, 19: 1319–1333.PubMedGoogle Scholar
  120. [120]
    Bennett AF, Baines AJ. Bundling of microtubules by synapsin 1 head and tail domains with different sites in tubulin. Eur J Biochem 1992, 206: 783–792.PubMedGoogle Scholar
  121. [121]
    Menegon A, Bonanomi D, Albertinazzi C, Lotti F, Ferrari G, Kao HT, et al. Protein kinase A-mediated synapsin I phosphorylation is a central modulator of Ca2+-dependent synaptic activity. J Neurosci 2006, 26: 11670–11681.PubMedGoogle Scholar
  122. [122]
    Kao HT, Song HJ, Porton B, Ming GL, Hoh J, Abraham M, et al. A protein kinase A-dependent molecular switch in synapsins regulates neurite outgrowth. Nat Neurosci 2002, 5: 431–437.PubMedGoogle Scholar
  123. [123]
    Kao HT, Porton B, Hilfiker S, Stefani G, Pieribone VA, DeSalle R, et al. Molecular evolution of the synapsin gene family. J Exp Zool 1999, 285: 360–377.PubMedGoogle Scholar
  124. [124]
    Llinas R, Gruner JA, Sugimori M, McGuinness TL, Greengard P. Regulation by synapsin I and Ca(2+)-calmodulindependen t protein kinase II of the transmitter release in squid giant synapse. J Physiol 1991, 436: 257–282.PubMedCentralPubMedGoogle Scholar
  125. [125]
    Takahashi N, Kadowaki T, Yazaki Y, Ellis-Davies GC, Miyashita Y, Kasai H. Post-priming actions of ATP on Ca2+-dependent exocytosis in pancreatic beta cells. Proc Natl Acad Sci U S A 1999, 96: 760–765.PubMedCentralPubMedGoogle Scholar
  126. [126]
    Moulder KL, Jiang X, Chang C, Taylor AA, Benz AM, Conti AC, et al. A specific role for Ca2+-dependent adenylyl cyclase s in recovery from adaptive presynaptic silencing. J Neurosci 2008, 28: 5159–5168.PubMedCentralPubMedGoogle Scholar
  127. [127]
    Hatakeyama H, Takahashi N, Kishimoto T, Nemoto T, Kasai H. Two cAMP-dependent pathways differentially regulate exocytos is of large dense-core and small vesicles in mouse beta-cells. J Physiol 2007, 582: 1087–1098.PubMedCentralPubMedGoogle Scholar
  128. [128]
    Seino S, Shibasaki T. PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiol Rev 2005, 85: 13 03–1342.Google Scholar
  129. [129]
    Sedej S, Rose T, Rupnik M. cAMP increases Ca2+-dependent exocytosis through both PKA and Epac2 in mouse melanotrophs from pituitary tissue slices. J Physiol 2005, 567: 799–813.PubMedCentralPubMedGoogle Scholar
  130. [130]
    Bradford A, Atkinson J, Fuller N, Rand RP. The effect of vitamin E on the structure of membrane lipid assemblies. J Lipid Res 2003, 44: 1940–1945.PubMedGoogle Scholar
  131. [131]
    Churchward MA, Rogasevskaia T, Hofgen J, Bau J, Coorssen JR. Cholesterol facilitates the native mechanism of Ca2+-triggered membrane fusion. J Cell Sci 2005, 118: 4833–4848.PubMedGoogle Scholar
  132. [132]
    Markin VS, Albanesi JP. Membrane fusion: stalk model revisited. Biophys J 2002, 82: 693–712.PubMedCentralPubMedGoogle Scholar
  133. [133]
    Efrat A, Chernomordik LV, Kozlov MM. Point-like protrusion as a prestalk intermediate in membrane fusion pathway. Biophys J 2007, 92: L61–63.PubMedCentralPubMedGoogle Scholar
  134. [134]
    Kozlovsky Y, Kozlov MM. Stalk model of membrane fusion: solution of energy crisis. Biophys J 2002, 82: 882–895.PubMedCentralPubMedGoogle Scholar
  135. [135]
    Rogasevskaia T, Coorssen JR. Sphingomyelin-enriched microdomains define the efficiency of native Ca(2+)-triggered membrane fu sion. J Cell Sci 2006, 119: 2688–2694.PubMedGoogle Scholar
  136. [136]
    de Mello WC, Motta GE, Chapeau M. A study on the healing-over of myocardial cells of toads. Circ Res 1969, 24: 475–487.PubMedGoogle Scholar
  137. [137]
    Young W. Ca paradox in neural injury: a hypothesis. Cent Nerv Syst Trauma 1986, 3: 235–251.PubMedGoogle Scholar
  138. [138]
    Young W, Yen V, Blight A. E xtracellular calcium ionic activity in experimental spinal cord contusion. Brain Res 1982, 253: 105–113.PubMedGoogle Scholar
  139. [139]
    Stokes BT, Fox P, Hollinden G. Extracellular calcium activity in the injured spinal cord. Exp Neurol 1983, 80: 561–572.PubMedGoogle Scholar
  140. [140]
    Castro IA, Rogero MM, Junqueira RM, Carrapeiro MM. Free radical scavenger and antioxidant capacity correlation of alpha-tocopherol and Trolox measured by three in vitro methodologies. Int J Food Sci Nutr 2006, 57: 75–82.PubMedGoogle Scholar
  141. [141]
    Niki E, Traber MG. A history of vitamin E. Ann Nutr Metab 2012, 61: 207–212.PubMedGoogle Scholar
  142. [142]
    Howard AC, McNeil AK, McNeil PL. Promotion of plasma membrane repair by vitamin E. Nat Commun 2011, 2: 597.PubMedCentralPubMedGoogle Scholar
  143. [143]
    Luo J, Shi R. A crolein induces axolemmal disruption, oxidative stress, and mitochondrial impairment in spinal cord tissue. Neuroc hem Int 2004, 44: 475–486.Google Scholar
  144. [144]
    Ricciarelli R, Tasinato A, Clement S, Ozer NK, Boscoboinik D, Azzi A. alpha-Tocopherol specifically inactivates cellular protein kinase C alpha by changing its phosphorylation state. Biochem J 1998, 334(Pt 1): 243–249.PubMedCentralPubMedGoogle Scholar
  145. [145]
    Azzi A, Stocker A. Vitamin E: non-antioxidant roles. Prog Lipid Res 2000, 39: 231–255.PubMedGoogle Scholar
  146. [146]
    Cachia O, Benna JE, Pedruzzi E, Descomps B, Gougerot-Pocidalo MA, Leger CL. alpha-tocopherol inhibits the respiratory burst in human monocytes. Attenuation of p47(phox) membrane translocation and phosphorylation. J Biol Chem 1998, 273: 32801–32805.PubMedGoogle Scholar
  147. [147]
    Suzen S. Melatonin and synthetic analogs as antioxidants. Curr Drug Deliv 2013, 10: 71–75.PubMedGoogle Scholar
  148. [148]
    McNeil P. Membrane repair redux: red ox of MG53. Nat Cell Biol 2009, 11: 7–9.PubMedGoogle Scholar
  149. [149]
    van Diepen MT, Spencer GE, van Minnen J, Gouwenberg Y, Bouwman J, Smit AB, et al. The molluscan RING-finger protein L-TRIM is essential for neuronal outgrowth. Mol Cell Neurosci 2005, 29: 74–81.PubMedGoogle Scholar
  150. [150]
    Jensen JM, Shi R. Effects of 4-aminopyridine on stretched mammalian spinal cord: the role of potassium channels in axonal conduction. J Neurophysiol 2003, 90: 2334–2340.PubMedGoogle Scholar
  151. [151]
    Luo J, Borgens R, Shi R. Polyethylene glycol immediately repairs neuronal membranes and inhibits free radical production after acute spin al cord injury. J Neurochem 2002, 83: 471–480.PubMedGoogle Scholar
  152. [152]
    Uhlig K, Boysen B, Lankenau A, Jaeger M, Wischerhoff E, Lutz JF, et al. On the influence of the architecture of poly(ethylene glycol)-base d thermoresponsive polymers on cell adhesion. Biomicrofluidics 2012, 6: 24129.PubMedGoogle Scholar
  153. [153]
    Gombotz WR, Wang GH, Horbett TA, Hoffman AS. Protein adsorption to poly(ethylene oxide) surfaces. J Biomed Mater Res 1991, 25: 1547–1562.PubMedGoogle Scholar
  154. [154]
    Sikkink CJ, Reijnen MM, Laverman P, Oyen WJ, van Goor H. Tc-99m-PEG-liposomes target both adhesions and abscesses and their reduction by hy aluronate in rats with fecal peritonitis. J Surg Res 2009, 154: 246–251.PubMedGoogle Scholar
  155. [155]
    Borgens RB, Bohnert D. Rapid recovery from spinal cord injury after subcutaneously administered polyethylene glycol. J Neurosci Res 2001, 66: 1179–1186.PubMedGoogle Scholar
  156. [156]
    Lee RC, River LP, Pan FS, Ji L, Wollmann RL. Surfactant-induced sealing of electropermeabilized skeletal muscle membranes in vivo. Proc Natl Acad Sci U S A 1992, 89: 4524–4528.PubMedCentralPubMedGoogle Scholar
  157. [157]
    Yu ZW, Quinn PJ. The modulation of membrane structure and stability by dimethyl sulphoxide (review). Mol Membr Biol 1998, 15: 59–68.PubMedGoogle Scholar
  158. [158]
    Shi R, Qiao X, Emerson N, Malcom A. Dimethylsulfoxide enhances CNS neuronal plasma membrane resealing after injury in low temperature or low calcium. J Neurocytol 2001, 30: 829–839.PubMedGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Basic Medical Sciences, College of Veterinary Medicine, Weldon School of Biomedical EngineeringPurdue UniversityWest LafayetteUSA
  2. 2.Indiana University School of Medicine-LafayetteWest LafayetteUSA

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