Mechanisms linking connexin mutations to human diseases

Cell and Tissue Research

Volumn 360, Issue 3, 2015, Pages 701-721

  Kelly, John J ^a   Simek, Jamie ^a   Laird, Dale W ^a  

^a UNIVERSITY OF WESTERN ONTARIO   (Canada)

Author keywords

Connexins; Disease; Gap junctions; Mutations

Indexed keywords

CALCIUM; CALCIUM CHANNEL; GAP JUNCTION PROTEIN; MEMBRANE PROTEIN; PANNEXIN; UNCLASSIFIED DRUG;

CALCIUM HOMEOSTASIS; CARDIOVASCULAR DISEASE; CELL COMMUNICATION; CONGENITAL CATARACT; CRANIOMETAPHYSEAL DYSPLASIA; DYSPLASIA; GAP JUNCTION; GENE MUTATION; GENE SEQUENCE; HEARING IMPAIRMENT; HUMAN; MOLECULAR MECHANICS; MULTIGENE FAMILY; OCULODENTODIGITAL SYNDROME; OLIGODENDROGLIA; OLIGOMERIZATION; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FOLDING; QUALITY CONTROL; REVIEW; SCHWANN CELL; SEQUENCE HOMOLOGY; SKIN DISEASE; ANIMAL; CELL MEMBRANE; GENETIC DISEASES, INBORN; GENETIC PREDISPOSITION; GENETICS; METABOLISM; MUTATION; PATHOLOGY;

MAMMALIA;

ANIMALS; CELL MEMBRANE; CONNEXINS; GENETIC DISEASES, INBORN; GENETIC PREDISPOSITION TO DISEASE; HUMANS; MUTATION;

EID: 84930277263     PISSN: 0302766X     EISSN: 14320878     Source Type: Journal    
DOI: 10.1007/s00441-014-2024-4     Document Type: Review

References (237)

1. Abe S, Usami S, Shinkawa H, Kelley PM, Kimberling WJ (2000) Prevalent connexin 26 gene (GJB2) mutations in Japanese. J Med Genet 37:41–43
2. Abrams CK, Bennett MV, Verselis VK, Bargiello TA (2002) Voltage opens unopposed gap junction hemichannels formed by a connexin 32 mutant associated with X-linked Charcot-Marie-Tooth disease. Proc Natl Acad Sci U S A 99:3980–3984
3. Ahmad S, Tang W, Chang Q, Qu Y, Hibshman J, Li Y, Sohl G, Willecke K, Chen P, Lin X (2007) Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness. Proc Natl Acad Sci U S A 104:1337–1341
4. Aiuti A, Biasco L, Scaramuzza S, Ferrua F, Cicalese MP, Baricordi C, Dionisio F, Calabria A, Giannelli S, Castiello MC, Bosticardo M, Evangelio C, Assanelli A, Casiraghi M, Di Nunzio S, Callegaro L, Benati C, Rizzardi P, Pellin D, Di Serio C, Schmidt M, Von Kalle C, Gardner J, Mehta N, Neduva V, Dow DJ, Galy A, Miniero R, Finocchi A, Metin A, Banerjee PP, Orange JS, Galimberti S, Valsecchi MG, Biffi A, Montini E, Villa A, Ciceri F, Roncarolo MG, Naldini L (2013) Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 341:1233151
5. Akiyama M, Ishida N, Ogawa T, Yogo K, Takeya T (2005) Molecular cloning and functional analysis of a novel Cx43 partner protein CIP150. Biochem Biophys Res Commun 335:1264–1271
6. Alapure BV, Stull JK, Firtina Z, Duncan MK (2012) The unfolded protein response is activated in connexin 50 mutant mouse lenses. Exp Eye Res 102:28–37
7. Ammerpohl O, Trauzold A, Schniewind B, Griep U, Pilarsky C, Grutzmann R, Saeger HD, Janssen O, Sipos B, Kloppel G, Kalthoff H (2007) Complementary effects of HDAC inhibitor 4-PB on gap junction communication and cellular export mechanisms support restoration of chemosensitivity of PDAC cells. Br J Cancer 96:73–81
8. 2+ signals across the inner ear. Proc Natl Acad Sci U S A 105:18770–18775
9. Arora A, Minogue PJ, Liu X, Reddy MA, Ainsworth JR, Bhattacharya SS, Webster AR, Hunt DM, Ebihara L, Moore AT, Beyer EC, Berthoud VM (2006) A novel GJA8 mutation is associated with autosomal dominant lamellar pulverulent cataract: further evidence for gap junction dysfunction in human cataract. J Med Genet 43:e2
10. Arora A, Minogue PJ, Liu X, Addison PK, Russel-Eggitt I, Webster AR, Hunt DM, Ebihara L, Beyer EC, Berthoud VM, Moore AT (2008) A novel connexin50 mutation associated with congenital nuclear pulverulent cataracts. J Med Genet 45:155–160
11. Asklund T, Appelskog IB, Ammerpohl O, Ekstrom TJ, Almqvist PM (2004) Histone deacetylase inhibitor 4-phenylbutyrate modulates glial fibrillary acidic protein and connexin 43 expression, and enhances gap-junction communication, in human glioblastoma cells. Eur J Cancer 40:1073–1081
12. Auth T, Schluter S, Urschel S, Kussmann P, Sonntag S, Hoher T, Kreuzberg MM, Dobrowolski R, Willecke K (2009) The TSG101 protein binds to connexins and is involved in connexin degradation. Exp Cell Res 315:1053–1062
13. Bai D (2014) Atrial fibrillation-linked GJA5/connexin40 mutants impaired gap junctions via different mechanisms. FEBS Lett 588:1238–1243
14. Bao X, Chen Y, Reuss L, Altenberg GA (2004) Functional expression in xenopus oocytes of gap-junctional hemichannels formed by a cysteine-less connexin 43. J Biol Chem 279:9689–9692
15. Baranova A, Ivanov D, Petrash N, Pestova A, Skoblov M, Kelmanson I, Shagin D, Nazarenko S, Geraymovych E, Litvin O, Tiunova A, Born TL, Usman N, Staroverov D, Lukyanov S, Panchin Y (2004) The mammalian pannexin family is homologous to the invertebrate innexin gap junction proteins. Genomics 83:706–716
16. Bejarano E, Girao H, Yuste A, Patel B, Marques C, Spray DC, Pereira P, Cuervo AM (2012) Autophagy modulates dynamics of connexins at the plasma membrane in a ubiquitin-dependent manner. Mol Biol Cell 23:2156–2169
17. Beltramello M, Piazza V, Bukauskas FF, Pozzan T, Mammano F (2005) Impaired permeability to Ins(1,4,5)P3 in a mutant connexin underlies recessive hereditary deafness. Nat Cell Biol 7:63–69
18. Berger AC, Kelly JJ, Lajoie P, Shao Q, Laird DW (2014) Mutations in Cx30 that are linked to skin disease and non-syndromic hearing loss exhibit several distinct cellular pathologies. J Cell Sci 127:1751–1764
19. Bergoffen J, Scherer SS, Wang S, Scott MO, Bone LJ, Paul DL, Chen K, Lensch MW, Chance PF, Fischbeck KH (1993) Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science 262:2039–2042
20. Berthoud VM, Minogue PJ, Guo J, Williamson EK, Xu X, Ebihara L, Beyer EC (2003) Loss of function and impaired degradation of a cataract-associated mutant connexin50. Eur J Cell Biol 82:209–221
21. Berthoud VM, Minogue PJ, Yu H, Schroeder R, Snabb JI, Beyer EC (2013) Connexin50D47A decreases levels of fiber cell connexins and impairs lens fiber cell differentiation. Invest Ophthalmol Vis Sci 54:7614–7622
22. Beyer EC, Ebihara L, Berthoud VM (2013) Connexin mutants and cataracts. Front Pharmacol 4:43
23. Bhalla-Gehi R, Penuela S, Churko JM, Shao Q, Laird DW (2010) Pannexin1 and pannexin3 delivery, cell surface dynamics, and cytoskeletal interactions. J Biol Chem 285:9147–9160
24. Biancheri R, Rosano C, Denegri L, Lamantea E, Pinto F, Lanza F, Severino M, Filocamo M (2013) Expanded spectrum of Pelizaeus-Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form. Eur J Hum Genet 21:34–39
25. Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo WB, Mehta NA, Cicalese MP, Casiraghi M, Boelens JJ, Del Carro U, Dow DJ, Schmidt M, Assanelli A, Neduva V, Di Serio C, Stupka E, Gardner J, Von Kalle C, Bordignon C, Ciceri F, Rovelli A, Roncarolo MG, Aiuti A, Sessa M, Naldini L (2013) Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 341:1233158
26. Bikou O, Thomas D, Trappe K, Lugenbiel P, Kelemen K, Koch M, Soucek R, Voss F, Becker R, Katus HA, Bauer A (2011) Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model. Cardiovasc Res 92:218–225
27. Birkenhager R, Prera N, Aschendorff A, Laszig R, Arndt S (2014) A novel homozygous mutation in the EC1/EC2 interaction domain of the gap junction complex connexon 26 leads to profound hearing impairment. Biomed Res Int 2014:307976
28. Bitner-Glindzicz M (2002) Hereditary deafness and phenotyping in humans. Br Med Bull 63:73–94
29. Bond SR, Naus CC (2014) The pannexins: past and present. Front Physiol 5:58
30. Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, Yuan J (2005) A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 307:935–939
31. Bruzzone R, White TW, Scherer SS, Fischbeck KH, Paul DL (1994) Null mutations of connexin32 in patients with X-linked Charcot-Marie-Tooth disease. Neuron 13:1253–1260
32. Bruzzone R, Veronesi V, Gomes D, Bicego M, Duval N, Marlin S, Petit C, D’Andrea P, White TW (2003) Loss-of-function and residual channel activity of connexin26 mutations associated with non-syndromic deafness. FEBS Lett 533:79–88
33. Bukauskas FF, Verselis VK (2004) Gap junction channel gating. Biochim Biophys Acta 1662:42–60
34. Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, Vidaud M, Abel U, Dal-Cortivo L, Caccavelli L, Mahlaoui N, Kiermer V, Mittelstaedt D, Bellesme C, Lahlou N, Lefrère F, Blanche S, Audit M, Payen E, Leboulch P, l'Homme B, Bougnères P, Von Kalle C, Fischer A, Cavazzana-Calvo M, Aubourg P (2009) Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science 326:818–823
35. Castillo FJ del, Rodriguez-Ballesteros M, Alvarez A, Hutchin T, Leonardi E, Oliveira CAde, Azaiez H, Brownstein Z, Avenarius MR, Marlin S, Pandya A, Shahin H, Siemering KR, Weil D, Wuyts W, Aguirre LA, Martín Y, Moreno-Pelayo MA, Villamar M, Avraham KB, Dahl HH, Kanaan M, Nance WE, Petit C, Smith RJ, Van Camp G, Sartorato EL, Murgia A, Moreno F, Castillo I del (2005) A novel deletion involving the connexin-30 gene, del(GJB6-d13s1854), found in trans with mutations in the GJB2 gene (connexin-26) in subjects with DFNB1 non-syndromic hearing impairment. J Med Genet 42:588–594
36. Castillo I del, Villamar M, Moreno-Pelayo MA, Castillo FJ del, Alvarez A, Telleria D, Menendez I, Moreno F (2002) A deletion involving the connexin 30 gene in nonsyndromic hearing impairment. N Engl J Med 346:243–249
37. Chan DK, Chang KW (2014) GJB2-associated hearing loss: systematic review of worldwide prevalence, genotype, and auditory phenotype. Laryngoscope 124:E34–E53
38. Chang Q, Tang W, Ahmad S, Zhou B, Lin X (2008) Gap junction mediated intercellular metabolite transfer in the cochlea is compromised in connexin30 null mice. PLoS One 3:e4088
39. Chanoux RA, Rubenstein RC (2012) Molecular chaperones as targets to circumvent the CFTR defect in cystic fibrosis. Front Pharmacol 3:137
40. Chekeni FB, Elliott MR, Sandilos JK, Walk SF, Kinchen JM, Lazarowski ER, Armstrong AJ, Penuela S, Laird DW, Salvesen GS, Isakson BE, Bayliss DA, Ravichandran KS (2010) Pannexin 1 channels mediate “find-me” signal release and membrane permeability during apoptosis. Nature 467:863–867
41. Chen Y, Zhou Y, Lin X, Wong HC, Xu Q, Jiang J, Wang S, Lurtz MM, Louis CF, Veenstra RD, Yang JJ (2011) Molecular interaction and functional regulation of connexin50 gap junctions by calmodulin. Biochem J 435:711–722
42. Chi J, Li L, Liu M, Tan J, Tang C, Pan Q, Wang D, Zhang Z (2012) Pathogenic connexin-31 forms constitutively active hemichannels to promote necrotic cell death. PLoS One 7:e32531
43. Christophersen IE, Holmegard HN, Jabbari J, Sajadieh A, Haunso S, Tveit A, Svendsen JH, Olesen MS (2013) Rare variants in GJA5 are associated with early-onset lone atrial fibrillation. Can J Cardiol 29:111–116
44. Churko JM, Langlois S, Pan X, Shao Q, Laird DW (2010) The potency of the fs260 connexin43 mutant to impair keratinocyte differentiation is distinct from other disease-linked connexin43 mutants. Biochem J 429:473–483
45. Cohen-Salmon M, Ott T, Michel V, Hardelin JP, Perfettini I, Eybalin M, Wu T, Marcus DC, Wangemann P, Willecke K, Petit C (2002) Targeted ablation of connexin26 in the inner ear epithelial gap junction network causes hearing impairment and cell death. Curr Biol 12:1106–1111
46. Cohn ES, Kelley PM, Fowler TW, Gorga MP, Lefkowitz DM, Kuehn HJ, Schaefer GB, Gobar LS, Hahn FJ, Harris DJ, Kimberling WJ (1999) Clinical studies of families with hearing loss attributable to mutations in the connexin 26 gene (GJB2/DFNB1). Pediatrics 103:546–550
47. Common JE, Bitner-Glindzicz M, O’Toole EA, Barnes MR, Jenkins L, Forge A, Kelsell DP (2005) Specific loss of connexin 26 expression in ductal sweat gland epithelium associated with the deletion mutation del(GJB6-D13S1830). Clin Exp Dermatol 30:688–693
48. Coutinho P, Qiu C, Frank S, Tamber K, Becker D (2003) Dynamic changes in connexin expression correlate with key events in the wound healing process. Cell Biol Int 27:525–541
49. Crispino G, Di Pasquale G, Scimemi P, Rodriguez L, Galindo Ramirez F, De Siati RD, Santarelli RM, Arslan E, Bortolozzi M, Chiorini JA, Mammano F (2011) BAAV mediated GJB2 gene transfer restores gap junction coupling in cochlear organotypic cultures from deaf Cx26Sox10Cre mice. PLoS One 6:e23279
50. Cronin M, Anderson PN, Green CR, Becker DL (2006) Antisense delivery and protein knockdown within the intact central nervous system. Front Biosci 11:2967–2975
51. Cronin M, Anderson PN, Cook JE, Green CR, Becker DL (2008) Blocking connexin43 expression reduces inflammation and improves functional recovery after spinal cord injury. Mol Cell Neurosci 39:152–160
52. Dai P, Nakagami T, Tanaka H, Hitomi T, Takamatsu T (2007) Cx43 mediates TGF-beta signaling through competitive smads binding to microtubules. Mol Biol Cell 18:2264–2273
53. Das Sarma J, Das S, Koval M (2005) Regulation of connexin43 oligomerization is saturable. Cell Commun Adhes 12:237–247
54. Das Sarma J, Kaplan BE, Willemsen D, Koval M (2008) Identification of rab20 as a potential regulator of connexin 43 trafficking. Cell Commun Adhes 15:65–74
55. Das S, Smith TD, Sarma JD, Ritzenthaler JD, Maza J, Kaplan BE, Cunningham LA, Suaud L, Hubbard MJ, Rubenstein RC, Koval M (2009) ERp29 restricts connexin43 oligomerization in the endoplasmic reticulum. Mol Biol Cell 20:2593–2604
56. Degen J, Schutz M, Dicke N, Strenzke N, Jokwitz M, Moser T, Willecke K (2011) Connexin32 can restore hearing in connexin26 deficient mice. Eur J Cell Biol 90:817–824
57. Delmar M, Coombs W, Sorgen P, Duffy HS, Taffet SM (2004) Structural bases for the chemical regulation of connexin43 channels. Cardiovasc Res 62:268–275
58. Deschenes SM, Walcott JL, Wexler TL, Scherer SS, Fischbeck KH (1997) Altered trafficking of mutant connexin32. J Neurosci 17:9077–9084
59. Di WL, Rugg EL, Leigh IM, Kelsell DP (2001) Multiple epidermal connexins are expressed in different keratinocyte subpopulations including connexin 31. J Invest Dermatol 117:958–964
60. Di WL, Monypenny J, Common JE, Kennedy CT, Holland KA, Leigh IM, Rugg EL, Zicha D, Kelsell DP (2002) Defective trafficking and cell death is characteristic of skin disease-associated connexin 31 mutations. Hum Mol Genet 11:2005–2014
61. Diestel S, Richard G, Doring B, Traub O (2002) Expression of a connexin31 mutation causing erythrokeratodermia variabilis is lethal for HeLa cells. Biochem Biophys Res Commun 296:721–728
62. Diez JA, Ahmad S, Evans WH (1999) Assembly of heteromeric connexons in guinea-pig liver en route to the Golgi apparatus, plasma membrane and gap junctions. Eur J Biochem 262:142–148
63. Dobrowolski R, Sommershof A, Willecke K (2007) Some oculodentodigital dysplasia-associated Cx43 mutations cause increased hemichannel activity in addition to deficient gap junction channels. J Membr Biol 219:9–17
64. 2+ homeostasis, Abeta levels, and Alzheimer’s disease risk. Cell 133:1149–1161
65. Essenfelder GM, Bruzzone R, Lamartine J, Charollais A, Blanchet-Bardon C, Barbe MT, Meda P, Waksman G (2004) Connexin30 mutations responsible for hidrotic ectodermal dysplasia cause abnormal hemichannel activity. Hum Mol Genet 13:1703–1714
66. Falk MM, Kumar NM, Gilula NB (1994) Membrane insertion of gap junction connexins: polytopic channel forming membrane proteins. J Cell Biol 127:343–355
67. Falk MM, Fong JT, Kells RM, O’Laughlin MC, Kowal TJ, Thevenin AF (2012) Degradation of endocytosed gap junctions by autophagosomal and endo-/lysosomal pathways: a perspective. J Membr Biol 245:465–476
68. Fong JT, Kells RM, Gumpert AM, Marzillier JY, Davidson MW, Falk MM (2012) Internalized gap junctions are degraded by autophagy. Autophagy 8:794–811
69. Foote CI, Zhou L, Zhu X, Nicholson BJ (1998) The pattern of disulfide linkages in the extracellular loop regions of connexin 32 suggests a model for the docking interface of gap junctions. J Cell Biol 140:1187–1197
70. Forge A, Becker D, Casalotti S, Edwards J, Marziano N, Nevill G (2003a) Gap junctions in the inner ear: comparison of distribution patterns in different vertebrates and assessement of connexin composition in mammals. J Comp Neurol 467:207–231
71. Forge A, Marziano NK, Casalotti SO, Becker DL, Jagger D (2003b) The inner ear contains heteromeric channels composed of cx26 and cx30 and deafness-related mutations in cx26 have a dominant negative effect on cx30. Cell Commun Adhes 10:341–346
72. Forge A, Jagger DJ, Kelly JJ, Taylor RR (2013) Connexin30-mediated intercellular communication plays an essential role in epithelial repair in the cochlea. J Cell Sci 126:1703–1712
73. Frischmeyer PA, Dietz HC (1999) Nonsense-mediated mRNA decay in health and disease. Hum Mol Genet 8:1893–1900
74. Gaietta G, Deerinck TJ, Adams SR, Bouwer J, Tour O, Laird DW, Sosinsky GE, Tsien RY, Ellisman MH (2002) Multicolor and electron microscopic imaging of connexin trafficking. Science 296:503–507
75. Gao J, Sun X, Moore LC, White TW, Brink PR, Mathias RT (2011) Lens intracellular hydrostatic pressure is generated by the circulation of sodium and modulated by gap junction coupling. J Gen Physiol 137:507–520
76. Geel M van, Steensel MA van, Steijlen PM (2002) Connexin 30.3 (GJB4) is not required for normal skin function in humans. Br J Dermatol 147:1275–1277
77. Gemel J, Valiunas V, Brink PR, Beyer EC (2004) Connexin43 and connexin26 form gap junctions, but not heteromeric channels in co-expressing cells. J Cell Sci 117:2469–2480
78. Gemel J, Simon AR, Patel D, Xu Q, Matiukas A, Veenstra RD, Beyer EC (2014) Degradation of a connexin40 mutant linked to atrial fibrillation is accelerated. J Mol Cell Cardiol 74:330–339
79. Gerido DA, DeRosa AM, Richard G, White TW (2007) Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness. Am J Physiol Cell Physiol 293:C337–C345
80. Ghatnekar GS, O’Quinn MP, Jourdan LJ, Gurjarpadhye AA, Draughn RL, Gourdie RG (2009) Connexin43 carboxyl-terminal peptides reduce scar progenitor and promote regenerative healing following skin wounding. Regen Med 4:205–23
81. Ghatnekar G, Grek C, Armstrong DG, Desai SC, Gourdie R (2014) The effect of a Connexin43-based peptide on the healing of chronic venous leg ulcers: a multicenter, randomized trial. J Invest Dermatol (in press)
82. Giepmans BN, Verlaan I, Hengeveld T, Janssen H, Calafat J, Falk MM, Moolenaar WH (2001a) Gap junction protein connexin-43 interacts directly with microtubules. Curr Biol 11:1364–1368
83. Giepmans BN, Verlaan I, Moolenaar WH (2001b) Connexin-43 interactions with ZO-1 and alpha- and beta-tubulin. Cell Commun Adhes 8:219–223
84. Gollob MH, Jones DL, Krahn AD, Danis L, Gong XQ, Shao Q, Liu X, Veinot JP, Tang AS, Stewart AF, Tesson F, Klein GJ, Yee R, Skanes AC, Guiraudon GM, Ebihara L, Bai D (2006) Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation. N Engl J Med 354:2677–2688
85. Gomez-Hernandez JM, Miguel M de, Larrosa B, Gonzalez D, Barrio LC (2003) Molecular basis of calcium regulation in connexin-32 hemichannels. Proc Natl Acad Sci U S A 100:16030–16035
86. Gong T, Wang Q, Lin Z, Chen ML, Sun GZ (2012) Endoplasmic reticulum (ER) stress inhibitor salubrinal protects against ceramide-induced SH-SY5Y cell death. Biochem Biophys Res Commun 427:461–465
87. Gong XQ, Shao Q, Lounsbury CS, Bai D, Laird DW (2006) Functional characterization of a GJA1 frameshift mutation causing oculodentodigital dysplasia and palmoplantar keratoderma. J Biol Chem 281:31801–31811
88. Gong XQ, Nakagawa S, Tsukihara T, Bai D (2013) A mechanism of gap junction docking revealed by functional rescue of a human-disease-linked connexin mutant. J Cell Sci 126:3113–3120
89. Gourdie RG, Severs NJ, Green CR, Rothery S, Germroth P, Thompson RP (1993) The spatial distribution and relative abundance of gap-junctional connexin40 and connexin43 correlate to functional properties of components of the cardiac atrioventricular conduction system. J Cell Sci 105:985–991
90. Gray KA, Daugherty LC, Gordon SM, Seal RL, Wright MW, Bruford EA (2013) Genenames.org: the HGNC resources in 2013. Nucleic Acids Res 41:D545–D552
91. Harris AL (2001) Emerging issues of connexin channels: biophysics fills the gap. Q Rev Biophys 34:325–472
92. He LQ, Liu Y, Cai F, Tan ZP, Pan Q, Liang DS, Long ZG, Wu LQ, Huang LQ, Dai HP, Xia K, Xia JH, Zhang ZH (2005) Intracellular distribution, assembly and effect of disease-associated connexin 31 mutants in HeLa cells. Acta Biochim Biophys Sin (Shanghai) 37:547–554
93. Hetz C, Chevet E, Harding HP (2013) Targeting the unfolded protein response in disease. Nat Rev Drug Discov 12:703–719
94. Hilgert N, Smith RJ, Van Camp G (2009) Function and expression pattern of nonsyndromic deafness genes. Curr Mol Med 9:546–564
95. Hoang Dinh E, Ahmad S, Chang Q, Tang W, Stong B, Lin X (2009) Diverse deafness mechanisms of connexin mutations revealed by studies using in vitro approaches and mouse models. Brain Res 1277:52–69
96. Hong HM, Yang JJ, Shieh JC, Lin ML, Li SY (2010a) Novel mutations in the connexin43 (GJA1) and GJA1 pseudogene may contribute to nonsyndromic hearing loss. Hum Genet 127:545–551
97. Hong HM, Yang JJ, Su CC, Chang JY, Li TC, Li SY (2010b) A novel mutation in the connexin 29 gene may contribute to nonsyndromic hearing loss. Hum Genet 127:191–199
98. Hu Y, Chen IP, Almeida S de, Tiziani V, Do Amaral CM, Gowrishankar K, Passos-Bueno MR, Reichenberger EJ (2013) A novel autosomal recessive GJA1 missense mutation linked to craniometaphyseal dysplasia. PLoS One 8:e73576
99. Huang T, Shao Q, MacDonald A, Xin L, Lorentz R, Bai D, Laird DW (2013) Autosomal recessive GJA1 (Cx43) gene mutations cause oculodentodigital dysplasia by distinct mechanisms. J Cell Sci 126:2857–2866
100. Igarashi T, Finet JE, Takeuchi A, Fujino Y, Strom M, Greener ID, Rosenbaum DS, Donahue JK (2012) Connexin gene transfer preserves conduction velocity and prevents atrial fibrillation. Circulation 125:216–225
101. Inoshita A, Karasawa K, Funakubo M, Miwa A, Ikeda K, Kamiya K (2014) Dominant negative connexin26 mutation R75W causing severe hearing loss influences normal programmed cell death in postnatal organ of Corti. BMC Genet 15:1
102. Jagger DJ, Forge A (2006) Compartmentalized and signal-selective gap junctional coupling in the hearing cochlea. J Neurosci 26:1260–1268
103. Jagger DJ, Nevill G, Forge A (2010) The membrane properties of cochlear root cells are consistent with roles in potassium recirculation and spatial buffering. J Assoc Res Otolaryngol 11:435–448
104. Jiang JX, Paul DL, Goodenough DA (1993) Posttranslational phosphorylation of lens fiber connexin46: a slow occurrence. Invest Ophthalmol Vis Sci 34:3558–3565
105. Kaufman J, Gordon C, Bergamaschi R, Wang HZ, Cohen IS, Valiunas V, Brink PR (2013) The effects of the histone deacetylase inhibitor 4-phenylbutyrate on gap junction conductance and permeability. Front Pharmacol 4:111
106. Kelley PM, Harris DJ, Comer BC, Askew JW, Fowler T, Smith SD, Kimberling WJ (1998) Novel mutations in the connexin 26 gene (GJB2) that cause autosomal recessive (DFNB1) hearing loss. Am J Hum Genet 62:792–799
107. Kelly JJ, Forge A, Jagger DJ (2011) Development of gap junctional intercellular communication within the lateral wall of the rat cochlea. Neuroscience 180:360–369
108. Khan Z, Akhtar M, Asklund T, Juliusson B, Almqvist PM, Ekstrom TJ (2007) HDAC inhibition amplifies gap junction communication in neural progenitors: potential for cell-mediated enzyme prodrug therapy. Exp Cell Res 313:2958–2967
109. Kikuchi T, Kimura RS, Paul DL, Adams JC (1995) Gap junctions in the rat cochlea: immunohistochemical and ultrastructural analysis. Anat Embryol (Berl) 191:101–118
110. Kleopa KA (2011) The role of gap junctions in Charcot-Marie-Tooth disease. J Neurosci 31:17753–17760
111. Kleopa KA, Abrams CK, Scherer SS (2012) How do mutations in GJB1 cause X-linked Charcot-Marie-Tooth disease? Brain Res 1487:198–205
112. Kochanek KD, Xu J, Murphy SL, Minino AM, Kung HC (2011) Deaths: final data for 2009. Natl Vital Stat Rep 60:1–116
113. Koval M (2006) Pathways and control of connexin oligomerization. Trends Cell Biol 16:159–166
114. Koval M, Harley JE, Hick E, Steinberg TH (1997) Connexin46 is retained as monomers in a trans-Golgi compartment of osteoblastic cells. J Cell Biol 137:847–857
115. Koval M, Molina SA, Burt JM (2014) Mix and match: investigating heteromeric and heterotypic gap junction channels in model systems and native tissues. FEBS Lett 588:1193–1204
116. Kudo T, Ikeda K, Kure S, Matsubara Y, Oshima T, Watanabe K, Kawase T, Narisawa K, Takasaka T (2000) Novel mutations in the connexin 26 gene (GJB2) responsible for childhood deafness in the Japanese population. Am J Med Genet 90:141–145
117. Kudo T, Kure S, Ikeda K, Xia AP, Katori Y, Suzuki M, Kojima K, Ichinohe A, Suzuki Y, Aoki Y, Kobayashi T, Matsubara Y (2003) Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness. Hum Mol Genet 12:995–1004
118. Kumar NM, Gilula NB (1992) Molecular biology and genetics of gap junction channels. Semin Cell Biol 3:3–16
119. Lagree V, Brunschwig K, Lopez P, Gilula NB, Richard G, Falk MM (2003) Specific amino-acid residues in the N-terminus and TM3 implicated in channel function and oligomerization compatibility of connexin43. J Cell Sci 116:3189–3201
120. Laird DW (2006) Life cycle of connexins in health and disease. Biochem J 394:527–543
121. Laird DW (2010) The gap junction proteome and its relationship to disease. Trends Cell Biol 20:92–101
122. Laird DW (2014) Syndromic and non-syndromic disease-linked Cx43 mutations. FEBS Lett 588:1339–1348
123. Laird DW, Castillo M, Kasprzak L (1995) Gap junction turnover, intracellular trafficking, and phosphorylation of connexin43 in brefeldin A-treated rat mammary tumor cells. J Cell Biol 131:1193–1203
124. Lan Z, Kurata WE, Martyn KD, Jin C, Lau AF (2005) Novel rab GAP-like protein, CIP85, interacts with connexin43 and induces its degradation. Biochemistry 44:2385–2396
125. Langlois S, Cowan KN, Shao Q, Cowan BJ, Laird DW (2008) Caveolin-1 and −2 interact with connexin43 and regulate gap junctional intercellular communication in keratinocytes. Mol Biol Cell 19:912–928
126. Lauf U, Giepmans BN, Lopez P, Braconnot S, Chen SC, Falk MM (2002) Dynamic trafficking and delivery of connexons to the plasma membrane and accretion to gap junctions in living cells. Proc Natl Acad Sci U S A 99:10446–10451
127. Leithe E, Kjenseth A, Sirnes S, Stenmark H, Brech A, Rivedal E (2009) Ubiquitylation of the gap junction protein connexin-43 signals its trafficking from early endosomes to lysosomes in a process mediated by Hrs and Tsg101. J Cell Sci 122:3883–3893
128. Levine BL, Humeau LM, Boyer J, MacGregor RR, Rebello T, Lu X, Binder GK, Slepushkin V, Lemiale F, Mascola JR, Bushman FD, Dropulic B, June CH (2006) Gene transfer in humans using a conditionally replicating lentiviral vector. Proc Natl Acad Sci U S A 103:17372–17377
129. Liang GS, Miguel M de, Gomez-Hernandez JM, Glass JD, Scherer SS, Mintz M, Barrio LC, Fischbeck KH (2005) Severe neuropathy with leaky connexin32 hemichannels. Ann Neurol 57:749–754
130. Liang WG, Su CC, Nian JH, Chiang AS, Li SY, Yang JJ (2011) Human connexin30.2/31.3 (GJC3) does not form functional gap junction channels but causes enhanced ATP release in HeLa cells. Cell Biochem Biophys 61:189–197
131. Lichtenstein A, Gaietta GM, Deerinck TJ, Crum J, Sosinsky GE, Beyer EC, Berthoud VM (2009) The cytoplasmic accumulations of the cataract-associated mutant, connexin50P88S, are long-lived and form in the endoplasmic reticulum. Exp Eye Res 88:600–609
132. Lubkemeier I, Andrie R, Lickfett L, Bosen F, Stockigt F, Dobrowolski R, Draffehn AM, Fregeac J, Schultze JL, Bukauskas FF, Schrickel JW, Willecke K (2013) The Connexin40A96S mutation from a patient with atrial fibrillation causes decreased atrial conduction velocities and sustained episodes of induced atrial fibrillation in mice. J Mol Cell Cardiol 65:19–32
133. 2+ regulation of neuronal excitability. Proc Natl Acad Sci U S A 109:E1963–E1971
134. Maeda Y, Fukushima K, Nishizaki K, Smith RJ (2005) In vitro and in vivo suppression of GJB2 expression by RNA interference. Hum Mol Genet 14:1641–1650
135. Maeda S, Nakagawa S, Suga M, Yamashita E, Oshima A, Fujiyoshi Y, Tsukihara T (2009a) Structure of the connexin 26 gap junction channel at 3.5 Å resolution. Nature 458:597–602
136. Maeda Y, Sheffield AM, Smith RJ (2009b) Therapeutic regulation of gene expression in the inner ear using RNA interference. Adv Otorhinolaryngol 66:13–36
137. Maltzahn J von, Kreuzberg MM, Matern G, Euwens C, Hoher T, Worsdorfer P, Willecke K (2009) C-terminal tagging with eGFP yields new insights into expression of connexin45 but prevents rescue of embryonic lethal connexin45-deficient mice. Eur J Cell Biol 88:481–494
138. Martin PE, Blundell G, Ahmad S, Errington RJ, Evans WH (2001) Multiple pathways in the trafficking and assembly of connexin 26, 32 and 43 into gap junction intercellular communication channels. J Cell Sci 114:3845–3855
139. Martin PE, Easton JA, Hodgins MB, Wright CS (2014) Connexins: sensors of epidermal integrity that are therapeutic targets. FEBS Lett 588:1304–1314
140. Marziano NK, Casalotti SO, Portelli AE, Becker DL, Forge A (2003) Mutations in the gene for connexin 26 (GJB2) that cause hearing loss have a dominant negative effect on connexin 30. Hum Mol Genet 12:805–812
141. Mathias RT, White TW, Gong X (2010) Lens gap junctions in growth, differentiation, and homeostasis. Physiol Rev 90:179–206
142. Maza J, Das Sarma J, Koval M (2005) Defining a minimal motif required to prevent connexin oligomerization in the endoplasmic reticulum. J Biol Chem 280:21115–21121
143. Menichella DM, Goodenough DA, Sirkowski E, Scherer SS, Paul DL (2003) Connexins are critical for normal myelination in the CNS. J Neurosci 23:5963–5973
144. Mese G, Sellitto C, Li L, Wang HZ, Valiunas V, Richard G, Brink PR, White TW (2011) The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome. Mol Biol Cell 22:4776–4786
145. Mhaske PV, Levit NA, Li L, Wang HZ, Lee JR, Shuja Z, Brink PR, White TW (2013) The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity. Am J Physiol Cell Physiol 304:C1150–C1158
146. Minogue PJ, Liu X, Ebihara L, Beyer EC, Berthoud VM (2005) An aberrant sequence in a connexin46 mutant underlies congenital cataracts. J Biol Chem 280:40788–40795
147. Minogue PJ, Tong JJ, Arora A, Russell-Eggitt I, Hunt DM, Moore AT, Ebihara L, Beyer EC, Berthoud VM (2009) A mutant connexin50 with enhanced hemichannel function leads to cell death. Invest Ophthalmol Vis Sci 50:5837–5845
148. Miwa T, Minoda R, Ise M, Yamada T, Yumoto E (2013) Mouse otocyst transuterine gene transfer restores hearing in mice with connexin 30 deletion-associated hearing loss. Mol Ther 21:1142–1150
149. Moore K, Bryant ZJ, Ghatnekar G, Singh UP, Gourdie RG, Potts JD (2013) A synthetic connexin 43 mimetic peptide augments corneal wound healing. Exp Eye Res 115:178–188
150. Morell RJ, Kim HJ, Hood LJ, Goforth L, Friderici K, Fisher R, Van Camp G, Berlin CI, Oddoux C, Ostrer H, Keats B, Friedman TB (1998) Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. N Engl J Med 339:1500–1505
151. Muller DJ, Hand GM, Engel A, Sosinsky GE (2002) Conformational changes in surface structures of isolated connexin 26 gap junctions. EMBO J 21:3598–3607
152. Musil LS, Goodenough DA (1993) Multisubunit assembly of an integral plasma membrane channel protein, gap junction connexin43, occurs after exit from the ER. Cell 74:1065–1077
153. Musil LS, Beyer EC, Goodenough DA (1990) Expression of the gap junction protein connexin43 in embryonic chick lens: molecular cloning, ultrastructural localization, and post-translational phosphorylation. J Membr Biol 116:163–175
154. Nagy JI, Ionescu AV, Lynn BD, Rash JE (2003) Coupling of astrocyte connexins Cx26, Cx30, Cx43 to oligodendrocyte Cx29, Cx32, Cx47: implications from normal and connexin32 knockout mice. Glia 44:205–218
155. Nakagawa S, Gong XQ, Maeda S, Dong Y, Misumi Y, Tsukihara T, Bai D (2011) Asparagine 175 of connexin32 is a critical residue for docking and forming functional heterotypic gap junction channels with connexin26. J Biol Chem 286:19672–19681
156. Nualart-Marti A, Solsona C, Fields RD (2013) Gap junction communication in myelinating glia. Biochim Biophys Acta 1828:69–78
157. O’Carroll SJ, Becker DL, Davidson JO, Gunn AJ, Nicholson LF, Green CR (2013) The use of connexin-based therapeutic approaches to target inflammatory diseases. Methods Mol Biol 1037:519–546
158. Ongstad EL, O’Quinn MP, Ghatnekar GS, Yost MJ, Gourdie RG (2013) A Connexin43 mimetic peptide promotes regenerative healing and improves mechanical properties in skin and heart. Adv Wound Care (New Rochelle) 2:55–62
159. Orthmann-Murphy JL, Enriquez AD, Abrams CK, Scherer SS (2007) Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus-Merzbacher-like disease. Mol Cell Neurosci 34:629–641
160. Panchin Y, Kelmanson I, Matz M, Lukyanov K, Usman N, Lukyanov S (2000) A ubiquitous family of putative gap junction molecules. Curr Biol 10:R473–R474
161. Pantano S, Zonta F, Mammano F (2008) A fully atomistic model of the Cx32 connexon. PLoS One 3:e2614
162. Paznekas WA, Boyadjiev SA, Shapiro RE, Daniels O, Wollnik B, Keegan CE, Innis JW, Dinulos MB, Christian C, Hannibal MC, Jabs EW (2003) Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet 72:408–418
163. Penuela S, Bhalla R, Gong XQ, Cowan KN, Celetti SJ, Cowan BJ, Bai D, Shao Q, Laird DW (2007) Pannexin 1 and pannexin 3 are glycoproteins that exhibit many distinct characteristics from the connexin family of gap junction proteins. J Cell Sci 120:3772–3783
164. Penuela S, Gehi R, Laird DW (2013) The biochemistry and function of pannexin channels. Biochim Biophys Acta 1828:15–22
165. Penuela S, Harland L, Simek J, Laird DW (2014) Pannexin channels and their links to human disease. Biochem J 461:371–381
166. Peracchia C, Sotkis A, Wang XG, Peracchia LL, Persechini A (2000) Calmodulin directly gates gap junction channels. J Biol Chem 275:26220–26224
167. Phelan P (2005) Innexins: members of an evolutionarily conserved family of gap-junction proteins. Biochim Biophys Acta 1711:225–245
168. Pizzuti A, Flex E, Mingarelli R, Salpietro C, Zelante L, Dallapiccola B (2004) A homozygous GJA1 gene mutation causes a Hallermann-Streiff/ODDD spectrum phenotype. Hum Mutat 23:286
169. Ponsaerts R, De Vuyst E, Retamal M, D’Hondt C, Vermeire D, Wang N, De Smedt H, Zimmermann P, Himpens B, Vereecke J, Leybaert L, Bultynck G (2010) Intramolecular loop/tail interactions are essential for connexin 43-hemichannel activity. FASEB J 24:4378–4395
170. Qiu C, Coutinho P, Frank S, Franke S, Law LY, Martin P, Green CR, Becker DL (2003) Targeting connexin43 expression accelerates the rate of wound repair. Curr Biol 13:1697–1703
171. Qu C, Gardner P, Schrijver I (2009) The role of the cytoskeleton in the formation of gap junctions by Connexin 30. Exp Cell Res 315:1683–1692
172. Ren Q, Riquelme MA, Xu J, Yan X, Nicholson BJ, Gu S, Jiang JX (2013) Cataract-causing mutation of human connexin 46 impairs gap junction, but increases hemichannel function and cell death. PLoS One 8:e74732
173. Ressot C, Gomes D, Dautigny A, Pham-Dinh D, Bruzzone R (1998) Connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease show two distinct behaviors: loss of function and altered gating properties. J Neurosci 18:4063–4075
174. Rhee DY, Zhao XQ, Francis RJ, Huang GY, Mably JD, Lo CW (2009) Connexin 43 regulates epicardial cell polarity and migration in coronary vascular development. Development 136:3185–3193
175. Richard G (2005) Connexin disorders of the skin. Clin Dermatol 23:23–32
176. Richardson RJ, Joss S, Tomkin S, Ahmed M, Sheridan E, Dixon MJ (2006) A nonsense mutation in the first transmembrane domain of connexin 43 underlies autosomal recessive oculodentodigital syndrome. J Med Genet 43:e37
177. Rouan F, White TW, Brown N, Taylor AM, Lucke TW, Paul DL, Munro CS, Uitto J, Hodgins MB, Richard G (2001) trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation. J Cell Sci 114:2105–2113
178. Rouan F, Lo CW, Fertala A, Wahl M, Jost M, Rodeck U, Uitto J, Richard G (2003) Divergent effects of two sequence variants of GJB3 (G12D and R32W) on the function of connexin 31 in vitro. Exp Dermatol 12:191–197
179. Rouger H, LeGuern E, Birouk N, Gouider R, Tardieu S, Plassart E, Gugenheim M, Vallat JM, Louboutin JP, Bouche P, Agid Y, Brice A (1997) Charcot-Marie-Tooth disease with intermediate motor nerve conduction velocities: characterization of 14 Cx32 mutations in 35 families. Hum Mutat 10:443–452
180. Rubenstein RC, Zeitlin PL (1998) A pilot clinical trial of oral sodium 4-phenylbutyrate (Buphenyl) in deltaF508-homozygous cystic fibrosis patients: partial restoration of nasal epithelial CFTR function. Am J Respir Crit Care Med 157:484–490
181. Rubenstein RC, Egan ME, Zeitlin PL (1997) In vitro pharmacologic restoration of CFTR-mediated chloride transport with sodium 4-phenylbutyrate in cystic fibrosis epithelial cells containing delta F508-CFTR. J Clin Invest 100:2457–2465
182. Saez JC, Retamal MA, Basilio D, Bukauskas FF, Bennett MV (2005) Connexin-based gap junction hemichannels: gating mechanisms. Biochim Biophys Acta 1711:215–224
183. Saez JC, Schalper KA, Retamal MA, Orellana JA, Shoji KF, Bennett MV (2010) Cell membrane permeabilization via connexin hemichannels in living and dying cells. Exp Cell Res 316:2377–2389
184. 2+ permeability in Cx26 hemichannels formed by the A40V and G45E mutations that cause keratitis ichthyosis deafness syndrome. J Gen Physiol 136:47–62
185. Sato S, Ward CL, Krouse ME, Wine JJ, Kopito RR (1996) Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation. J Biol Chem 271:635–638
186. Sbidian E, Feldmann D, Bengoa J, Fraitag S, Abadie V, Prost Y de, Bodemer C, Hadj-Rabia S (2010) Germline mosaicism in keratitis-ichthyosis-deafness syndrome: pre-natal diagnosis in a familial lethal form. Clin Genet 77:587–592
187. Scott CA, Kelsell DP (2011) Key functions for gap junctions in skin and hearing. Biochem J 438:245–254
188. Seki A, Duffy HS, Coombs W, Spray DC, Taffet SM, Delmar M (2004) Modifications in the biophysical properties of connexin43 channels by a peptide of the cytoplasmic loop region. Circ Res 95:e22–e28
189. Shao Q, Liu Q, Lorentz R, Gong XQ, Bai D, Shaw GS, Laird DW (2012) Structure and functional studies of N-terminal Cx43 mutants linked to oculodentodigital dysplasia. Mol Biol Cell 23:3312–3321
190. Shaw RM, Fay AJ, Puthenveedu MA, von Zastrow M, Jan YN, Jan LY (2007) Microtubule plus-end-tracking proteins target gap junctions directly from the cell interior to adherens junctions. Cell 128:547–560
191. Shiels A, Bennett TM, Hejtmancik JF (2010) Cat-Map: putting cataract on the map. Mol Vis 16:2007–2015
192. Siebert AP, Ma Z, Grevet JD, Demuro A, Parker I, Foskett JK (2013) Structural and functional similarities of calcium homeostasis modulator 1 (CALHM1) ion channel with connexins, pannexins, and innexins. J Biol Chem 288:6140–6153
193. Silander K, Meretoja P, Juvonen V, Ignatius J, Pihko H, Saarinen A, Wallden T, Herrgard E, Aula P, Savontaus ML (1998) Spectrum of mutations in finnish patients with Charcot-Marie-Tooth disease and related neuropathies. Hum Mutat 12:59–68
194. Simonsen KT, Moerman DG, Naus CC (2014) Gap junctions in C. elegans. Front Physiol 5:40
195. Smith TD, Mohankumar A, Minogue PJ, Beyer EC, Berthoud VM, Koval M (2012) Cytoplasmic amino acids within the membrane interface region influence connexin oligomerization. J Membr Biol 245:221–230
196. Solan JL, Lampe PD (2009) Connexin43 phosphorylation: structural changes and biological effects. Biochem J 419:261–272
197. Solan JL, Lampe PD (2014) Specific Cx43 phosphorylation events regulate gap junction turnover in vivo. FEBS Lett 588:1423–1429
198. Sosinsky GE, Boassa D, Dermietzel R, Duffy HS, Laird DW, MacVicar B, Naus CC, Penuela S, Scemes E, Spray DC, Thompson RJ, Zhao HB, Dahl G (2011) Pannexin channels are not gap junction hemichannels. Channels (Austin) 5:193–197
199. Steensel MA van, Spruijt L, Burgt I van der, Bladergroen RS, Vermeer M, Steijlen PM, Geel M van (2005) A 2-bp deletion in the GJA1 gene is associated with oculo-dento-digital dysplasia with palmoplantar keratoderma. Am J Med Genet A 132A:171–174
200. Stewart MK, Gong XQ, Barr KJ, Bai D, Fishman GI, Laird DW (2013) The severity of mammary gland developmental defects is linked to the overall functional status of Cx43 as revealed by genetically modified mice. Biochem J 449:401–413
201. Stong BC, Chang Q, Ahmad S, Lin X (2006) A novel mechanism for connexin 26 mutation linked deafness: cell death caused by leaky gap junction hemichannels. Laryngoscope 116:2205–2210
202. Su CC, Li SY, Su MC, Chen WC, Yang JJ (2010) Mutation R184Q of connexin 26 in hearing loss patients has a dominant-negative effect on connexin 26 and connexin 30. Eur J Hum Genet 18:1061–1064
203. Suaud L, Miller K, Alvey L, Yan W, Robay A, Kebler C, Kreindler JL, Guttentag S, Hubbard MJ, Rubenstein RC (2011) ERp29 regulates DeltaF508 and wild-type cystic fibrosis transmembrane conductance regulator (CFTR) trafficking to the plasma membrane in cystic fibrosis (CF) and non-CF epithelial cells. J Biol Chem 286:21239–21253
204. 2+ signaling than homomeric counterparts. Am J Physiol Cell Physiol 288:C613–C623
205. Sun Y, Tang W, Chang Q, Wang Y, Kong W, Lin X (2009) Connexin30 null and conditional connexin26 null mice display distinct pattern and time course of cellular degeneration in the cochlea. J Comp Neurol 516:569–579
206. Sun Y, Hills MD, Ye WG, Tong X, Bai D (2014a) Atrial fibrillation-linked germline GJA5/connexin40 mutants showed an increased hemichannel function. PLoS One 9:e95125
207. Sun Y, Tong X, Chen H, Huang T, Shao Q, Huang W, Laird DW, Bai D (2014b) An atrial-fibrillation-linked connexin40 mutant is retained in the endoplasmic reticulum and impairs the function of atrial gap-junction channels. Dis Model Mech 7:561–569
208. Taruno A, Matsumoto I, Ma Z, Marambaud P, Foskett JK (2013) How do taste cells lacking synapses mediate neurotransmission? CALHM1, a voltage-gated ATP channel. Bioessays 35:1111–1118
209. Tattersall D, Scott CA, Gray C, Zicha D, Kelsell DP (2009) EKV mutant connexin 31 associated cell death is mediated by ER stress. Hum Mol Genet 18:4734–4745
210. Thomas T, Jordan K, Laird DW (2001) Role of cytoskeletal elements in the recruitment of Cx43-GFP and Cx26-YFP into gap junctions. Cell Commun Adhes 8:231–236
211. Thomas T, Telford D, Laird DW (2004) Functional domain mapping and selective trans-dominant effects exhibited by Cx26 disease-causing mutations. J Biol Chem 279:19157–19168
212. Thomas T, Jordan K, Simek J, Shao Q, Jedeszko C, Walton P, Laird DW (2005) Mechanisms of Cx43 and Cx26 transport to the plasma membrane and gap junction regeneration. J Cell Sci 118:4451–4462
213. Thonnissen E, Rabionet R, Arbones ML, Estivill X, Willecke K, Ott T (2002) Human connexin26 (GJB2) deafness mutations affect the function of gap junction channels at different levels of protein expression. Hum Genet 111:190–197
214. Tong JJ, Sohn BC, Lam A, Walters DE, Vertel BM, Ebihara L (2013) Properties of two cataract-associated mutations located in the NH2 terminus of connexin 46. Am J Physiol Cell Physiol 304:C823–C832
215. Uhlenberg B, Schuelke M, Ruschendorf F, Ruf N, Kaindl AM, Henneke M, Thiele H, Stoltenburg-Didinger G, Aksu F, Topaloglu H, Nürnberg P, Hübner C, Weschke B, Gärtner J (2004) Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease. Am J Hum Genet 75:251–260
216. Van Norstrand DW, Asimaki A, Rubinos C, Dolmatova E, Srinivas M, Tester DJ, Saffitz JE, Duffy HS, Ackerman MJ (2012) Connexin43 mutation causes heterogeneous gap junction loss and sudden infant death. Circulation 125:474–481
217. VanSlyke JK, Musil LS (2005) Cytosolic stress reduces degradation of connexin43 internalized from the cell surface and enhances gap junction formation and function. Mol Biol Cell 16:5247–5257
218. VanSlyke JK, Deschenes SM, Musil LS (2000) Intracellular transport, assembly, and degradation of wild-type and disease-linked mutant gap junction proteins. Mol Biol Cell 11:1933–1946
219. Velasquez S, Eugenin EA (2014) Role of Pannexin-1 hemichannels and purinergic receptors in the pathogenesis of human diseases. Front Physiol 5:96
220. Vozzi C, Dupont E, Coppen SR, Yeh HI, Severs NJ (1999) Chamber-related differences in connexin expression in the human heart. J Mol Cell Cardiol 31:991–1003
221. Vreeburg M, Zwart-Storm EA de, Schouten MI, Nellen RG, Marcus-Soekarman D, Devies M, Geel M van, Steensel MA van (2007) Skin changes in oculo-dento-digital dysplasia are correlated with C-terminal truncations of connexin 43. Am J Med Genet A 143:360–363
222. Wang Y, Chang Q, Tang W, Sun Y, Zhou B, Li H, Lin X (2009) Targeted connexin26 ablation arrests postnatal development of the organ of Corti. Biochem Biophys Res Commun 385:33–37
223. + cycling and the endocochlear potential. Hear Res 165:1–9
224. White TW (2002) Unique and redundant connexin contributions to lens development. Science 295:319–320
225. White TW, Bruzzone R, Goodenough DA, Paul DL (1992) Mouse Cx50, a functional member of the connexin family of gap junction proteins, is the lens fiber protein MP70. Mol Biol Cell 3:711–720
226. Xia CH, Cheung D, DeRosa AM, Chang B, Lo WK, White TW, Gong X (2006) Knock-in of alpha3 connexin prevents severe cataracts caused by an alpha8 point mutation. J Cell Sci 119:2138–2144
227. Xu J, Nicholson BJ (2013) The role of connexins in ear and skin physiology—functional insights from disease-associated mutations. Biochim Biophys Acta 1828:167–178
228. Yam GH, Gaplovska-Kysela K, Zuber C, Roth J (2007) Sodium 4-phenylbutyrate acts as a chemical chaperone on misfolded myocilin to rescue cells from endoplasmic reticulum stress and apoptosis. Invest Ophthalmol Vis Sci 48:1683–1690
229. Yang JJ, Huang SH, Chou KH, Liao PJ, Su CC, Li SY (2007) Identification of mutations in members of the connexin gene family as a cause of nonsyndromic deafness in Taiwan. Audiol Neurootol 12:198–208
230. Yeager M, Nicholson BJ (1996) Structure of gap junction intercellular channels. Curr Opin Struct Biol 6:183–192
231. Yu Q, Wang Y, Chang Q, Wang J, Gong S, Li H, Lin X (2014) Virally expressed connexin26 restores gap junction function in the cochlea of conditional Gjb2 knockout mice. Gene Ther 21:71–80
232. Yum SW, Kleopa KA, Shumas S, Scherer SS (2002) Diverse trafficking abnormalities of connexin32 mutants causing CMTX. Neurobiol Dis 11:43–52
233. Zelante L, Gasparini P, Estivill X, Melchionda S, D’Agruma L, Govea N, Mila M, Monica MD, Lutfi J, Shohat M, Mansfield E, Delgrosso K, Rappaport E, Surrey S, Fortina P (1997) Connexin26 mutations associated with the most common form of non-syndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. Hum Mol Genet 6:1605–1609
234. Zhang Y, Hao H (2013) Conserved glycine at position 45 of major cochlear connexins constitutes a vital component of the Ca(2)(+) sensor for gating of gap junction hemichannels. Biochem Biophys Res Commun 436:424–429
235. Zhao HB, Yu N, Fleming CR (2005) Gap junctional hemichannel-mediated ATP release and hearing controls in the inner ear. Proc Natl Acad Sci U S A 102:18724–18729
236. Zhou Y, Yang W, Lurtz MM, Ye Y, Huang Y, Lee HW, Chen Y, Louis CF, Yang JJ (2007) Identification of the calmodulin binding domain of connexin 43. J Biol Chem 282:35005–35017
237. Zou J, Salarian M, Chen Y, Veenstra R, Louis CF, Yang JJ (2014) Gap junction regulation by calmodulin. FEBS Lett 588:1430–1438