Table of Contents Author Guidelines Submit a Manuscript
Mediators of Inflammation
Volume 2015, Article ID 257471, 18 pages
http://dx.doi.org/10.1155/2015/257471
Review Article

Intracellular Cleavage of the Cx43 C-Terminal Domain by Matrix-Metalloproteases: A Novel Contributor to Inflammation?

1Physiology Group, Department of Basic Medical Sciences, Ghent University, 9000 Ghent, Belgium
2Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, 3000 Leuven, Belgium

Received 12 July 2015; Accepted 13 August 2015

Academic Editor: Mauro Prato

Copyright © 2015 Marijke De Bock et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. V. W. Yong, “Metalloproteinases: mediators of pathology and regeneration in the CNS,” Nature Reviews Neuroscience, vol. 6, no. 12, pp. 931–944, 2005. View at Publisher · View at Google Scholar · View at Scopus
  2. A. K. Chow, J. Cena, and R. Schulz, “Acute actions and novel targets of matrix metalloproteinases in the heart and vasculature,” British Journal of Pharmacology, vol. 152, no. 2, pp. 189–205, 2007. View at Publisher · View at Google Scholar · View at Scopus
  3. B. Cauwe and G. Opdenakker, “Intracellular substrate cleavage: a novel dimension in the biochemistry, biology and pathology of matrix metalloproteinases,” Critical Reviews in Biochemistry and Molecular Biology, vol. 45, no. 5, pp. 351–423, 2010. View at Publisher · View at Google Scholar · View at Scopus
  4. L. Nissinen and V.-M. Kähäri, “Matrix metalloproteinases in inflammation,” Biochimica et Biophysica Acta—General Subjects, vol. 1840, no. 8, pp. 2571–2580, 2014. View at Publisher · View at Google Scholar · View at Scopus
  5. R. Khokha, A. Murthy, and A. Weiss, “Metalloproteinases and their natural inhibitors in inflammation and immunity,” Nature Reviews Immunology, vol. 13, no. 9, pp. 649–665, 2013. View at Publisher · View at Google Scholar · View at Scopus
  6. M. Giannandrea and W. C. Parks, “Diverse functions of matrix metalloproteinases during fibrosis,” Disease Models and Mechanisms, vol. 7, no. 2, pp. 193–203, 2014. View at Publisher · View at Google Scholar · View at Scopus
  7. M. L. Lindsey, G. P. Escobar, R. Mukherjee et al., “Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction,” Circulation, vol. 113, no. 25, pp. 2919–2928, 2006. View at Publisher · View at Google Scholar · View at Scopus
  8. P. Van Lint and C. Libert, “Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation,” Journal of Leukocyte Biology, vol. 82, no. 6, pp. 1375–1381, 2007. View at Publisher · View at Google Scholar · View at Scopus
  9. A. Schubert-Unkmeir, C. Konrad, H. Slanina, F. Czapek, S. Hebling, and M. Frosch, “Neisseria meningitidis induces brain microvascular endothelial cell detachment from the matrix and cleavage of occludin: a role for MMP-8,” PLoS Pathogens, vol. 6, no. 4, Article ID e1000874, 2010. View at Publisher · View at Google Scholar · View at Scopus
  10. A. Reijerkerk, G. Kooij, S. M. A. Van Der Pol, S. Khazen, C. D. Dijkstra, and H. E. De Vries, “Diapedesis of monocytes is associated with MMP-mediated occludin disappearance in brain endothelial cells,” The FASEB Journal, vol. 20, no. 14, pp. 2550–2552, 2006. View at Publisher · View at Google Scholar · View at Scopus
  11. D.-Y. Lu, W.-H. Yu, W.-L. Yeh et al., “Hypoxia-induced matrix metalloproteinase-13 expression in astrocytes enhances permeability of brain endothelial cells,” Journal of Cellular Physiology, vol. 220, no. 1, pp. 163–173, 2009. View at Publisher · View at Google Scholar · View at Scopus
  12. D. Navaratna, P. G. McGuire, G. Menicucci, and A. Das, “Proteolytic degradation of VE-cadherin alters the blood-retinal barrier in diabetes,” Diabetes, vol. 56, no. 9, pp. 2380–2387, 2007. View at Publisher · View at Google Scholar · View at Scopus
  13. J. K. McGuire, Q. Li, and W. C. Parks, “Matrilysin (matrix metalloproteinase-7) mediates E-cadherin ectodomain shedding in injured lung epithelium,” The American Journal of Pathology, vol. 162, no. 6, pp. 1831–1843, 2003. View at Publisher · View at Google Scholar · View at Scopus
  14. Y. Ichikawa, T. Ishikawa, N. Momiyama et al., “Matrilysin (MMP-7) degrades VE-cadherin and accelerates accumulation of beta-catenin in the nucleus of human umbilical vein endothelial cells,” Oncology Reports, vol. 15, no. 2, pp. 311–315, 2006. View at Google Scholar · View at Scopus
  15. G. A. McQuibban, J.-H. Gong, E. M. Tam, C. A. G. McCulloch, I. Clark-Lewis, and C. M. Overall, “Inflammation dampened by gelatinase a cleavage of monocyte chemoattractant protein-3,” Science, vol. 289, no. 5482, pp. 1202–1206, 2000. View at Publisher · View at Google Scholar · View at Scopus
  16. A. Ito, A. Mukaiyama, Y. Itoh et al., “Degradation of interleukin 1beta by matrix metalloproteinases,” The Journal of Biological Chemistry, vol. 271, no. 25, pp. 14657–14660, 1996. View at Publisher · View at Google Scholar · View at Scopus
  17. Y.-P. Han, T.-L. Tuan, M. Hughes, H. Wu, and W. L. Garner, “Transforming growth factor-β- and tumor necrosis factor-α -mediated induction and proteolytic activation of MMP-9 in human skin,” Journal of Biological Chemistry, vol. 276, no. 25, pp. 22341–22350, 2001. View at Publisher · View at Google Scholar · View at Scopus
  18. T. Sakai, F. Kambe, H. Mitsuyama et al., “Tumor necrosis factor α induces expression of genes for matrix degradation in human chondrocyte-like HCS-2/8 cells through activation of NF-κB: abrogation of the tumor necrosis factor α effect by proteasome inhibitors,” Journal of Bone and Mineral Research, vol. 16, no. 7, pp. 1272–1280, 2001. View at Publisher · View at Google Scholar · View at Scopus
  19. M. P. Vincenti, C. I. Coon, and C. E. Brinckerhoff, “Nuclear factor κB/p50 activates an element in the distal matrix metalloproteinase 1 promoter in interleukin-1β-stimulated synovial fibroblasts,” Arthritis & Rheumatism, vol. 41, no. 11, pp. 1987–1994, 1998. View at Publisher · View at Google Scholar · View at Scopus
  20. F. Mannello, F. Luchetti, E. Falcieri, and S. Papa, “Multiple roles of matrix metalloproteinases during apoptosis,” Apoptosis, vol. 10, no. 1, pp. 19–24, 2005. View at Publisher · View at Google Scholar · View at Scopus
  21. R. E. Vandenbroucke and C. Libert, “Is there new hope for therapeutic matrix metalloproteinase inhibition?” Nature Reviews Drug Discovery, 2014. View at Publisher · View at Google Scholar · View at Scopus
  22. N. T. V. Le, M. Xue, L. A. Castelnoble, and C. J. Jackson, “The dual personalities of matrix metalloproteinases in inflammation,” Frontiers in Bioscience, vol. 12, no. 4, pp. 1475–1487, 2007. View at Publisher · View at Google Scholar · View at Scopus
  23. G. A. Rosenberg, “Matrix metalloproteinases in neuroinflammation,” Glia, vol. 39, no. 3, pp. 279–291, 2002. View at Publisher · View at Google Scholar · View at Scopus
  24. D. B. Alexander and G. S. Goldberg, “Transfer of biologically important molecules between cells through gap junction channels,” Current Medicinal Chemistry, vol. 10, no. 19, pp. 2045–2058, 2003. View at Publisher · View at Google Scholar · View at Scopus
  25. J. Neuhaus, A. Weimann, J.-U. Stolzenburg, H. Wolburg, L.-C. Horn, and W. Dorschner, “Smooth muscle cells from human urinary bladder express connexin 43 in vivo and in vitro,” World journal of urology, vol. 20, no. 4, pp. 250–254, 2002. View at Google Scholar · View at Scopus
  26. H. Miyoshi, M. B. Boyle, L. B. MacKay, and R. E. Garfield, “Voltage-clamp studies of gap junctions between uterine muscle cells during term and preterm labor,” Biophysical Journal, vol. 71, no. 3, pp. 1324–1334, 1996. View at Publisher · View at Google Scholar · View at Scopus
  27. L. Leybaert and M. J. Sanderson, “Intercellular Ca2+ waves: mechanisms and function,” Physiological Reviews, vol. 92, no. 3, pp. 1359–1392, 2012. View at Publisher · View at Google Scholar · View at Scopus
  28. N. Rouach, A. Koulakoff, V. Abudara, K. Willecke, and C. Giaume, “Astroglial metabolic networks sustain hippocampal synaptic transmission,” Science, vol. 322, no. 5907, pp. 1551–1555, 2008. View at Publisher · View at Google Scholar · View at Scopus
  29. C. Giaume, A. Tabernero, and J. M. Medina, “Metabolic trafficking through astrocytic gap junctions,” Glia, vol. 21, no. 1, pp. 114–123, 1997. View at Publisher · View at Google Scholar · View at Scopus
  30. M. Maes, E. Decrock, B. Cogliati et al., “Connexin and pannexin (hemi)channels in the liver,” Frontiers in Physiology, vol. 4, article 405, 2014. View at Publisher · View at Google Scholar · View at Scopus
  31. N. Batra, R. Kar, and J. X. Jiang, “Gap junctions and hemichannels in signal transmission, function and development of bone,” Biochimica et Biophysica Acta: Biomembranes, vol. 1818, no. 8, pp. 1909–1918, 2012. View at Publisher · View at Google Scholar · View at Scopus
  32. E. Decrock, D. V. Krysko, M. Vinken et al., “Transfer of IP3 through gap junctions is critical, but not sufficient, for the spread of apoptosis,” Cell Death and Differentiation, vol. 19, no. 6, pp. 947–957, 2012. View at Publisher · View at Google Scholar · View at Scopus
  33. D. L. Paul, L. Ebihara, L. J. Takemoto, K. I. Swenson, and D. A. Goodenough, “Connexin46, a novel lens gap junction protein, induces voltage-gated currents in nonjunctional plasma membrane of Xenopus oocytes,” The Journal of Cell Biology, vol. 115, no. 4, pp. 1077–1089, 1991. View at Publisher · View at Google Scholar · View at Scopus
  34. J. Kang, N. Kang, D. Lovatt et al., “Connexin 43 hemichannels are permeable to ATP,” The Journal of Neuroscience, vol. 28, no. 18, pp. 4702–4711, 2008. View at Publisher · View at Google Scholar · View at Scopus
  35. Z.-C. Ye, M. S. Wyeth, S. Baltan-Tekkok, and B. R. Ransom, “Functional hemichannels in astrocytes: a novel mechanism of glutamate release,” Journal of Neuroscience, vol. 23, no. 9, pp. 3588–3596, 2003. View at Google Scholar · View at Scopus
  36. S. Rana and R. Dringen, “Gap junction hemichannel-mediated release of glutathione from cultured rat astrocytes,” Neuroscience Letters, vol. 415, no. 1, pp. 45–48, 2007. View at Publisher · View at Google Scholar · View at Scopus
  37. D. A. Goodenough and D. L. Paul, “Beyond the gap: functions of unpaired connexon channels,” Nature Reviews Molecular Cell Biology, vol. 4, no. 4, pp. 285–294, 2003. View at Publisher · View at Google Scholar · View at Scopus
  38. J. X. Jiang and P. P. Cherian, “Hemichannels formed by connexin 43 play an important role in the release of prostaglandin E(2) by osteocytes in response to mechanical strain,” Cell Communication and Adhesion, vol. 10, pp. 259–264, 2003. View at Google Scholar
  39. J. A. Orellana, X. F. Figueroa, H. A. Sánchez, S. Contreras-Duarte, V. Velarde, and J. C. Sáez, “Hemichannels in the neurovascular unit and white matter under normal and inflamed conditions,” CNS and Neurological Disorders—Drug Targets, vol. 10, no. 3, pp. 404–414, 2011. View at Publisher · View at Google Scholar · View at Scopus
  40. C. D'hondt, J. Iyyathurai, B. Himpens, L. Leybaert, and G. Bultynck, “Cx43-hemichannel function and regulation in physiology and pathophysiology: insights from the bovine corneal endothelial cell system and beyond,” Frontiers in Physiology, vol. 5, article 348, 2014. View at Publisher · View at Google Scholar
  41. M. Kamermans, I. Fahrenfort, K. Schultz, U. Janssen-Bienhold, T. Sjoerdsma, and R. Weiler, “Hemichannel-mediated inhibition in the outer retina,” Science, vol. 292, no. 5519, pp. 1178–1180, 2001. View at Publisher · View at Google Scholar · View at Scopus
  42. R. Civitelli, “Cell-cell communication in the osteoblast/osteocyte lineage,” Archives of Biochemistry and Biophysics, vol. 473, no. 2, pp. 188–192, 2008. View at Publisher · View at Google Scholar · View at Scopus
  43. M. De Bock, M. Culot, N. Wang et al., “Connexin channels provide a target to manipulate brain endothelial calcium dynamics and blood-brain barrier permeability,” Journal of Cerebral Blood Flow and Metabolism, vol. 31, no. 9, pp. 1942–1957, 2011. View at Publisher · View at Google Scholar · View at Scopus
  44. R. T. R. Huckstepp, R. IdBihi, R. Eason et al., “Connexin hemichannel-mediated CO2-dependent release of ATP in the medulla oblongata contributes to central respiratory chemosensitivity,” The Journal of Physiology, vol. 588, no. 20, pp. 3901–3920, 2010. View at Publisher · View at Google Scholar · View at Scopus
  45. C. W. Wong, T. Christen, I. Roth et al., “Connexin37 protects against atherosclerosis by regulating monocyte adhesion,” Nature Medicine, vol. 12, no. 8, pp. 950–954, 2006. View at Publisher · View at Google Scholar · View at Scopus
  46. N. Karpuk, M. Burkovetskaya, T. Fritz, A. Angle, and T. Kielian, “Neuroinflammation leads to region-dependent alterations in astrocyte gap junction communication and hemichannel activity,” Journal of Neuroscience, vol. 31, no. 2, pp. 414–425, 2011. View at Publisher · View at Google Scholar · View at Scopus
  47. S. J. O'Carroll, M. Alkadhi, L. F. B. Nicholson, and C. R. Green, “Connexin43 mimetic peptides reduce swelling, astrogliosis, and neuronal cell death after spinal cord injury,” Cell Communication and Adhesion, vol. 15, no. 1-2, pp. 27–42, 2008. View at Publisher · View at Google Scholar · View at Scopus
  48. N. Wang, E. de Vuyst, R. Ponsaerts et al., “Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury,” Basic Research in Cardiology, vol. 108, no. 1, article 309, 2013. View at Publisher · View at Google Scholar · View at Scopus
  49. X. Wang, A. Ma, W. Zhu et al., “The role of connexin 43 and hemichannels correlated with the astrocytic death following ischemia/reperfusion insult,” Cellular and Molecular Neurobiology, vol. 33, no. 3, pp. 401–410, 2013. View at Publisher · View at Google Scholar · View at Scopus
  50. H. V. Danesh-Meyer, N. M. Kerr, J. Zhang et al., “Connexin43 mimetic peptide reduces vascular leak and retinal ganglion cell death following retinal ischaemia,” Brain, vol. 135, no. 2, pp. 506–520, 2012. View at Publisher · View at Google Scholar · View at Scopus
  51. H. V. Danesh-Meyer, R. Huang, L. F. B. Nicholson, and C. R. Green, “Connexin43 antisense oligodeoxynucleotide treatment down-regulates the inflammatory response in an in vitro interphase organotypic culture model of optic nerve ischaemia,” Journal of Clinical Neuroscience, vol. 15, no. 11, pp. 1253–1263, 2008. View at Publisher · View at Google Scholar · View at Scopus
  52. J. O. Davidson, C. R. Green, L. F. B. Nicholson et al., “Connexin hemichannel blockade improves outcomes in a model of fetal ischemia,” Annals of Neurology, vol. 71, no. 1, pp. 121–132, 2012. View at Publisher · View at Google Scholar · View at Scopus
  53. J. E. Contreras, H. A. Sánchez, L. P. Véliz, F. F. Bukauskas, M. V. L. Bennett, and J. C. Sáez, “Role of connexin-based gap junction channels and hemichannels in ischemia-induced cell death in nervous tissue,” Brain Research Reviews, vol. 47, no. 1–3, pp. 290–303, 2004. View at Publisher · View at Google Scholar · View at Scopus
  54. P. Bargiotas, H. Monyer, and M. Schwaninger, “Hemichannels in cerebral ischemia,” Current Molecular Medicine, vol. 9, no. 2, pp. 186–194, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. E. Decrock, E. De Vuyst, M. Vinken et al., “Connexin 43 hemichannels contribute to the propagation of apoptotic cell death in a rat C6 glioma cell model,” Cell Death and Differentiation, vol. 16, no. 1, pp. 151–163, 2009. View at Publisher · View at Google Scholar · View at Scopus
  56. D. W. Laird, “Life cycle of connexins in health and disease,” Biochemical Journal, vol. 394, no. 3, pp. 527–543, 2006. View at Publisher · View at Google Scholar · View at Scopus
  57. D. H. Choi, E.-M. Kim, H. J. Son et al., “A novel intracellular role of matrix metalloproteinase-3 during apoptosis of dopaminergic cells,” Journal of Neurochemistry, vol. 106, no. 1, pp. 405–415, 2008. View at Publisher · View at Google Scholar · View at Scopus
  58. B. Cauwe, E. Martens, P. Proost, and G. Opdenakker, “Multidimensional degradomics identifies systemic autoantigens and intracellular matrix proteins as novel gelatinase B/MMP-9 substrates,” Integrative Biology, vol. 1, no. 5-6, pp. 404–426, 2009. View at Publisher · View at Google Scholar · View at Scopus
  59. E. Hadler-Olsen, A. I. Solli, A. Hafstad, J.-O. Winberg, and L. Uhlin-Hansen, “Intracellular MMP-2 activity in skeletal muscle is associated with type II fibers,” Journal of Cellular Physiology, vol. 230, no. 1, pp. 160–169, 2015. View at Publisher · View at Google Scholar · View at Scopus
  60. G. Soslau, C. Mason, S. Lynch et al., “Intracellular matrix metalloproteinase-2 (MMP-2) regulates human platelet activation via hydrolysis of talin,” Thrombosis and Haemostasis, vol. 111, no. 1, pp. 140–153, 2013. View at Publisher · View at Google Scholar · View at Scopus
  61. G. Sawicki, E. J. Sanders, E. Salas, M. Wozniak, J. Rodrigo, and M. W. Radomski, “Localization and translocation of MMP-2 during aggregation of human platelets,” Thrombosis and Haemostasis, vol. 80, no. 5, pp. 836–839, 1998. View at Google Scholar · View at Scopus
  62. S.-T. Vilen, P. Nyberg, M. Hukkanen et al., “Intracellular co-localization of trypsin-2 and matrix metalloprotease-9: possible proteolytic cascade of trypsin-2, MMP-9 and enterokinase in carcinoma,” Experimental Cell Research, vol. 314, no. 4, pp. 914–926, 2008. View at Publisher · View at Google Scholar · View at Scopus
  63. G. Sawicki, “Intracellular regulation of matrix metalloproteinase-2 activity: new strategies in treatment and protection of heart subjected to oxidative stress,” Scientifica, vol. 2013, Article ID 130451, 12 pages, 2013. View at Publisher · View at Google Scholar
  64. E. R. Frears, Z. Zhang, D. R. Blake, J. P. O'Connell, and P. G. Winyard, “Inactivation of tissue inhibitor of metalloproteinase-1 by peroxynitrite,” FEBS Letters, vol. 381, no. 1-2, pp. 21–24, 1996. View at Publisher · View at Google Scholar · View at Scopus
  65. D. H. Lovett, R. Mahimkar, R. L. Raffai et al., “N-terminal truncated intracellular matrix metalloproteinase-2 induces cardiomyocyte hypertrophy, inflammation and systolic heart failure,” PLoS ONE, vol. 8, no. 7, Article ID e68154, 2013. View at Publisher · View at Google Scholar · View at Scopus
  66. M. A. M. Ali, A. K. Chow, A. D. Kandasamy et al., “Mechanisms of cytosolic targeting of matrix metalloproteinase-2,” Journal of Cellular Physiology, vol. 227, no. 10, pp. 3397–3404, 2012. View at Publisher · View at Google Scholar · View at Scopus
  67. D. Luo, B. Mari, I. Stoll, and P. Anglard, “Alternative splicing and promoter usage generates an intracellular stromelysin 3 isoform directly translated as an active matrix metalloproteinase,” The Journal of Biological Chemistry, vol. 277, no. 28, pp. 25527–25536, 2002. View at Publisher · View at Google Scholar · View at Scopus
  68. N. S. Fedarko, A. Jain, A. Karadag, and L. W. Fisher, “Three small integrin binding ligand N-linked glycoproteins (SIBLINGs) bind and activate specific matrix metalloproteinases,” The FASEB Journal, vol. 18, no. 6, pp. 734–736, 2004. View at Google Scholar · View at Scopus
  69. S. Giovannone, B. F. Remo, and G. I. Fishman, “Channeling diversity: gap junction expression in the heart,” Heart Rhythm, vol. 9, no. 7, pp. 1159–1162, 2012. View at Publisher · View at Google Scholar · View at Scopus
  70. S. Verheule and S. Kaese, “Connexin diversity in the heart: insights from transgenic mouse models,” Frontiers in Pharmacology, vol. 4, article 81, 2013. View at Publisher · View at Google Scholar · View at Scopus
  71. R. Liew, K. Khairunnisa, Y. Gu et al., “Role of tumor necrosis factor-alpha in the pathogenesis of atrial fibrosis and development of an arrhythmogenic substrate,” Circulation Journal, vol. 77, no. 5, pp. 1171–1179, 2013. View at Publisher · View at Google Scholar · View at Scopus
  72. J. Wang, J.-S. Li, H.-Z. Liu et al., “Dynamic alterations of connexin43, matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2 during ventricular fibrillation in canine,” Molecular and Cellular Biochemistry, vol. 391, no. 1-2, pp. 259–266, 2014. View at Publisher · View at Google Scholar · View at Scopus
  73. S. Givvimani, S. Kundu, N. Narayanan et al., “TIMP-2 mutant decreases MMP-2 activity and augments pressure overload induced LV dysfunction and heart failure,” Archives of Physiology and Biochemistry, vol. 119, no. 2, pp. 65–74, 2013. View at Publisher · View at Google Scholar · View at Scopus
  74. H.-J. Peng, D.-Z. Dai, H. Ji, and Y. Dai, “The separate roles of endothelin receptors participate in remodeling of matrix metalloproteinase and connexin 43 of cardiac fibroblasts in maladaptive response to isoproterenol,” European Journal of Pharmacology, vol. 634, no. 1–3, pp. 101–106, 2010. View at Publisher · View at Google Scholar · View at Scopus
  75. N. Tyagi, J. C. Vacek, S. Givvimani, U. Sen, and S. C. Tyagi, “Cardiac specific deletion of N-methyl-d-aspartate receptor 1 ameliorates mtMMP-9 mediated autophagy/mitophagy in hyperhomocysteinemia,” Journal of Receptors and Signal Transduction, vol. 30, no. 2, pp. 78–87, 2010. View at Publisher · View at Google Scholar · View at Scopus
  76. G. Mohammad and R. A. Kowluru, “Novel role of mitochondrial matrix metalloproteinase-2 in the development of diabetic retinopathy,” Investigative Ophthalmology and Visual Science, vol. 52, no. 6, pp. 3832–3841, 2011. View at Publisher · View at Google Scholar · View at Scopus
  77. S. Kundu, S. B. Pushpakumar, A. Tyagi, D. Coley, and U. Sen, “Hydrogen sulfide deficiency and diabetic renal remodeling: role of matrix metalloproteinase-9,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 304, no. 12, pp. E1365–E1378, 2013. View at Publisher · View at Google Scholar · View at Scopus
  78. X. Wu, W. Huang, G. Luo, and L. A. Alain, “Hypoxia induces connexin 43 dysregulation by modulating matrix metalloproteinases via MAPK signaling,” Molecular and Cellular Biochemistry, vol. 384, no. 1-2, pp. 155–162, 2013. View at Publisher · View at Google Scholar · View at Scopus
  79. J. Song, H. Tan, A. J. Perry et al., “PROSPER: an integrated feature-based tool for predicting protease substrate cleavage sites,” PLoS ONE, vol. 7, no. 11, Article ID e50300, 2012. View at Publisher · View at Google Scholar · View at Scopus
  80. J. Verspurten, K. Gevaert, W. Declercq, and P. Vandenabeele, “SitePredicting the cleavage of proteinase substrates,” Trends in Biochemical Sciences, vol. 34, no. 7, pp. 319–323, 2009. View at Publisher · View at Google Scholar · View at Scopus
  81. B. N. G. Giepmans, I. Verlaan, and W. H. Moolenaar, “Connexin-43 interactions with ZO-1 and alpha- and beta-tubulin,” Cell Communication and Adhesion, vol. 8, no. 4–6, pp. 219–223, 2001. View at Publisher · View at Google Scholar · View at Scopus
  82. S. Langlois, K. N. Cowan, Q. Shao, B. J. Cowan, and D. W. Laird, “Caveolin-1 and -2 interact with connexin43 and regulate gap junctional intercellular communication in keratinocytes,” Molecular Biology of the Cell, vol. 19, no. 3, pp. 912–928, 2008. View at Publisher · View at Google Scholar · View at Scopus
  83. A. Saidi Brikci-Nigassa, M.-J. Clement, T. Ha-Duong et al., “Phosphorylation controls the interaction of the connexin43 C-terminal domain with tubulin and microtubules,” Biochemistry, vol. 51, no. 21, pp. 4331–4342, 2012. View at Publisher · View at Google Scholar · View at Scopus
  84. M. A. Retamal, C. J. Cortés, L. Reuss, M. V. L. Bennett, and J. C. Sáez, “S-nitrosylation and permeation through connexin 43 hemichannels in astrocytes: induction by oxidant stress and reversal by reducing agents,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 12, pp. 4475–4480, 2006. View at Google Scholar · View at Scopus
  85. S. R. Johnstone, M. Billaud, A. W. Lohman, E. P. Taddeo, and B. E. Isakson, “Posttranslational modifications in connexins and pannexins,” Journal of Membrane Biology, vol. 245, no. 5-6, pp. 319–332, 2012. View at Publisher · View at Google Scholar · View at Scopus
  86. P. Yahuaca, J. F. Ek-Vitorin, P. Rush, M. Delmar, and S. M. Taffet, “Identification of a protein kinase activity that phosphorylates connexin43 in a pH-dependent manner,” Brazilian Journal of Medical and Biological Research, vol. 33, no. 4, pp. 399–406, 2000. View at Google Scholar · View at Scopus
  87. H. S. Duffy, P. L. Sorgen, M. E. Girvin et al., “pH-dependent intramolecular binding and structure involving Cx43 cytoplasmic domains,” The Journal of Biological Chemistry, vol. 277, no. 39, pp. 36706–36714, 2002. View at Publisher · View at Google Scholar · View at Scopus
  88. A. Seki, H. S. Duffy, W. Coombs, D. C. Spray, S. M. Taffet, and M. Delmar, “Modifications in the biophysical properties of connexin43 channels by a peptide of the cytoplasmic loop region,” Circulation Research, vol. 95, no. 4, pp. e22–e28, 2004. View at Publisher · View at Google Scholar · View at Scopus
  89. M. Delmar, W. Coombs, P. Sorgen, H. S. Duffy, and S. M. Taffet, “Structural bases for the chemical regulation of Connexin43 channels,” Cardiovascular Research, vol. 62, no. 2, pp. 268–275, 2004. View at Publisher · View at Google Scholar · View at Scopus
  90. J. F. Ek-Vitorín, G. Calero, G. E. Morley, W. Coombs, S. M. Taffet, and M. Delmar, “pH regulation of connexin43: molecular analysis of the gating particle,” Biophysical Journal, vol. 71, no. 3, pp. 1273–1284, 1996. View at Publisher · View at Google Scholar · View at Scopus
  91. F. F. Bukauskas, K. Jordan, A. Bukauskiene et al., “Clustering of connexin 43-enhanced green fluorescent protein gap junction channels and functional coupling in living cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 6, pp. 2556–2561, 2000. View at Publisher · View at Google Scholar · View at Scopus
  92. J. M. B. Anumonwo, S. M. Taffet, H. Gu, M. Chanson, A. P. Moreno, and M. Delmar, “The carboxyl terminal domain regulates the unitary conductance and voltage dependence of connexin40 gap junction channels,” Circulation Research, vol. 88, no. 7, pp. 666–673, 2001. View at Publisher · View at Google Scholar · View at Scopus
  93. A. P. Moreno, M. Chanson, J. Anumonwo et al., “Role of the carboxyl terminal of connexin43 in transjunctional fast voltage gating,” Circulation Research, vol. 90, no. 4, pp. 450–457, 2002. View at Publisher · View at Google Scholar · View at Scopus
  94. J. Shibayama, C. Gutiérrez, D. González et al., “Effect of charge substitutions at residue His-142 on voltage gating of connexin43 channels,” Biophysical Journal, vol. 91, no. 11, pp. 4054–4063, 2006. View at Publisher · View at Google Scholar · View at Scopus
  95. J. F. Ek, M. Delmar, R. Perzova, and S. M. Taffet, “Role of histidine 95 on pH gating of the cardiac gap junction protein connexin43,” Circulation Research, vol. 74, no. 6, pp. 1058–1064, 1994. View at Publisher · View at Google Scholar · View at Scopus
  96. N. Wang, M. De Bock, E. Decrock et al., “Connexin targeting peptides as inhibitors of voltage- and intracellular Ca2+-triggered Cx43 hemichannel opening,” Neuropharmacology, vol. 75, pp. 506–516, 2013. View at Publisher · View at Google Scholar · View at Scopus
  97. N. Wang, M. De Bock, G. Antoons et al., “Connexin mimetic peptides inhibit Cx43 hemichannel opening triggered by voltage and intracellular Ca2+ elevation,” Basic Research in Cardiology, vol. 107, article 304, 2012. View at Publisher · View at Google Scholar · View at Scopus
  98. E. De Vuyst, N. Wang, E. Decrock et al., “Ca2+ regulation of connexin 43 hemichannels in C6 glioma and glial cells,” Cell Calcium, vol. 46, no. 3, pp. 176–187, 2009. View at Publisher · View at Google Scholar · View at Scopus
  99. K. Shintani-Ishida, K. Uemura, and K.-I. Yoshida, “Hemichannels in cardiomyocytes open transiently during ischemia and contribute to reperfusion injury following brief ischemia,” American Journal of Physiology—Heart and Circulatory Physiology, vol. 293, no. 3, pp. H1714–H1720, 2007. View at Publisher · View at Google Scholar · View at Scopus
  100. R. Ponsaerts, E. De Vuyst, M. Retamal et al., “Intramolecular loop/tail interactions are essential for connexin 43-hemichannel activity,” The FASEB Journal, vol. 24, no. 11, pp. 4378–4395, 2010. View at Publisher · View at Google Scholar · View at Scopus
  101. R. Ponsaerts, C. D'hondt, F. Hertens et al., “RhoA GTPase switch controls Cx43-hemichannel activity through the contractile system,” PLoS ONE, vol. 7, no. 7, Article ID e42074, 2012. View at Publisher · View at Google Scholar · View at Scopus
  102. J. Iyyathurai, C. D'Hondt, N. Wang et al., “Peptides and peptide-derived molecules targeting the intracellular domains of Cx43: gap junctions versus hemichannels,” Neuropharmacology, vol. 75, pp. 491–505, 2013. View at Publisher · View at Google Scholar · View at Scopus
  103. M. M. Falk, “Cell-free synthesis for analyzing the membrane integration, oligomerization, and assembly characteristics of gap junction connexins,” Methods, vol. 20, no. 2, pp. 165–179, 2000. View at Publisher · View at Google Scholar · View at Scopus
  104. J. K. VanSlyke, C. C. Naus, and L. S. Musil, “Conformational maturation and post-er multisubunit assembly of gap junction proteins,” Molecular Biology of the Cell, vol. 20, no. 9, pp. 2451–2463, 2009. View at Publisher · View at Google Scholar · View at Scopus
  105. G. Gaietta, T. J. Deerinck, S. R. Adams et al., “Multicolor and electron microscopic imaging of connexin trafficking,” Science, vol. 296, no. 5567, pp. 503–507, 2002. View at Publisher · View at Google Scholar · View at Scopus
  106. P. D. Lampe and A. F. Lau, “The effects of connexin phosphorylation on gap junctional communication,” The International Journal of Biochemistry & Cell Biology, vol. 36, no. 7, pp. 1171–1186, 2004. View at Publisher · View at Google Scholar · View at Scopus
  107. K. Maass, J. Shibayama, S. E. Chase, K. Willecke, and M. Delmar, “C-terminal truncation of connexin43 changes number, size, and localization of cardiac gap junction plaques,” Circulation Research, vol. 101, no. 12, pp. 1283–1291, 2007. View at Publisher · View at Google Scholar · View at Scopus
  108. V. M. Unger, N. M. Kumar, N. B. Gilula, and M. Yeager, “Three-dimensional structure of a recombinant gap junction membrane channel,” Science, vol. 283, no. 5405, pp. 1176–1180, 1999. View at Publisher · View at Google Scholar · View at Scopus
  109. T.-C. Kang, D.-S. Kim, S.-E. Kwak et al., “Epileptogenic roles of astroglial death and regeneration in the dentate gyrus of experimental temporal lobe epilepsy,” Glia, vol. 54, no. 4, pp. 258–271, 2006. View at Publisher · View at Google Scholar · View at Scopus
  110. X.-Q. Gong, Q. Shao, S. Langlois, D. Bai, and D. W. Laird, “Differential potency of dominant negative connexin43 mutants in oculodentodigital dysplasia,” The Journal of Biological Chemistry, vol. 282, no. 26, pp. 19190–19202, 2007. View at Publisher · View at Google Scholar · View at Scopus
  111. A. Lai, D.-N. Le, W. A. Paznekas, W. D. Gifford, E. W. Jabs, and A. C. Charles, “Oculodentodigital dysplasia connexin43 mutations result in non-functional connexin hemichannels and gap junctions in C6 glioma cells,” Journal of Cell Science, vol. 119, no. 3, pp. 532–541, 2006. View at Publisher · View at Google Scholar · View at Scopus
  112. J. M. Churko, Q. Shao, X.-Q. Gong et al., “Human dermal fibroblasts derived from oculodentodigital dysplasia patients suggest that patients may have wound-healing defects,” Human Mutation, vol. 32, no. 4, pp. 456–466, 2011. View at Publisher · View at Google Scholar · View at Scopus
  113. H. M. Hong, J. J. Yang, J. C. Shieh, M. L. Lin, and S. Y. Li, “Novel mutations in the connexin43 (GJA1) and GJA1 pseudogene may contribute to nonsyndromic hearing loss,” Human Genetics, vol. 127, pp. 545–551, 2010. View at Google Scholar
  114. E. De Vuyst, E. Decrock, M. De Bock et al., “Connexin hemichannels and gap junction channels are differentially influenced by lipopolysaccharide and basic fibroblast growth factor,” Molecular Biology of the Cell, vol. 18, no. 1, pp. 34–46, 2007. View at Publisher · View at Google Scholar · View at Scopus
  115. I. Lübkemeier, R. P. Requardt, X. Lin et al., “Deletion of the last five C-terminal amino acid residues of connexin43 leads to lethal ventricular arrhythmias in mice without affecting coupling via gap junction channels,” Basic Research in Cardiology, vol. 108, article 348, 2013. View at Publisher · View at Google Scholar · View at Scopus
  116. M. G. Kozoriz, J. F. Bechberger, G. R. Bechberger et al., “The connexin43 C-terminal region mediates neuroprotection during stroke,” Journal of Neuropathology and Experimental Neurology, vol. 69, no. 2, pp. 196–206, 2010. View at Publisher · View at Google Scholar · View at Scopus
  117. G. E. Morley, S. M. Taffet, and M. Delmar, “Intramolecular interactions mediate pH regulation of connexin43 channels,” Biophysical Journal, vol. 70, no. 3, pp. 1294–1302, 1996. View at Publisher · View at Google Scholar · View at Scopus
  118. A. W. Hunter, R. J. Barker, C. Zhu, and R. G. Gourdie, “Zonula occludens-1 alters connexin43 gap junction size and organization by influencing channel accretion,” Molecular Biology of the Cell, vol. 16, no. 12, pp. 5686–5698, 2005. View at Publisher · View at Google Scholar · View at Scopus
  119. J. M. Rhett, J. Jourdan, and R. G. Gourdie, “Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1,” Molecular Biology of the Cell, vol. 22, no. 9, pp. 1516–1528, 2011. View at Publisher · View at Google Scholar · View at Scopus
  120. B. L. Soder, J. T. Propst, T. M. Brooks et al., “The connexin43 carboxyl-terminal peptide ACT1 modulates the biological response to silicone implants,” Plastic and Reconstructive Surgery, vol. 123, no. 5, pp. 1440–1451, 2009. View at Publisher · View at Google Scholar · View at Scopus
  121. G. S. Ghatnekar, C. L. Grek, D. G. Armstrong, S. C. Desai, and R. G. Gourdie, “The effect of a connexin43-based Peptide on the healing of chronic venous leg ulcers: a multicenter, randomized trial,” Journal of Investigative Dermatology, vol. 135, pp. 289–298, 2015. View at Publisher · View at Google Scholar · View at Scopus
  122. C. L. Grek, G. M. Prasad, V. Viswanathan, D. G. Armstrong, R. G. Gourdie, and G. S. Ghatnekar, “Topical administration of a connexin43-based peptide augments healing of chronic neuropathic diabetic foot ulcers: a multicenter, randomized trial,” Wound Repair and Regeneration, vol. 23, no. 2, pp. 203–212, 2015. View at Publisher · View at Google Scholar
  123. K. Moore, G. Ghatnekar, R. G. Gourdie, and J. D. Potts, “Impact of the controlled release of a connexin 43 peptide on corneal wound closure in an STZ model of type I diabetes,” PLoS ONE, vol. 9, no. 1, Article ID e86570, 2014. View at Publisher · View at Google Scholar · View at Scopus
  124. M. P. O'Quinn, J. A. Palatinus, B. S. Harris, K. W. Hewett, and R. G. Gourdie, “A peptide mimetic of the connexin43 carboxyl terminus reduces gap junction remodeling and induced arrhythmia following ventricular injury,” Circulation Research, vol. 108, no. 6, pp. 704–715, 2011. View at Publisher · View at Google Scholar · View at Scopus
  125. C. L. Grek, J. M. Rhett, J. S. Bruce, M. A. Abt, G. S. Ghatnekar, and E. S. Yeh, “Targeting connexin 43 with α–connexin carboxyl-terminal (ACT1) peptide enhances the activity of the targeted inhibitors, tamoxifen and lapatinib, in breast cancer: clinical implication for ACT1,” BMC Cancer, vol. 15, article 296, 2015. View at Publisher · View at Google Scholar
  126. M. F. Santiago, P. Alcami, K. M. Striedinger, D. C. Spray, and E. Scemes, “The carboxyl-terminal domain of connexin43 is a negative modulator of neuronal differentiation,” Journal of Biological Chemistry, vol. 285, no. 16, pp. 11836–11845, 2010. View at Publisher · View at Google Scholar · View at Scopus
  127. X. Dang, B. W. Doble, and E. Kardami, “The carboxy-tail of connexin-43 localizes to the nucleus and inhibits cell growth,” Molecular and Cellular Biochemistry, vol. 242, no. 1-2, pp. 35–38, 2003. View at Publisher · View at Google Scholar · View at Scopus
  128. C. Moorby and M. Patel, “Dual functions for connexins: Cx43 regulates growth independently of gap junction formation,” Experimental Cell Research, vol. 271, no. 2, pp. 238–248, 2001. View at Publisher · View at Google Scholar · View at Scopus
  129. M. Vinken, E. Decrock, L. Leybaert et al., “Non-channel functions of connexins in cell growth and cell death,” Biochimica et Biophysica Acta—Biomembranes, vol. 1818, no. 8, pp. 2002–2008, 2012. View at Publisher · View at Google Scholar · View at Scopus
  130. D. Johansen, V. Cruciani, R. Sundset, K. Ytrehus, and S.-O. Mikalsen, “Ischemia induces closure of gap junctional channels and opening of hemichannels in heart-derived cells and tissue,” Cellular Physiology and Biochemistry, vol. 28, no. 1, pp. 103–114, 2011. View at Publisher · View at Google Scholar · View at Scopus
  131. R. Joshi-Mukherjee, W. Coombs, C. Burrer, I. Alvarez de Mora, M. Delmar, and S. M. Taffet, “Evidence for the presence of a free C-Terminal fragment of Cx43 in cultured cells,” Cell Communication and Adhesion, vol. 14, no. 2-3, pp. 75–84, 2007. View at Publisher · View at Google Scholar · View at Scopus
  132. J. W. Smyth and R. M. Shaw, “Autoregulation of connexin43 gap junction formation by internally translated isoforms,” Cell Reports, vol. 5, no. 3, pp. 611–618, 2013. View at Publisher · View at Google Scholar · View at Scopus
  133. C. Salat-Canela, M. Sesé, C. Peula, S. Ramón Y Cajal, and T. Aasen, “Internal translation of the connexin 43 transcript,” Cell Communication and Signaling, vol. 12, article 31, 2014. View at Publisher · View at Google Scholar · View at Scopus
  134. C. Salat-Canela, M. Muñoz, M. Sesé, S. Ramón y Cajal, and T. Aasen, “Post-transcriptional regulation of connexins,” Biochemical Society Transactions, vol. 43, no. 3, pp. 465–470, 2015. View at Publisher · View at Google Scholar
  135. R. Schulz, P. M. Görge, A. Görbe, P. Ferdinandy, P. D. Lampe, and L. Leybaert, “Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection,” Pharmacology & Therapeutics, vol. 153, pp. 90–106, 2015. View at Publisher · View at Google Scholar
  136. G. Hawat, P. Hélie, and G. Baroudi, “Single intravenous low-dose injections of connexin 43 mimetic peptides protect ischemic heart in vivo against myocardial infarction,” Journal of Molecular and Cellular Cardiology, vol. 53, no. 4, pp. 559–566, 2012. View at Publisher · View at Google Scholar · View at Scopus
  137. J. J. Yoon, C. R. Green, S. J. O'Carroll, and L. F. B. Nicholson, “Dose-dependent protective effect of connexin43 mimetic peptide against neurodegeneration in an ex vivo model of epileptiform lesion,” Epilepsy Research, vol. 92, no. 2-3, pp. 153–162, 2010. View at Publisher · View at Google Scholar · View at Scopus
  138. Y.-S. Chen, I. Toth, H. V. Danesh-Meyer, C. R. Green, and I. D. Rupenthal, “Cytotoxicity and vitreous stability of chemically modified connexin43 mimetic peptides for the treatment of optic neuropathy,” Journal of Pharmaceutical Sciences, vol. 102, no. 7, pp. 2322–2331, 2013. View at Publisher · View at Google Scholar · View at Scopus
  139. J. A. Orellana, D. E. Hernández, P. Ezan et al., “Hypoxia in high glucose followed by reoxygenation in normal glucose reduces the viability of cortical astrocytes through increased permeability of connexin 43 hemichannels,” Glia, vol. 58, no. 3, pp. 329–343, 2010. View at Publisher · View at Google Scholar · View at Scopus
  140. D. Umebayashi, A. Natsume, H. Takeuchi et al., “Blockade of gap junction hemichannel protects secondary spinal cord injury from activated microglia-mediated glutamate exitoneurotoxicity,” Journal of Neurotrauma, vol. 31, no. 24, pp. 1967–1974, 2014. View at Publisher · View at Google Scholar · View at Scopus
  141. J. A. Orellana, K. F. Shoji, V. Abudara et al., “Amyloid β-induced death in neurons involves glial and neuronal hemichannels,” Journal of Neuroscience, vol. 31, no. 13, pp. 4962–4977, 2011. View at Publisher · View at Google Scholar · View at Scopus
  142. J. Shijie, H. Takeuchi, I. Yawata et al., “Blockade of glutamate release from microglia attenuates experimental autoimmune encephalomyelitis in mice,” Tohoku Journal of Experimental Medicine, vol. 217, no. 2, pp. 87–92, 2009. View at Publisher · View at Google Scholar · View at Scopus
  143. C. Huang, X. Han, X. Li et al., “Critical role of connexin 43 in secondary expansion of traumatic spinal cord injury,” Journal of Neuroscience, vol. 32, no. 10, pp. 3333–3338, 2012. View at Publisher · View at Google Scholar · View at Scopus
  144. M. V. L. Bennett, J. M. Garré, J. A. Orellana, F. F. Bukauskas, M. Nedergaard, and J. C. Sáez, “Connexin and pannexin hemichannels in inflammatory responses of glia and neurons,” Brain Research, vol. 1487, pp. 3–15, 2012. View at Publisher · View at Google Scholar · View at Scopus
  145. S. B. Shaikh, B. Uy, A. Perera, and L. F. B. Nicholson, “AGEs-RAGE mediated up-regulation of connexin43 in activated human microglial CHME-5 cells,” Neurochemistry International, vol. 60, no. 6, pp. 640–651, 2012. View at Publisher · View at Google Scholar · View at Scopus
  146. M. A. Retamal, N. Froger, N. Palacios-Prado et al., “Cx43 hemichannels and gap junction channels in astrocytes are regulated oppositely by proinflammatory cytokines released from activated microglia,” The Journal of Neuroscience, vol. 27, no. 50, pp. 13781–13792, 2007. View at Publisher · View at Google Scholar · View at Scopus
  147. M. Morita, C. Saruta, N. Kozuka et al., “Dual regulation of astrocyte gap junction hemichannels by growth factors and a pro-inflammatory cytokine via the mitogen-activated protein kinase cascade,” Glia, vol. 55, no. 5, pp. 508–515, 2007. View at Publisher · View at Google Scholar · View at Scopus
  148. J. Xiong, M. Burkovetskaya, N. Karpuk, and T. Kielian, “IL-1RI (interleukin-1 receptor type I) signalling is essential for host defence and hemichannel activity during acute central nervous system bacterial infection,” ASN Neuro, vol. 4, no. 3, 2012. View at Publisher · View at Google Scholar · View at Scopus
  149. N. Wang, M. De Bock, E. Decrock et al., “Paracrine signaling through plasma membrane hemichannels,” Biochimica et Biophysica Acta, vol. 1828, no. 1, pp. 35–50, 2013. View at Publisher · View at Google Scholar · View at Scopus
  150. G. Arcuino, J. H.-C. Lin, T. Takano et al., “Intercellular calcium signaling mediated by point-source burst release of ATP,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 15, pp. 9840–9845, 2002. View at Publisher · View at Google Scholar · View at Scopus
  151. C. Lecut, K. Frederix, D. M. Johnson et al., “P2X1 ion channels promote neutrophil chemotaxis through Rho kinase activation,” Journal of Immunology, vol. 183, no. 4, pp. 2801–2809, 2009. View at Publisher · View at Google Scholar · View at Scopus
  152. Y. Sumi, T. Woehrle, Y. Chen et al., “Plasma ATP is required for neutrophil activation in a mouse sepsis model,” Shock, vol. 42, no. 2, pp. 142–147, 2014. View at Publisher · View at Google Scholar · View at Scopus
  153. N. Riteau, P. Gasse, L. Fauconnier et al., “Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis,” American Journal of Respiratory and Critical Care Medicine, vol. 182, no. 6, pp. 774–783, 2010. View at Publisher · View at Google Scholar · View at Scopus
  154. Y. Chen, R. Corriden, Y. Inoue et al., “ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors,” Science, vol. 314, no. 5806, pp. 1792–1795, 2006. View at Publisher · View at Google Scholar · View at Scopus
  155. B. W. Calder, J. M. Rhett, H. Bainbridge, S. A. Fann, R. G. Gourdie, and M. J. Yost, “Inhibition of connexin 43 hemichannel-mediated ATP release attenuates early inflammation during the foreign body response,” Tissue Engineering Part A, vol. 21, no. 11-12, pp. 1752–1762, 2015. View at Publisher · View at Google Scholar
  156. H. K. Eltzschig, T. Eckle, A. Mager et al., “ATP release from activated neutrophils occurs via connexin 43 and modulates adenosine-dependent endothelial cell function,” Circulation Research, vol. 99, no. 10, pp. 1100–1108, 2006. View at Publisher · View at Google Scholar · View at Scopus
  157. H. K. Eltzschig, C. F. MacManus, and S. P. Colgan, “Neutrophils as sources of extracellular nucleotides: functional consequences at the vascular interface,” Trends in Cardiovascular Medicine, vol. 18, no. 3, pp. 103–107, 2008. View at Publisher · View at Google Scholar · View at Scopus
  158. A. Gombault, L. Baron, and I. Couillin, “ATP release and purinergic signaling in NLRP3 inflammasome activation,” Frontiers in Immunology, vol. 3, article 414, 2012. View at Publisher · View at Google Scholar · View at Scopus
  159. J. Robertson, S. Lang, P. A. Lambert, and P. E. Martin, “Peptidoglycan derived from Staphylococcus epidermidis induces Connexin43 hemichannel activity with consequences on the innate immune response in endothelial cells,” Biochemical Journal, vol. 432, no. 1, pp. 133–143, 2010. View at Publisher · View at Google Scholar · View at Scopus
  160. G. Chen, C.-K. Park, R.-G. Xie, T. Berta, M. Nedergaard, and R.-R. Ji, “Connexin-43 induces chemokine release from spinal cord astrocytes to maintain late-phase neuropathic pain in mice,” Brain, vol. 137, no. 8, pp. 2193–2209, 2014. View at Publisher · View at Google Scholar · View at Scopus
  161. J. Y. Lee, H. Y. Choi, and T. Y. Yune, “MMP-3 secreted from endothelial cells of blood vessels after spinal cord injury activates microglia, leading to oligodendrocyte cell death,” Neurobiology of Disease, vol. 82, pp. 141–151, 2015. View at Publisher · View at Google Scholar
  162. J. Y. Lee, H. Y. Choi, W. H. Na, B. G. Ju, and T. Y. Yune, “17β-estradiol inhibits MMP-9 and SUR1/TrpM4 expression and activation and thereby attenuates BSCB disruption/hemorrhage after spinal cord injury in male rats,” Endocrinology, vol. 156, no. 5, pp. 1838–1850, 2015. View at Publisher · View at Google Scholar
  163. B. Zinnhardt, T. Viel, L. Wachsmuth et al., “Multimodal imaging reveals temporal and spatial microglia and matrix metalloproteinase activity after experimental stroke,” Journal of Cerebral Blood Flow & Metabolism, 2015. View at Publisher · View at Google Scholar
  164. E. Pollock, M. Everest, A. Brown, and M. O. Poulter, “Metalloproteinase inhibition prevents inhibitory synapse reorganization and seizure genesis,” Neurobiology of Disease, vol. 70, pp. 21–31, 2014. View at Publisher · View at Google Scholar · View at Scopus
  165. H. Mizoguchi and K. Yamada, “Roles of matrix metalloproteinases and their targets in epileptogenesis and seizures,” Clinical Psychopharmacology and Neuroscience, vol. 11, no. 2, pp. 45–52, 2013. View at Publisher · View at Google Scholar · View at Scopus
  166. X. Zhang, M. Cheng, and S. K. Chintala, “Optic nerve ligation leads to astrocyte-associated matrix metalloproteinase-9 induction in the mouse retina,” Neuroscience Letters, vol. 356, no. 2, pp. 140–144, 2004. View at Publisher · View at Google Scholar · View at Scopus
  167. D. B. Corry, A. Kiss, L.-Z. Song et al., “Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell egression through decreased CC chemokines,” The FASEB Journal, vol. 18, no. 9, pp. 995–997, 2004. View at Publisher · View at Google Scholar · View at Scopus
  168. D. B. Corry, K. Rishi, J. Kanellis et al., “Decreased allergic lung inflammatory cell egression and increased susceptibility to asphyxiation in MMP2-deficiency,” Nature Immunology, vol. 3, no. 4, pp. 347–353, 2002. View at Publisher · View at Google Scholar · View at Scopus
  169. K. B. Deatrick, C. E. Luke, M. A. Elfline et al., “The effect of matrix metalloproteinase 2 and matrix metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling,” Journal of Vascular Surgery, vol. 58, no. 5, pp. 1375–e2, 2013. View at Publisher · View at Google Scholar · View at Scopus
  170. D. D. Cataldo, K. G. Tournoy, K. Vermaelen et al., “Matrix metalloproteinase-9 deficiency impairs cellular infiltration and bronchial hyperresponsiveness during allergen-induced airway inflammation,” The American Journal of Pathology, vol. 161, no. 2, pp. 491–498, 2002. View at Publisher · View at Google Scholar · View at Scopus
  171. A. Luttun, E. Lutgens, A. Manderveld et al., “Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth,” Circulation, vol. 109, no. 11, pp. 1408–1414, 2004. View at Publisher · View at Google Scholar · View at Scopus
  172. Q. Li, P. W. Park, C. L. Wilson, and W. C. Parks, “Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury,” Cell, vol. 111, no. 5, pp. 635–646, 2002. View at Publisher · View at Google Scholar · View at Scopus
  173. N. Mitsiades, W.-H. Yu, V. Poulaki, M. Tsokos, and I. Stamenkovic, “Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity,” Cancer Research, vol. 61, no. 2, pp. 577–581, 2001. View at Google Scholar · View at Scopus
  174. W. Tian and T. R. Kyriakides, “Matrix metalloproteinase-9 deficiency leads to prolonged foreign body response in the brain associated with increased IL-1beta levels and leakage of the blood-brain barrier,” Matrix Biology, vol. 28, no. 3, pp. 148–159, 2009. View at Publisher · View at Google Scholar · View at Scopus
  175. S. J. McMillan, J. Kearley, J. D. Campbell et al., “Matrix metalloproteinase-9 deficiency results in enhanced allergen-induced airway inflammation,” Journal of Immunology, vol. 172, no. 4, pp. 2586–2594, 2004. View at Publisher · View at Google Scholar · View at Scopus
  176. S. Lanone, T. Zheng, Z. Zhu et al., “Overlapping and enzyme-specific contributions of matrix metalloproteinases-9 and -12 in IL-13-induced inflammation and remodeling,” The Journal of Clinical Investigation, vol. 110, no. 4, pp. 463–474, 2002. View at Publisher · View at Google Scholar · View at Scopus
  177. P. J. Sáez, K. F. Shoji, M. A. Retamal et al., “ATP is required and advances cytokine-induced gap junction formation in microglia in vitro,” Mediators of Inflammation, vol. 2013, Article ID 216402, 16 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  178. N. Froger, J. A. Orellana, C.-F. Calvo et al., “Inhibition of cytokine-induced connexin43 hemichannel activity in astrocytes is neuroprotective,” Molecular and Cellular Neuroscience, vol. 45, no. 1, pp. 37–46, 2010. View at Publisher · View at Google Scholar · View at Scopus
  179. C.-Y. Wu, H.-L. Hsieh, C.-C. Sun, and C.-M. Yang, “IL-1β induces MMP-9 expression via a Ca2+-dependent CaMKII/JNK/c-Jun cascade in rat brain astrocytes,” Glia, vol. 57, no. 16, pp. 1775–1789, 2009. View at Publisher · View at Google Scholar · View at Scopus
  180. B. J. Hirst-Jensen, P. Sahoo, F. Kieken, M. Delmar, and P. L. Sorgen, “Characterization of the pH-dependent interaction between the gap junction protein connexin43 carboxyl terminus and cytoplasmic loop domains,” Journal of Biological Chemistry, vol. 282, no. 8, pp. 5801–5813, 2007. View at Publisher · View at Google Scholar · View at Scopus
  181. F. Liu, F. T. Arce, S. Ramachandran, and R. Lal, “Nanomechanics of hemichannel conformations: connexin flexibility underlying channel opening and closing,” Journal of Biological Chemistry, vol. 281, no. 32, pp. 23207–23217, 2006. View at Publisher · View at Google Scholar · View at Scopus
  182. E. Butkevich, S. Hülsmann, D. Wenzel, T. Shirao, R. Duden, and I. Majoul, “Drebrin is a novel connexin-43 binding partner that links gap junctions to the submembrane cytoskeleton,” Current Biology, vol. 14, no. 8, pp. 650–658, 2004. View at Publisher · View at Google Scholar · View at Scopus
  183. M. L. Vitale, C. D. Akpovi, and R.-M. Pelletier, “Cortactin/tyrosine-phosphorylated cortactin interaction with connexin 43 in mouse seminiferous tubules,” Microscopy Research and Technique, vol. 72, no. 11, pp. 856–867, 2009. View at Publisher · View at Google Scholar · View at Scopus
  184. G. Pidoux, P. Gerbaud, J. Dompierre et al., “A PKA-ezrin-Cx43 signaling complex controls gap junction communication and thereby trophoblast cell fusion,” Journal of Cell Science, vol. 127, no. 19, pp. 4172–4185, 2014. View at Publisher · View at Google Scholar · View at Scopus
  185. P. L. Sorgen, H. S. Duffy, P. Sahoo, W. Coombs, M. Delmar, and D. C. Spray, “Structural changes in the carboxyl terminus of the gap junction protein connexin43 indicates signaling between binding domains for c-Src and zonula occludens-1,” The Journal of Biological Chemistry, vol. 279, no. 52, pp. 54695–54701, 2004. View at Publisher · View at Google Scholar · View at Scopus
  186. Z. Lan, W. E. Kurata, K. D. Martyn, C. Jin, and A. F. Lau, “Novel Rab GAP-like protein, CIP85, interacts with connexin43 and induces its degradation,” Biochemistry, vol. 44, no. 7, pp. 2385–2396, 2005. View at Publisher · View at Google Scholar · View at Scopus
  187. C. S. Wun, J. F. Bechberger, W. J. Rushlow, and C. C. Naus, “Dose-dependent differential upregulation of CCN1/Cyr61 and CCN3/NOV by the gap junction protein connexin43 in glioma cells,” Journal of Cellular Biochemistry, vol. 103, no. 6, pp. 1772–1782, 2008. View at Publisher · View at Google Scholar · View at Scopus
  188. B. N. G. Giepmans and W. H. Moolenaar, “The gap junction protein connexin43 interacts with the second PDZ domain of the zona occludens-1 protein,” Current Biology, vol. 8, no. 16, pp. 931–934, 1998. View at Publisher · View at Google Scholar · View at Scopus
  189. R. Ponsaerts, N. Wang, B. Himpens, L. Leybaert, and G. Bultynck, “The contractile system as a negative regulator of the connexin 43 hemichannel,” Biology of the Cell, vol. 104, no. 7, pp. 367–377, 2012. View at Publisher · View at Google Scholar · View at Scopus
  190. G. Ermak and K. J. A. Davies, “Calcium and oxidative stress: from cell signaling to cell death,” Molecular Immunology, vol. 38, no. 10, pp. 713–721, 2002. View at Publisher · View at Google Scholar · View at Scopus
  191. S. Ramachandra, L.-H. Xie, S. A. John, S. Subramaniam, and R. Lal, “A novel role for connexin hemichannel in oxidative stress and smoking-induced cell injury,” PLoS ONE, vol. 2, no. 8, article e712, 2007. View at Publisher · View at Google Scholar · View at Scopus
  192. R. Kar, M. A. Riquelme, S. Werner, and J. X. Jiang, “Connexin 43 channels protect osteocytes against oxidative stress-induced cell death,” Journal of Bone and Mineral Research, vol. 28, no. 7, pp. 1611–1621, 2013. View at Publisher · View at Google Scholar · View at Scopus
  193. P. P. Cherian, A. J. Siller-Jackson, S. Gu et al., “Mechanical strain opens connexin 43 hemichannels in osteocytes: a novel mechanism for the release of prostaglandin,” Molecular Biology of the Cell, vol. 16, no. 7, pp. 3100–3106, 2005. View at Publisher · View at Google Scholar · View at Scopus
  194. L. I. Plotkin, S. C. Manolagas, and T. Bellido, “Transduction of cell survival signals by connexin-43 hemichannels,” The Journal of Biological Chemistry, vol. 277, no. 10, pp. 8648–8657, 2002. View at Publisher · View at Google Scholar · View at Scopus
  195. D. E. Lee, B. J. Shin, H. J. Hur et al., “Quercetin, the active phenolic component in kiwifruit, prevents hydrogen peroxide-induced inhibition of gap-junction intercellular communication,” British Journal of Nutrition, vol. 104, no. 2, pp. 164–170, 2010. View at Publisher · View at Google Scholar · View at Scopus
  196. A. A. Sovari, C. A. Rutledge, E.-M. Jeong et al., “Mitochondria oxidative stress, connexin43 remodeling, and sudden arrhythmic death,” Circulation: Arrhythmia and Electrophysiology, vol. 6, no. 3, pp. 623–631, 2013. View at Publisher · View at Google Scholar · View at Scopus
  197. G. R. John, E. Scemes, S. O. Suadicani et al., “IL-1β differentially regulates calcium wave propagation between primary human fetal astrocytes via pathways involving P2 receptors and gap junction channels,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 20, pp. 11613–11618, 1999. View at Publisher · View at Google Scholar · View at Scopus
  198. H. S. Duffy, G. R. John, S. C. Lee, C. F. Brosnan, and D. C. Spray, “Reciprocal regulation of the junctional proteins claudin-1 and connexin43 by interleukin-1beta in primary human fetal astrocytes,” The Journal of Neuroscience, vol. 20, Article ID RC114, 2000. View at Google Scholar · View at Scopus
  199. W. Même, P. Ezan, L. Venance, J. Glowinski, and C. Giaume, “ATP-induced inhibition of gap junctional communication is enhanced by interleukin-1 beta treatment in cultured astrocytes,” Neuroscience, vol. 126, no. 1, pp. 95–104, 2004. View at Publisher · View at Google Scholar · View at Scopus
  200. P. Castellano and E. A. Eugenin, “Regulation of gap junction channels by infectious agents and inflammation in the CNS,” Frontiers in Cellular Neuroscience, vol. 8, article 122, 2014. View at Publisher · View at Google Scholar · View at Scopus
  201. C. A. Kasper, I. Sorg, C. Schmutz et al., “Cell-cell propagation of NF-kappaB transcription factor and MAP kinase activation amplifies innate immunity against bacterial infection,” Immunity, vol. 33, no. 5, pp. 804–816, 2010. View at Publisher · View at Google Scholar · View at Scopus
  202. E. A. Eugenín, M. C. Brañes, J. W. Berman, and J. C. Sáez, “TNF-αα plus IFN-γ induce connexin43 expression and formation of gap junctions between human monocytes/macrophages that enhance physiological responses,” Journal of Immunology, vol. 170, no. 3, pp. 1320–1328, 2003. View at Publisher · View at Google Scholar · View at Scopus
  203. I. Feine, I. Pinkas, Y. Salomon, and A. Scherz, “Local oxidative stress expansion through endothelial cells—a key role for gap junction intercellular communication,” PLoS ONE, vol. 7, no. 7, Article ID e41633, 2012. View at Publisher · View at Google Scholar · View at Scopus
  204. J. Neijssen, C. Herberts, J. W. Drijfhout, E. Reits, L. Janssen, and J. Neefjes, “Cross-presentation by intercellular peptide transfer through gap junctions,” Nature, vol. 434, no. 7029, pp. 83–88, 2005. View at Publisher · View at Google Scholar · View at Scopus
  205. J.-C. Hervé, N. Bourmeyster, D. Sarrouilhe, and H. S. Duffy, “Gap junctional complexes: from partners to functions,” Progress in Biophysics and Molecular Biology, vol. 94, no. 1-2, pp. 29–65, 2007. View at Publisher · View at Google Scholar · View at Scopus
  206. A. Tabernero, E. Gangoso, M. Jaraíz-Rodríguez, and J. Medina, “The role of connexin43–Src interaction in astrocytomas: a molecular puzzle,” Neuroscience, 2015. View at Publisher · View at Google Scholar
  207. E. Scemes, N. Duval, and P. Meda, “Reduced expression of P2Y1 receptors in connexin43-null mice alters calcium signaling and migration of neural progenitor cells,” Journal of Neuroscience, vol. 23, no. 36, pp. 11444–11452, 2003. View at Google Scholar · View at Scopus
  208. E. Scemes, “Modulation of astrocyte P2Y1 receptors by the carboxyl terminal domain of the gap junction protein Cx43,” Glia, vol. 56, no. 2, pp. 145–153, 2008. View at Publisher · View at Google Scholar · View at Scopus
  209. M. W. M. Li, D. D. Mruk, and C. Y. Cheng, “Gap junctions and blood-tissue barriers,” Advances in Experimental Medicine and Biology, vol. 763, pp. 260–280, 2013. View at Publisher · View at Google Scholar · View at Scopus
  210. M. W. M. Li, D. D. Mruk, W. M. Lee, and C. Y. Cheng, “Connexin 43 is critical to maintain the homeostasis of the blood-testis barrier via its effects on tight junction reassembly,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 42, pp. 17998–18003, 2010. View at Publisher · View at Google Scholar · View at Scopus
  211. H. Morita, T. Katsuno, A. Hoshimoto, N. Hirano, Y. Saito, and Y. Suzuki, “Connexin 26-mediated gap junctional intercellular communication suppresses paracellular permeability of human intestinal epithelial cell monolayers,” Experimental Cell Research, vol. 298, no. 1, pp. 1–8, 2004. View at Publisher · View at Google Scholar · View at Scopus
  212. T. Kojima, M. Murata, M. Go, D. C. Spray, and N. Sawada, “Connexins induce and maintain tight junctions in epithelial cells,” Journal of Membrane Biology, vol. 217, no. 1–3, pp. 13–19, 2007. View at Publisher · View at Google Scholar · View at Scopus
  213. J.-C. Wu, R.-Y. Tsai, and T.-H. Chung, “Role of catenins in the development of gap junctions in rat cardiomyocytes,” Journal of Cellular Biochemistry, vol. 88, no. 4, pp. 823–835, 2003. View at Publisher · View at Google Scholar · View at Scopus
  214. C.-J. Wei, R. Francis, X. Xu, and C. W. Lo, “Connexin43 associated with an N-cadherin-containing multiprotein complex is required for gap junction formation in NIH3T3 cells,” The Journal of Biological Chemistry, vol. 280, no. 20, pp. 19925–19936, 2005. View at Publisher · View at Google Scholar · View at Scopus