Gap junction proteins and their role in spinal cord injury

Frontiers in Molecular Neuroscience

Volumn 7, Issue JAN, 2015, Pages

  Tonkin, Ryan S ^a   Mao, Yilin ^b   O'carroll, Simon J ^c   Nicholson, Louise F B ^c   Green, Colin R ^c   Gorrie, Catherine A ^b   Moalem Taylor, Gila ^a  

^a UNIVERSITY OF NEW SOUTH WALES   (Australia)

^b UNIVERSITY OF TECHNOLOGY SYDNEY   (Australia)

^c UNIVERSITY OF AUCKLAND   (New Zealand)

Author keywords

Connexins; Gap junctions; Hemichannels; Neuropathic pain; Spinal cord injury

Indexed keywords

ADENOSINE TRIPHOSPHATE; ANTISENSE OLIGODEOXYNUCLEOTIDE; CALCIUM ION; CARBENOXOLONE; CONNEXIN 43; FIBROBLAST GROWTH FACTOR 1; GAP JUNCTION PROTEIN; GLIAL FIBRILLARY ACIDIC PROTEIN; GLUTAMIC ACID; INTERLEUKIN 1BETA; MEFLOQUINE; MESSENGER RNA; MODAFINIL; PEPTIDE; PHOSPHOLIPASE C; POTASSIUM ION; REACTIVE OXYGEN METABOLITE; TUMOR NECROSIS FACTOR ALPHA;

APOPTOSIS; ARTICLE; ASTROCYTE; CELL ACTIVATION; DOWN REGULATION; FOLLOW UP; GLIA CELL; HUMAN; HYPERREFLEXIA; IMMUNE RESPONSE; IMMUNOGOLD LABELING; IMMUNOHISTOCHEMISTRY; NERVE CELL; NEUROBLASTOMA CELL; NEUROPATHIC PAIN; NONHUMAN; OLIGODENDROGLIA; PROTEIN EXPRESSION; SPASTICITY; SPINAL CORD INJURY;

EID: 84920588815     PISSN: 16625099     EISSN: None     Source Type: Journal    
DOI: 10.3389/fnmol.2014.00102     Document Type: Article

References (114)

1. Altevogt, B. M., Kleopa, K. A., Postma, F. R., Scherer, S. S., and Paul, D. L. (2002). Connexin29 is uniquely distributed within myelinating glial cells of the central and peripheral nervous systems. J. Neurosci. 22, 6458-6470.
2. Altevogt, B. M., and Paul, D. L. (2004). Four classes of intercellular channels between glial cells in the CNS. J. Neurosci. 24,4313-4323. doi: 10.1523/JNEUROSCI.3303-03.2004
3. Austin, P. J., Kim, C. F., Perera, C. J., and Moalem-Taylor, G. (2012). Regulatory T cells attenuate neuropathic pain following peripheral nerve injury and experimental autoimmune neuritis. Pain 153, 1916-1931. doi: 10.1016/j.pain.2012.06.005
4. Bautista, W., Mccrea, D., and Nagy, J. (2014). Connexin36 identified at mor-phologicallymixed chemical/electrical synapses on trigeminal motoneurons and at primary afferent terminals on spinal cord neurons in adult mouse and rat. Neuroscience 236, 159-180. doi: 10.1016/j.neuroscience.2013.12.057
5. Becker, D. L., Thrasivoulou, C., and Phillips, A. R. (2012). Connexins in wound healing; perspectives in diabetic patients. Biochim. Biophys. Acta 1818,2068-2075. doi: 10.1016/j.bbamem.2011.11.017
6. Bennett, M. V., Contreras, J. E., Bukauskas, F. F., and Saez, J. C. (2003). New roles for astrocytes: gap junction hemichannels have something to communicate. Trends Neurosci. 26, 610-617. doi: 10.1016/j.tins.2003.09.008
7. Bennett, M. V., Garre, J. M., Orellana, J. A., Bukauskas, F. F., Neder-gaard, M., Giaume, C., et al. (2012). Connexin and pannexin hemichannels in inflammatory responses of glia and neurons. Brain Res. 1487, 3-15. doi: 10.1016/j.brainres.2012.08.042
8. Betageri, G., and Rogers, J. (1987). Thermodynamics of partitioning of β-blockers in the n-octanol-buffer and liposome systems. Int. J. Pharm. 36, 165-173. doi: 10.1016/0378-5173(87)90152-9
9. 2+ signaling through gap junctions in airway cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 279, 623-630.
10. Bopp, T., Becker, C., Klein, M., Klein-HeCling, S., Palmetshofer, A., Serfling, E., et al. (2007). Cyclic adenosine monophosphate is a key component of regulatory T cell mediated suppression. J. Exp. Med. 204, 1303-1310. doi: 10.1084/jem.20062129
11. Buzsaki, G., and Chrobak, J. J. (1995). Temporal structure in spatially organized neuronal ensembles: a role for interneuronal networks. Curr. Opin. Neurobiol. 5, 504-510. doi: 10.1016/0959-4388(95)80012-3
12. Cairns, D. M., Adkins, R. H., and Scott, M. D. (1996). Pain and depression in acute traumatic spinal cord injury: origins of chronic problematic pain? Arch. Phys. Med. Rehabil. 77, 329-335. doi: 10.1016/S0003-9993(96)90079-9
13. Carlton, S. M., Du, J., Tan, H. Y., Nesic, O., Hargett, G. L., Bopp, A. C., et al. (2009). Peripheral and central sensitization in remote spinal cord regions contribute to central neuropathic pain after spinal cord injury. Pain 147, 265-276. doi: 10.1016/j.pain.2009.09.030
14. Chang, Q., and Balice-Gordon, R. J. (2000). Gap junctional communication among developing and injured motor neurons. Brain Res. Brain Res. Rev. 32, 242-249. doi: 10.1016/S0165-0173(99)00085-5
15. Chang, Q., Gonzalez, M., Pinter, M. J., and Balice-Gordon, R. J. (1999). Gap junc-tional coupling and patterns of connexin expression among neonatal rat lumbar spinal motor neurons. J. Neurosci. 19, 10813-10828.
16. Chaytor, A., Evans, W., Griffith, T., and Thornbury, K. (1997). Peptides homologous to extracellular loop motifs of connexin 43 reversibly abolish rhythmic contractile activity in rabbit arteries. J. Physiol. 503, 99-110. doi: 10.1111/j.1469-7793.1997.099bi.x
17. Chen, M. J., Kress, B., Han, X., Moll, K., Peng, W., Ji, R. R., et al. (2012). Astrocytic CX43 hemichannels and gap junctions play a crucial role in development of chronic neuropathic pain following spinal cord injury. Glia 60, 1660-1670. doi: 10.1002/glia.22384
18. Chever, O., Lee, C.-Y., and Rouach, N. (2014). Astroglial connexin43 hemichannels tune basal excitatory synaptic transmission. J. Neurosci. 34, 11228-11232. doi: 10.1523/JNEUROSCI.0015-14.2014
19. Clarke, T. C., Williams, O. J., Martin, P. E., and Evans, W. H. (2009). ATP release by cardiac myocytes in a simulated ischaemia model: inhibition by a connexin mimetic and enhancement by an antiarrhythmic peptide. Eur. J. Pharmacol. 605, 9-14. doi: 10.1016/j.ejphar.2008.12.005
20. Contreras, J. E., Saez, J. C., Bukauskas, F. F., and Bennett, M. V. (2003). Gating and regulation ofconnexin 43 (Cx43) hemichannels. Proc. Natl. Acad. Sci. U.S.A. 100, 11388-11393. doi: 10.1073/pnas.1434298100
21. Contreras, J. E., Sanchez, H. A., Eugenln, E. A., Speidel, D., Theis, M., Willecke, K., et al. (2002). Metabolic inhibition induces opening of unapposed connexin 43 gap junction hemichannels and reduces gap junctional communication in cortical astrocytes in culture. Proc. Natl. Acad. Sci. U.S.A. 99, 495-500. doi: 10.1073/pnas.012589799
22. Contreras, J. E., Sanchez, H. A., Veliz, L. P., Bukauskas, F. F., Bennett, M. V., and Saez, J. C. (2004). Role of connexin-based gap junction channels and hemichannels in ischemia-induced cell death in nervous tissue. Brain Res. Brain Res. Rev. 47, 290-303. doi: 10.1016/j.brainresrev.2004.08.002
23. Coutinho, P., Qiu, C., Frank, S., Tamber, K., and Becker, D. (2003). Dynamicchanges in connexin expression correlate with key events in the wound healing process. Cell Biol. Int. 27, 525-541. doi: 10.1016/S1065-6995(03)00077-5
24. Coutinho, P., Qiu, C., Frank, S., Wang, C., Brown, T., Green, C., et al. (2005). Limiting burn extension by transient inhibition of connexin43 expression at the site of injury. Br. J. Plast. Surg. 58, 658-667. doi: 10.1016/j.bjps.2004.12.022
25. Cronin, M., Anderson, P. N., Cook, J. E., Green, C. R., and Becker, D. L. (2008). Blocking connexin43 expression reduces inflammation and improves functional recovery after spinal cord injury. Mol. Cell. Neurosci. 39, 152-160. doi: 10.1016/j.mcn.2008.06.005
26. Crowe, M. J., Bresnahan, J. C., Shuman, S. L., Masters, J. N., and Crowe, M. S. (1997). Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat. Med. 3, 73-76. doi: 10.1038/nm0197-73
27. Cruikshank, S. J., Hopperstad, M., Younger, M., Connors, B. W., Spray, D. C., and Srinivas, M. (2004). Potent block of Cx36 and Cx50 gap junction channels by mefloquine. Proc. Natl. Acad. Sci. U.S.A. 101, 12364-12369. doi: 10.1073/pnas.0402044101
28. Cursiefen, C., Bock, F., Horn, F. K., Kruse, F. E., Seitz, B., Borderie, V., et al. (2009). GS-101 antisense oligonucleotide eye drops inhibit corneal neovascularization: interim results of a randomized phase II trial. Ophthalmology 116, 1630-1637. doi: 10.1016/j.ophtha.2009.04.016
29. Dahl, E., Manthey, D., Chen, Y., Schwarz, H.-J., Chang, Y. S., Lalley, P. A., et al. (1996). Molecular cloning and functional expression of mouse connexin-30, a gap junction gene highly expressed in adult brain and skin. J. Biol. Chem. 271, 17903-17910. doi: 10.1074/jbc.271.30.17903
30. Del Bigio, M. R., and Johnson, G. E. (1989). Clinical presentation of spinal cord concussion. Spine 14, 37-40. doi: 10.1097/00007632-198901000-00007
31. Evans, W., De Vuyst, E., and Leybaert, L. (2006). The gap junction cellular internet: connexin hemichannels enter the signalling limelight. Biochem. J. 397, 1-14. doi: 10.1042/BJ20060175
32. Faustmann, P. M., Haase, C. G., Romberg, S., Hinkerohe, D., Szlachta, D., Smikalla, D., et al. (2003). Microglia activation influences dye coupling and Cx43 expression ofthe astrocytic network. Glia 42, 101-108. doi: 10.1002/glia.10141
33. Filippov, M. A., Hormuzdi, S. G., Fuchs, E. C., and Monyer, E. (2003). A reporter allele for investigating connexin 26 gene expression in the mouse brain. Eur. J. Neurosci. 18, 3183-3192. doi: 10.1111/j.1460-9568.2003.03042.x
34. Finnerup, N. B., and Baastrup, C. (2012). Spinal cord injurypain: mechanisms and management. Curr. Pain Headache Rep. 16, 207-216. doi: 10.1007/s11916-012-0259-x
35. Fitch, M. T., and Silver, J. (2008). CNS injury, glial scars, and inflammation: inhibitory extracellular matrices and regeneration failure. Exp. Neurol. 209, 294-301. doi: 10.1016/j.expneurol.2007.05.014
36. Fricker, D., and Miles, R. (2001). Interneurons, spike timing, and perception. Neuron 32, 771-774. doi: 10.1016/S0896-6273(01)00528-1
37. Garre, J. M., Retamal, M. A., Cassina, P., Barbeito, L., Bukauskas, F. F., Saez, J. C., et al. (2010). FGF-1 induces ATP release from spinal astrocytes in culture and opens pannexin and connexin hemichannels. Proc. Natl. Acad. Sci. U.S.A. 107, 22659-22664. doi: 10.1073/pnas.1013793107
38. Giaume, C., Leybaert, L., Naus, C. C., and Saez, J. C. (2013). Connexin and pannexin hemichannels in brain glial cells: properties, pharmacology, and roles. Front. Pharmacol. 4:88. doi: 10.3389/fphar.2013.00088
39. Gibson, J. R., Beierlein, M., and Connors, B. W. (2005). Functional properties of electrical synapses between inhibitory interneurons of neocortical layer 4. J. Neurophysiol. 93, 467-480. doi: 10.1152/jn.00520.2004
40. Gorbe, A., Becker, D. L., Dux, L., Krenacs, L., and Krenacs, T. (2006). In differentiating prefusion myoblasts connexin43 gap junction coupling is upregulated before myoblast alignment then reduced in post-mitotic cells. Histochem. Cell Biol. 125, 705-716. doi: 10.1007/s00418-005-0121-x
41. Grupcheva, C. N., Laux, W. T., Rupenthal, I. D., Mcghee, J., Mcghee, C. N., and Green, C. R. (2012). Improved corneal wound healing through modulation of gap junction communication using connexin43-specific antisense oligodeoxynucleotides. Invest. Ophthalmol. Vis. Sci. 53, 1130-1138. doi: 10.1167/iovs.11-8711
42. Gwak, Y. S., Crown, E. D., Unabia, G. C., and Hulsebosch, C. E. (2008). Propento-fylline attenuates allodynia, glial activation and modulates GABAergic tone after spinal cord injuryin the rat. Pain 138, 410-422. doi: 10.1016/j.pain.2008.01.021
43. Gwak, Y. S., and Hulsebosch, C. E. (2009). Remote astrocytic and microglial activation modulates neuronal hyperexcitability and below-level neuropathic pain after spinal injury in rat. Neuroscience 161, 895-903. doi: 10.1016/j.neuroscience.2009.03.055
44. Gwak, Y. S., and Hulsebosch, C. E. (2011). Neuronal hyperexcitability: a substrate for central neuropathic pain after spinal cord injury. Curr. Pain Headache Rep. 15, 215-222. doi: 10.1007/s11916-011-0186-2
45. Haghikia, A., Ladage, K., Lafenetre, P., Haghikia, A., Hinkeroche, D., Smikalla, D., et al. (2008). Intracellular application of TNF-alpha impairs cell to cell communication via gap junctions in glioma cells. J. Neurooncol. 86, 143-152. doi: 10.1007/s11060-007-9462-8
46. Hains, B. C., and Waxman, S. G. (2006). Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J. Neurosci. 26, 4308-4317. doi: 10.1523/JNEUROSCI.0003-06.2006
47. Hertzberg, E. L., Lawrence, T. S., and Gilula, N. B. (1981). Gap junctional communication. Annu. Rev. Physiol. 43, 479-491. doi: 10.1146/annurev.ph.43.030181.002403
48. Hinkerohe, D., Smikalla, D., Haghikia, A., Heupel, K., Haase, C. G., Dermietzel, R., et al. (2005). Effects of cytokines on microglial phenotypes and astroglial coupling in an inflammatory coculture model. Glia 52, 85-97. doi: 10.1002/glia.20223
49. Hong, T., Wang, H., Wang, Y., and Wang, H. (2009). Effectsofgap junctionalblockers on cerebral vasospasm after subarachnoid hemorrhage in rabbits. Neurol. Res. 31, 238-244. doi: 10.1179/174313208X322770
50. Hormuzdi, S. G., Filippov, M. A., Mitropoulou, G., Monyer, H., and Bruz-zone, R. (2004). Electrical synapses: a dynamic signaling system that shapes the activity of neuronal networks. Biochim. Biophys. Acta 1662, 113-137. doi: 10.1016/j.bbamem.2003.10.023
51. Huang, C., Han, X., Li, X., Lam, E., Peng, W., Lou, N., et al. (2012). Critical role of connexin 43 in secondary expansion of traumatic spinal cord injury. J. Neurosci. 32, 3333-3338. doi: 10.1523/JNEUROSCI.1216-11.2012
52. Hulsebosch, C. E., Hains, B. C., Crown, E. D., and Carlton, S. M. (2009). Mechanisms of chronic central neuropathic pain after spinal cord injury. Brain Res. Rev. 60, 202-213. doi: 10.1016/j.brainresrev.2008.12.010
53. Ilvesaro, J., Tavi, P., and Tukkanen, J. (2001). Connexin mimetic peptide Gap27 decreases osteoclastic activity. BMC Musculoskelet. Disord. 2:10. doi: 10.1186/1471-2474-2-10
54. Iyyathurai, J., D'hondt, C., Wang, N., De Bock, M., Himpens, B., Retamal, M. A., et al. (2013). Peptides and peptide derived molecules targetting the intracellular domains of Cx43: gap junctions versus hemichannels. Neuropharmacology 75, 491-505. doi: 10.1016/j.neuropharm.2013.04.050
55. Kamasawa, N., Sik, A., Morita, M., Yasumura, T., Davidson, K., Nagy, J., et al. (2005). Connexin-47 and connexin-32 in gap junctions of oligodendrocyte somata, myelin sheaths, paranodal loops and Schmidt-Lanterman incisures: implications for ionic homeostasis and potassium siphoning. Neuroscience 136, 65-86. doi: 10.1016/j.neuroscience.2005.08.027
56. Kiehn, O., Kjaerulff, O., Tresch, M. C., and Harris-Warrick, R. M. (2000). Contributions of intrinsic motor neuron properties to the production of rhythmic motor output in the mammalian spinal cord. Brain Res. Bull. 53, 649-659. doi: 10.1016/S0361-9230(00)00398-1
57. Kiehn, O., and Tresch, M. C. (2002). Gap junctions and motor behavior. Trends Neurosci. 25, 108-115. doi: 10.1016/S0166-2236(02)02038-6
58. Kleopa, K. A., Orthmann, J. L., Enriquez, A., Paul, D. L., and Scherer, S. S. (2004). Unique distributions of the gap junction proteins connexin29, connexin32, and connexin47 in oligodendrocytes. Glia 47, 346-357. doi: 10.1002/glia.20043
59. Kunzelmann, P., Schroder, W., Traub, O., Steinhauser, C., Dermietzel, R., and Willecke, K. (1999). Late onset and increasing expression of the gap junction protein connexin 30 in adult murine brain and long-term cultured astrocytes. Glia 25, 111-119. doi: 10.1002/(SICI)1098-1136(19990115)25:2<111::AID-GLIA2>3.0.CO;2-I
60. Kwak, B. R., and Jongsma, H. J. (1999). Selective inhibition of gap junction channel activity by synthetic peptides. J. Physiol. 516, 679-685. doi: 10.1111/j.1469-7793.1999.0679u.x
61. Kwak, B. R., Pepper, M. S., Gros, D. B., and Meda, P. (2001). Inhibition of endothelial wound repair by dominant negative connexin inhibitors. Mol. Biol. Cell 12, 831-845. doi: 10.1091/mbc.12.4.831
62. Lampe, P. D., and Lau, A. F. (2000). Regulation ofgap junctions byphosphorylation ofconnexins. Arch. Biochem. Biophys. 384, 205-215. doi: 10.1006/abbi.2000.2131
63. Lee, I. H., Lindqvist, E., Kiehn, O., Widenfalk, J., and Olson, L. (2005). Glial and neuronal connexin expression patterns in the rat spinal cord during development and following injury. J. Comp. Neurol. 489, 1-10. doi: 10.1002/cne.20567
64. Li, X., Ionescu, A., Lynn, B., Lu, S., Kamasawa, N., Morita, M., et al. (2004). Connexin47, connexin29 and connexin32 co-expression in oligodendrocytes and Cx47 association with zonula occludens-1 (ZO-1) in mouse brain. Neuroscience 126, 611-630. doi: 10.1016/j.neuroscience.2004.03.063
65. Liao, Y., and Duling, B. R. (2000). Blockade of connexin 43 expression by stable transfection of antisense cDNA in cultured vascular smooth muscle cells. Antisense Nucleic Acid DrugDev. 10, 275-281. doi: 10.1089/108729000421457
66. Marchand, F., Tsantoulas, C., Singh, D., Grist, J., Clark, A. K., Bradbury, E. J., et al. (2009). Effects ofetanerceptand minocycline in arat model ofspinal cord injury. Eur. J. Pain 13, 673-681. doi: 10.1016/j.ejpain.2008.08.001
67. Martin, P. E., Wall, C., and Griffith, T. M. (2005). Effects of connexin-mimetic pep-tides on gap junction functionalityand connexin expression in cultured vascular cells. Br. J. Pharmacol. 144, 617-627. doi: 10.1038/sj.bjp.0706102
68. Matsue, H., Yao, J., Matsue, K., Nagasaka, A., Sugiyama, H., Aoki, R., et al. (2006). Gap junction-mediated intercellular communication between dendritic cells (DCs) is required for effective activation of DCs. J. Immunol. 176, 181-190. doi: 10.4049/jimmunol.176.1.181
69. Menichella, D. M., Goodenough, D. A., Sirkowski, E., Scherer, S. S., and Paul, D. L. (2003). Connexins are critical for normal myelination in the CNS. J. Neurosci. 23, 5963-5973.
70. Meyer, A., Hilgen, G., Dorgau, B., Sammler, E. M., Weiler, R., Monyer, H., et al. (2014). All amacrine cells discriminate between heterocellular and homocellular locations when assembling connexin36 containing gap junctions. J. Cell Sci. 127, 1190-1202. doi: 10.1242/jcs.133066
71. Mori, R., Power, K. T., Wang, C. M., Martin, P., and Becker, D. L. (2006). Acute downregulation of connexin43 at wound sites leads to a reduced inflammatory response, enhanced keratinocyte proliferation and wound fibroblast migration. J. Cell Sci. 119, 5193-5203. doi: 10.1242/jcs.03320
72. Nagy, J. I., Li, X., Rempel, J., Stelmack, G., Patel, D., Staines, W. A., et al. (2001). Connexin26 in adult rodent central nervous system: demonstration at astrocytic gap junctions and colocalization with connexin30 and connexin43. J. Comp. Neurol. 441, 302-323. doi: 10.1002/cne.1414
73. Nagy, J. I., and Rash, J. E. (2003). Astrocyte and oligodendrocyte connexins of the glial syncytium in relation to astrocyte anatomical domains and spatial buffering. Cell Commun. Adhes. 10, 401-406. doi: 10.1080/cac.10.4-6.401.406
74. Neijssen, J., Herberts, C., Drijfhout, J. W., Reits, E., Janssen, L., and Neefjes, J. (2005). Cross-presentation by intercellular peptide transfer through gap junctions. Nature 434, 83-88. doi: 10.1038/nature03290
75. Norenberg, M. D., Smith, J., and Marcillo, A. (2004). The pathology of human spinal cord injury: defining the problems. J. Neurotrauma 21, 429-440. doi: 10.1089/089771504323004575
76. O'Carroll, S. J., Alkadhi, M., Nicholson, L. F., and Green, C. R. (2008). Connexin43 mimetic peptides reduce swelling, astrogliosis, and neuronal cell death after spinal cord injury. Cell Commun. Adhes. 15, 27-42. doi: 10.1080/154190608020 14164
77. O'Carroll, S. J., Gorrie, C. A., Velamoor, S., Green, C. R., and Nicholson, L. F. (2013). Connexin43 mimetic peptide is neuroprotective and improves function following spinal cord injury. Neurosci. Res. 75, 256-267. doi: 10.1016/j.neures.2013.01.004
78. Odermatt, B., Wellershaus, K., Wallraff, A., Seifert, G., Degen, J., Euwens, C., et al. (2003). Connexin 47 (Cx47)-deficient mice with enhanced green fluorescent protein reporter gene reveal predominant oligodendrocytic expression of Cx47 and display vacuolized myelin in the CNS. J. Neurosci. 23, 4549-4559.
79. Ormonde, S., Chou, C.-Y., Goold, L., Petsoglou, C., Al-Taie, R., Sherwin, T., et al. (2012). Regulation ofconnexin43 gap junction protein triggers vascular recovery and healing in human ocular persistent epithelial defect wounds. J. Membr. Biol. 245, 381-388. doi: 10.1007/s00232-012-9460-4
80. Orthmann-Murphy, J. L., Abrams, C. K., and Scherer, S. S. (2008). Gap junctions couple astrocytes and oligodendrocytes. J. Mol. Neurosci. 35, 101-116. doi: 10.1007/s12031-007-9027-5
81. Pannasch, U., Vargova, L., Reingruber, J., Ezan, P., Holcman, D., Giaume, C., et al. (2011). Astroglial networks scale synaptic activityand plasticity. Proc. Natl. Acad. Sci. U.S.A. 108, 8467-8472. doi: 10.1073/pnas.1016650108
82. Peng, X. M., Zhou, Z. G., Glorioso, J. C., Fink, D. J., and Mata, M. (2006). Tumor necrosis factor-a contributes to below-level neuropathic pain after spinal cord injury. Ann. Neurol. 59, 843-851. doi: 10.1002/ana.20855
83. Profyris, C., Cheema, S. S., Zang, D., Azari, M. F., Boyle, K., and Petratos, S. (2004). Degenerative and regenerative mechanisms governing spinal cord injury. Neurobiol. Dis. 15, 415-436. doi: 10.1016/j.nbd.2003.11.015
84. Qiu, C., Coutinho, P., Frank, S., Franke, S., Law, L.-Y., Martin, P., et al. (2003). Targeting connexin43 expression accelerates the rate of wound repair. Curr. Biol. 13, 1697-1703. doi: 10.1016/j.cub.2003.09.007
85. Ramachandran, S., Xie, L.-H., John, S. A., Subramaniam, S., and Lal, R. (2007). A novel role for connexin hemichannel in oxidative stress and smoking-induced cell injury. PLoS ONE 2:e712. doi: 10.1371/journal.pone.0000712
86. Rash, J., Staines, W., Yasumura, T., Patel, D., Furman, C., Stelmack, G., et al. (2000). Immunogold evidence that neuronal gap junctions in adult rat brain and spinal cord contain connexin-36 but not connexin-32 or connexin-43. Proc. Natl. Acad. Sci. U.S.A. 97, 7573-7578. doi: 10.1073/pnas.97.13.7573
87. Rash, J. E. (2010). Molecular disruptions ofthe panglial syncytium block potassium siphoning and axonal saltatory conduction: pertinence to neuromyelitis optica and other demyelinatingdiseases ofthecentral nervous system. Neuroscience 168, 982-1008. doi: 10.1016/j.neuroscience.2009.10.028
88. Ratkay-Traub, I., Hopp, B., Bor, Z., Dux, L., Becker, D., and Krenacs, T. (2001). Regeneration of rabbit cornea following excimer laser photorefractive kerate-ctomy: a study on gap junctions, epithelial junctions and epidermal growth factor receptor expression in correlation with cell proliferation. Exp. Eye Res. 73, 291-302. doi: 10.1006/exer.2001.1040
89. Retamal, M. A., Cortes, C. J., Reuss, L., Bennett, M. V., and Saez, J. C. (2006). S-nitrosylation and permeation through connexin 43 hemichannels in astrocytes: induction byoxidant stress and reversal byreducing agents. Proc. Natl. Acad. Sci. U.S.A. 103, 4475-4480. doi: 10.1073/pnas.0511118103
90. Retamal, M. A., Schalper, K. A., Shoji, K. F., Bennett, M. V., and Saez, J. C. (2007). Opening of connexin 43 hemichannels is increased by lowering intra-cellular redox potential. Proc. Natl. Acad. Sci. U.S.A. 104, 8322-8327. doi: 10.1073/pnas.0702456104
91. Roh, D. H., Yoon, S. Y., Seo, H. S., Kang, S. Y., Han, H. J., Beitz, A. J., et al. (2010). Intrathecal injection of carbenoxolone, a gap junction decoupler, attenuates the induction of below-level neuropathic pain after spinal cord injury in rats. Exp. Neurol. 224, 123-132. doi: 10.1016/j.expneurol.2010.03.002
92. Shintani-Ishida, K., Uemura, K., and Yoshida, K.-I. (2007). Hemichannels in cardiomyocytes open transiently during ischemia and contribute to reperfu-sion injury following brief ischemia. Am. J. Physiol. Heart Circ. Physiol. 293, 1714-1720. doi: 10.1152/ajpheart.00022.2007
93. Siddall, P. J., Taylor, D. A., Mcclelland, J. M., Rutkowski, S. B., and Cousins, M. J. (1999). Pain report and the relationship of pain to physical factors in the first 6 months following spinal cord injury. Pain 81, 187-197. doi: 10.1016/S0304-3959(99)00023-8
94. Sohl, G., Maxeiner, S., andWillecke, K. (2005). Expression and functions of neuronal gap junctions. Nat. Rev. Neurosci. 6, 191-200. doi: 10.1038/nrn1627
95. Sohl, G., and Willecke, K. (2003). An update on connexin genes and their nomenclature in mouse and man. Cell Commun. Adhes. 10, 173-180. doi: 10.1080/cac.10.4-6.173.180
96. Springer, J. E., Azbill, R. D., and Knapp, P. E. (1999). Activation of the caspase-3 apoptotic cascade in traumatic spinal cord injury. Nat. Med. 5, 943-946. doi: 10.1038/11387
97. Stehberg, J., Moraga-Amaro, R., Salazar, C., Becerra, A., Echeverrla, C., Orellana, J. A., et al. (2012). Release of gliotransmitters through astroglial connexin 43 hemichannels is necessary for fear memory consolidation in the basolateral amygdala. FASEB J. 26, 3649-3657. doi: 10.1096/fj.11-198416
98. Takeuchi, H., Jin, S., Wang, J., Zhang, G., Kawanokuchi, J., Kuno, R., et al. (2006). Tumor necrosis factor-a induces neurotoxicityvia glutamate release from hemichannels of activated microglia in an autocrine manner. J. Biol. Chem. 281, 21362-21368. doi: 10.1074/jbc.M600504200
99. Takeuchi, H., Mizoguchi, H., Doi, Y., Jin, S., Noda, M., Liang, J., et al. (2011). Blockade of gap junction hemichannel suppressess disease progression in mouse models of amyotrophic lateral sclerosis and Alzheimers disease. PLoS ONE 6:e21108. doi: 10.1371/journal.pone.0021108
100. Theriault, E., Frankenstein, U., Hertzberg, E., and Nagy, J. (1997). Con-nexin43 and astrocytic gap junctions in the rat spinal cord after acute compression injury. J. Comp. Neurol. 382, 199-214. doi: 10.1002/(SICI)1096-9861(19970602)382:2<199::AID-CNE5>3.0.CO;2-Z
101. Umebayashi, D., Natsume, A., Takeuchi, H., Hara, M., Nishimura, Y., Fukuyama, R., et al. (2014). Blockade of gap junction hemichannels protects secondary spinal cord injury from activated microglia mediated glutamate exitoneurotoxicity. J. Neurotrauma 21, 1-8. doi: 10.1089/neu.2013.3223
102. Wang, C. M., Lincoln, J., Cook, J. E., and Becker, D. L. (2007). Abnormal connexin expression underlies delayed wound healing in diabetic skin. Diabetes 56, 28092817. doi: 10.2337/db07-0613
103. Wang, X., Arcuino, G., Takano, T., Lin, J., Peng, W. G., Wan, P., et al. (2004). P2X7 receptor inhibition improves recovery after spinal cord injury. Nat. Med. 10, 821-827. doi: 10.1038/nm1082
104. Warner, A., Clements, D., Parikh, S., Evans, W., and Dehaan, R. (1995). Specific motifs in the external loops of connexin proteins can determine gap junction formation between chick heart myocytes. J. Physiol. 488, 721-728.
105. Wilson, J. M., Cowan, A. I., and Brownstone, R. M. (2007). Heterogeneous electrotonic coupling and synchronization of rhythmic bursting activity in mouse Hb9 interneurons. J. Neurophysiol. 98, 2370-2381. doi: 10.1152/jn.0033 8.2007
106. Wong, C. W., Christen, T., Roth, I., Chadjichristos, C. E., Derouette, J.-P., Foglia, B. F., et al. (2006). Connexin37 protects against atherosclerosis byregulating monocyte adhesion. Nat. Med. 12, 950-954. doi: 10.1038/nm1441
107. Woolf, C. J., and Mannion, R. J. (1999). Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353, 1959-1964. doi: 10.1016/S0140-6736(99)01307-0
108. Wu, A., Green, C. R., Rupenthal, I. D., and Moalem-Taylor, G. (2012). Role of gap junctions in chronic pain. J. Neurosci. Res. 90, 337-345. doi: 10.1002/jnr.22764
109. Yasui, K., Kada, K., Hojo, M., Lee, J.-K., Kamiya, K., Toyama, J., et al. (2000). Cell-to-cell interaction prevents cell death in cultured neonatal rat ventricular myocytes. Cardiovasc. Res. 48, 68-76. doi: 10.1016/S0008-6363(00)00145-0
110. Yates, C., Charlesworth, A., Allen, S., Reese, N., Skinner, R., and Garcia-Rill, E. (2008). The onset of hyperreflexia in the rat following complete spinal cord transection. Spinal Cord 46, 798-803. doi: 10.1038/sc.2008.49
111. Yates, C., Garrison, K., Reese, N. B., Charlesworth, A., and Garcia-Rill, E. (2011). Chapter 11-Novel mechanism for hyperreflexia and spasticity. Prog. Brain Res. 188, 167-180. doi: 10.1016/B978-0-444-53825-3.00016-4
112. Yeh, H. I., Lai, Y. J., Chang, H. M., Ko, Y. S., Severs, N. J., and Tsai, C. H. (2000). Multiple connexin expression in regenerating arterial endothelial gap junctions. Arterioscler. Thromb. Vasc. Biol. 20, 1753-1762. doi: 10.1161/01.ATV.20.7.1753
113. Yeh, H. I., Lupu, F., Dupont, E., and Severs, N. J. (1997). Upregulation of con-nexin43 gap junctions between smooth muscle cells after balloon catheter injury in the rat carotid artery. Arterioscler. Thromb. Vasc. Biol. 17, 3174-3184. doi: 10.1161/01.ATV.17.11.3174
114. Zhang, J., O'Carroll, S. J., Wu, A., Nicholson, L. F. B., and Green, C. R. (2010). A model for ex vivo spinal cord segment culture – a tool for analysis of injury repair strategies. J. Neurosci. Methods 192, 49-57. doi: 10.1016/j.jneumeth.2010.07.012