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Biochemistry of Connexins

  • Chapter
Connexins

Abstract

Vertebrate gap junctions, composed of integral membrane proteins encoded by the connexin gene family, are critically important in regulation of embryonic development, coordinated contraction of excitable cells, tissue homeostasis, normal cell growth, and differentiation. Connexin proteins typically have short half-lives and detergent-specific solubilities, and interact with a variety of protein-binding partners during the assembly, trafficking, assembly/disassembly, and degradation of the oligomeric forms that constitute hemichannels and junctional channels. Phosphorylation has been implicated in the regulation of gap junctional communication at several stages of the connexin life cycle including hemichannel oligomerization, export of the protein to the plasma membrane, hemichannel activity, gap junction assembly, gap junction channel gating, and connexin degradation.

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References

  1. Lampe PD, Lau AF. The effects of connexin phosphorylation on gap junctional communication. Int J Biochem Cell Biol. 2004;36:1171–86.

    Article  CAS  PubMed  Google Scholar 

  2. Sáez JC, Martínez AD, Brañes MC, Gonzalez HE. Regulation of gap junctions by protein phosphorylation. Braz J Med Biol Res. 1998;31:593–600.

    CAS  Google Scholar 

  3. Solan JL, Lampe PD. Connexin phosphorylation as a regulatory event linked to gap junction channel assembly. Biochim Biophys Acta. 2005;1711:154–63.

    Article  CAS  PubMed  Google Scholar 

  4. Locke D, Koreen IV, Harris AL. Isoelectric points and posttranslational modifications of connexin26 and connexin32. FASEB J. 2006;20:1221–3.

    Article  CAS  PubMed  Google Scholar 

  5. Huang Y, Sirkowski EE, Stickney JT, Scherer SS. Prenylation-defective human connexin32 mutants are normally localized and function equivalently to wildtype connexin32 in myelinating Schwann cells. J Neurosci. 2005;25:7111–20.

    Article  CAS  PubMed  Google Scholar 

  6. VanSlyke JK, Musil LS. Dislocation and degradation from the ER are regulated by cytosolic stress. J Cell Biol. 2002;157:381–94.

    Article  CAS  PubMed  Google Scholar 

  7. Lampe PD. Analyzing phorbol ester effects on gap junction communication: a dramatic inhibition of assembly. J Cell Biol. 1994;127:1895–905.

    Article  CAS  PubMed  Google Scholar 

  8. Laird DW, Puranam KL, Revel JP. Turnover and phosphorylation dynamics of connexin43 gap junction protein in cultured cardiac myocytes. Biochem J. 1991;273:67–72.

    CAS  PubMed  Google Scholar 

  9. Crow DS, Beyer EC, Paul DL, Kobe SS, Lau AF. Phosphorylation of connexin43 gap junction protein in uninfected and Rous sarcoma virus-transformed mammalian fibroblasts. Mol Cell Biol. 1990;10:1754–63.

    CAS  PubMed  Google Scholar 

  10. Beardslee M, Laing J, Beyer E, Saffitz J. Rapid turnover of connexin43 in the adult rat heart. Circ Res. 1998;83:629–35.

    CAS  PubMed  Google Scholar 

  11. Musil LS, Beyer EC, Goodenough DA. Expression of the gap junction protein connexin43 in embryonic chick lens: molecular cloning, ultrastructural localization, and posttranslational phosphorylation. J Membr Biol. 1990;116:163–75.

    Article  CAS  PubMed  Google Scholar 

  12. Berthoud VM, Ledbetter MLS, Hertzberg EL, Sáez JC. Connexin43 in MDCK cells: regulation by a tumor-promoting phorbol ester and calcium. Eur J Cell Biol. 1992;57:40–50.

    CAS  PubMed  Google Scholar 

  13. Brissette JL, Kumar NM, Gilula NB, Dotto GP. The tumor promotor 12-O-tetradecanoylphorbol-13-acetate and the ras oncogene modulate expression and phosphorylation of gap junction proteins. Mol Cell Biol. 1991;11:5364–71.

    CAS  PubMed  Google Scholar 

  14. Kadle R, Zhang JT, Nicholson BJ. Tissue-specific distribution of differentially phosphorylated forms of Cx43. Mol Cell Biol. 1991;11:363–9.

    CAS  PubMed  Google Scholar 

  15. Musil LS, Cunningham BA, Edelman GM, Goodenough DA. Differential phosphorylation of gap junction protein connexin43 in junctional communication-competent and deficient cell lines. J Cell Biol. 1990;111:2077–88.

    Article  CAS  PubMed  Google Scholar 

  16. Musil LS, Goodenough DA. Biochemical analysis of connexin43 intracellular transport, phosphorylation and assembly into gap junctional plaques. J Cell Biol. 1991;115:1357–74.

    Article  CAS  PubMed  Google Scholar 

  17. Solan JL, Fry MD, TenBroek EM, Lampe PD. Connexin43 phosphorylation at S368 is acute during S and G2/M and in response to protein kinase C activation. J Cell Sci. 2003;116:2203–11.

    Article  CAS  PubMed  Google Scholar 

  18. Urschel S, Hoher T, Schubert T, Alev C, Söhl G, Worsdorfer P, Asahara T, Dermietzel R, Weiler R, Willecke K. Protein kinase A-mediated phosphorylation of connexin36 in mouse retina results in decreased gap junctional communication between AII amacrine cells. J Biol Chem. 2006;281:33163–71.

    Google Scholar 

  19. Berthoud VM, Beyer EC, Kurata WE, Lau AF, Lampe PD. The gap junction protein connexin 56 is phosphorylated in the intracellular loop and the carboxy-terminal region. Eur J Biochem. 1997;244:89–97.

    Article  CAS  PubMed  Google Scholar 

  20. VanSlyke JK, Musil LS. Analysis of connexin intracellular transport and assembly. Methods. 2000;20:156–64.

    Article  CAS  PubMed  Google Scholar 

  21. Locke D, Liu J, Harris AL. Lipid rafts prepared by different methods contain different connexin channels, but gap junctions are not lipid rafts. Biochemistry. 2005;44:13027–42.

    Article  CAS  PubMed  Google Scholar 

  22. Larson DM, Seul KH, Berthoud VM, Lau AF, Sagar GD, Beyer EC. Functional expression and biochemical characterization of an epitope-tagged connexin37. Mol Cell Biol Res Commun. 2000;3:115–21.

    Article  CAS  PubMed  Google Scholar 

  23. Lin D, Zhou J, Zelenka PS, Takemoto DJ. Protein kinase Cγ regulation of gap junction activity through caveolin-1-containing lipid rafts. Invest Ophthalmol Vis Sci. 2003;44:5259–68.

    Article  PubMed  Google Scholar 

  24. Schubert AL, Schubert W, Spray DC, Lisanti MP. Connexin family members target to lipid raft domains and interact with caveolin-1. Biochemistry. 2002;41:5754–64.

    Article  CAS  PubMed  Google Scholar 

  25. Barth K, Gentsch M, Blasche R, Pfuller A, Parshyna I, Koslowski R, Barth G, Kasper M. Distribution of caveolin-1 and connexin43 in normal and injured alveolar epithelial R3/1 cells. Histochem Cell Biol. 2005;123:239–47.

    Article  CAS  PubMed  Google Scholar 

  26. Biswas SK, Lo WK. Gap junctions contain different amounts of cholesterol which undergo unique sequestering processes during fiber cell differentiation in the embryonic chicken lens. Mol Vis. 2007;13:345–59.

    CAS  PubMed  Google Scholar 

  27. Alcala J, Katar M, Maisel H. Lipid composition of chick lens fiber cell gap junctions. Curr Eye Res. 1982;2:569–78.

    Article  PubMed  Google Scholar 

  28. Henderson D, Eibl H, Weber K. Structure and biochemistry of mouse hepatic gap junctions. J Mol Biol. 1979;132:193–218.

    Article  CAS  PubMed  Google Scholar 

  29. Giepmans BN. Gap junctions and connexin-interacting proteins. Cardiovasc Res. 2004;62:233–45.

    Article  CAS  PubMed  Google Scholar 

  30. Giepmans BN. Role of connexin43-interacting proteins at gap junctions. Adv Cardiol. 2006;42:41–56.

    Article  CAS  PubMed  Google Scholar 

  31. Herve JC, Bourmeyster N, Sarrouilhe D. Diversity in protein-protein interactions of connexins: emerging roles. Biochim Biophys Acta. 2004;1662:22–41.

    Article  CAS  PubMed  Google Scholar 

  32. Duffy HS, Iacobas I, Hotchkiss K, Hirst-Jensen BJ, Bosco A, Dandachi N, Dermietzel R, Sorgen PL, Spray DC. The gap junction protein connexin32 interacts with the Src homology 3/Hook domain of discs large homolog 1. J Biol Chem. 2007;282:9789–96.

    Article  CAS  PubMed  Google Scholar 

  33. VanSlyke JK, Deschenes SM, Musil LS. Intracellular transport, assembly, and degradation of wildtype and disease-linked mutant gap junction proteins. Mol Biol Cell. 2000;11:1933–46.

    CAS  PubMed  Google Scholar 

  34. VanSlyke JK, Musil LS. Cytosolic stress reduces degradation of connexin43 internalized from the cell surface and enhances gap junction formation and function. Mol Biol Cell. 2005;16:5247–57.

    Article  CAS  PubMed  Google Scholar 

  35. Sosinsky GE, Solan JL, Gaietta GM, Ngan L, Mackey M, Lampe PD. The C-terminus of Connexin43 present in the Golgi and in gap junctions is conformationally distinct: specific serines and prolines influence subcellular localization and ZO-1 interaction. Biochem J. 2007;408:375–85.

    Article  CAS  PubMed  Google Scholar 

  36. Ek-Vitorin JF, King TJ, Heyman NS, Lampe PD, Burt JM. Selectivity of connexin 43 channels is regulated through protein kinase C-dependent phosphorylation. Circ Res. 2006;98:1498–505.

    Article  CAS  PubMed  Google Scholar 

  37. Atkinson MM, Lampe PD, Lin HH, Kollander R, Li X-R, Kiang DT. Cyclic AMP modifies the cellular distribution of connexin 43 and induces a persistent increase in the junctional permeability of mouse mammary tumor cells. J Cell Sci. 1995;108:3079–90.

    CAS  PubMed  Google Scholar 

  38. Burghardt RC, Barhoumi R, Sewall TC, Bowen JA. Cyclic AMP induces rapid increases in gap junction permeability and changes in the cellular distribution of connexin43. J Membr Biol. 1995;148:243–53.

    CAS  PubMed  Google Scholar 

  39. Bolon ML, Kidder GM, Simon AM, Tyml K. Lipopolysaccharide reduces electrical coupling in microvascular endothelial cells by targeting connexin40 in a tyrosine-, ERK1/2-, PKA-, and PKC-dependent manner. J Cell Physiol. 2007;211:159–66.

    Article  CAS  PubMed  Google Scholar 

  40. Bolon ML, Ouellette Y, Li F, Tyml K. Abrupt reoxygenation following hypoxia reduces electrical coupling between endothelial cells of wildtype but not connexin40 null mice in oxidant- and PKA-dependent manner. FASEB J. 2005;19:1725–7.

    CAS  PubMed  Google Scholar 

  41. Chanson M, White MM, Garber SS. cAMP promotes gap junctional coupling in T84 cells. Am J Physiol. 1996;271:C533–C9.

    CAS  PubMed  Google Scholar 

  42. van Veen TAB, van Rijen HvM, Jongsma HJ. Electrical conductance of mouse connexin45 gap junction channels is modulated by phosphorylation. Cardiovasc Res. 2000;46:496–510.

    Article  Google Scholar 

  43. Paulson AF, Lampe PD, Meyer RA, Atkinson MA, Walseth TF, Johnson RG. Cyclic AMP and LDL trigger a rapid enhancement in gap junction assembly through a stimulation of connexin trafficking. J Cell Sci. 2000;113:3037–49.

    CAS  PubMed  Google Scholar 

  44. Johnson RG, Meyer RA, Li XR, Preus DM, Tan L, Grunenwald H, Paulson AF, Laird DW, Sheridan JD. Gap junctions assemble in the presence of cytoskeletal inhibitors, but enhanced assembly requires microtubules. Exp Cell Res. 2002;275:67–80.

    Article  CAS  PubMed  Google Scholar 

  45. TenBroek EM, Lampe PD, Solan JL, Reynhout JK, Johnson RG. Ser364 of connexin43 and the upregulation of gap junction assembly by cAMP. J Cell Biol. 2001;155:1307–18.

    Article  CAS  PubMed  Google Scholar 

  46. Yogo K, Ogawa T, Akiyama M, Ishida N, Takeya T. Identification and functional analysis of novel phosphorylation sites in Cx43 in rat primary granulosa cells. FEBS Lett. 2002;531:132–6.

    Article  CAS  PubMed  Google Scholar 

  47. Yogo K, Ogawa T, Akiyama M, Ishida-Kitagawa N, Sasada H, Sato E, Takeya T. PKA implicated in the phosphorylation of Cx43 induced by stimulation with FSH in rat granulosa cells. J Reprod Dev. 2006;52:321–8.

    Article  CAS  PubMed  Google Scholar 

  48. Shah MM, Martínez A-M, Fletcher WH. The connexin43 gap junction protein is phosphorylated by protein kinase A and protein kinase C: in vivo and in vtitro studies. Mol Cell Biochem. 2002;238:57–68.

    Article  CAS  PubMed  Google Scholar 

  49. TenBroek E, Lampe PD, Taffet S, Reynhout J, Martyn K, Kurata WE, Lau AF, Johnson RG. Enhanced gap junction assembly following the elevation of cAMP requires full-length Cx43. In: Werner R, editor. Gap Junctions. Amsterdam: IOS Press; 1998. pp.215–9.

    Google Scholar 

  50. Kawasaki H, Springett GM, Mochizuki N, Toki S, Nakaya M, Matsuda M, Housman DE, Graybiel AM. A family of cAMP-binding proteins that directly activate Rap1. Science. 1998;282:2275–9.

    Article  CAS  PubMed  Google Scholar 

  51. de Rooij J, Zwartkruis FJ, Verheijen MH, Cool RH, Nijman SM, Wittinghofer A, Bos JL. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature. 1998;396:474–7.

    Article  PubMed  CAS  Google Scholar 

  52. Rangarajan S, Enserink JM, Kuiperij HB, de Rooij J, Price LS, Schwede F, Bos JL. Cyclic AMP induces integrin-mediated cell adhesion through Epac and Rap1 upon stimulation of the β2-adrenergic receptor. J Cell Biol. 2003;160:487–93.

    Article  CAS  PubMed  Google Scholar 

  53. Cullere X, Shaw SK, Andersson L, Hirahashi J, Luscinskas FW, Mayadas TN. Regulation of vascular endothelial barrier function by Epac, a cAMP-activated exchange factor for Rap GTPase. Blood. 2005;105:1950–5.

    Article  CAS  PubMed  Google Scholar 

  54. Fukuhara S, Sakurai A, Sano H, Yamagishi A, Somekawa S, Takakura N, Saito Y, Kangawa K, Mochizuki N. Cyclic AMP potentiates vascular endothelial cadherin-mediated cell-cell contact to enhance endothelial barrier function through an Epac-Rap1 signaling pathway. Mol Cell Biol. 2005;25:136–46.

    Article  CAS  PubMed  Google Scholar 

  55. Somekawa S, Fukuhara S, Nakaoka Y, Fujita H, Saito Y, Mochizuki N. Enhanced functional gap junction neoformation by protein kinase A-dependent and Epac-dependent signals downstream of cAMP in cardiac myocytes. Circ Res. 2005;97:655–62.

    Article  CAS  PubMed  Google Scholar 

  56. Van Rijen HV, Van Veen TA, Hermans MM, Jongsma HJ. Human connexin40 gap junction channels are modulated by cAMP. Cardiovasc Res. 2000;45:941–51.

    Article  PubMed  Google Scholar 

  57. Mitropoulou G, Bruzzone R. Modulation of perch connexin35 hemi-channels by cyclic AMP requires a protein kinase A phosphorylation site. J Neurosci Res. 2003;72:147–57.

    Article  CAS  PubMed  Google Scholar 

  58. Ouyang X, Winbow VM, Patel LS, Burr GS, Mitchell CK, O'Brien J. Protein kinase A mediates regulation of gap junctions containing connexin35 through a complex pathway. Brain Res Mol Brain Res. 2005;135:1–11.

    Article  CAS  PubMed  Google Scholar 

  59. Keane RW, Mehta P, Rose B, Honig LS, Loewenstein WR, Rutishauser U. Neural differentiation, NCAM-mediated adhesion and gap junctional communication in neuroectoderm. A study in vitro. J Cell Biol. 1988;106:1307–19.

    Article  CAS  PubMed  Google Scholar 

  60. Meyer RA, Laird DW, Revel J-P, Johnson RG. Inhibition of gap junction and adherens junction assembly by connexin and A-CAM antibodies. J Cell Biol. 1992;119:179–89.

    Article  CAS  PubMed  Google Scholar 

  61. Xu X, Li WE, Huang GY, Meyer R, Chen T, Luo Y, Thomas MP, Radice GL, Lo CW. Modulation of mouse neural crest cell motility by N-cadherin and connexin 43 gap junctions. J Cell Biol. 2001;154:217–30.

    Article  CAS  PubMed  Google Scholar 

  62. Fujimoto K, Nagafuchi A, Tsukita S, Kuraoka A, Ohokuma A, Shibata Y. Dynamics of connexins, E-cadherin and α-catenin on cell membranes during gap junction formation. J Cell Sci. 1997;110:311–22.

    CAS  PubMed  Google Scholar 

  63. Wu JC, Tsai RY, Chung TH. Role of catenins in the development of gap junctions in rat cardiomyocytes. J Cell Biochem. 2003;88:823–35.

    Article  CAS  PubMed  Google Scholar 

  64. Luo Y, Radice GL. Cadherin-mediated adhesion is essential for myofibril continuity across the plasma membrane but not for assembly of the contractile apparatus. J Cell Sci. 2003;116:1471–9.

    Article  CAS  PubMed  Google Scholar 

  65. Paul DL, Yu K, Bruzzone R, Gimlich RL, Goodenough DA. Expression of a dominant-negative inhibitor of intercellular communication in the early Xenopus embryo causes delamination and extrusion of cells. Development. 1995;121:371–81.

    CAS  PubMed  Google Scholar 

  66. Lee S, Gilula NB, Warner AE. Gap junctional communication and compaction during preimplantation stages of mouse development. Cell. 1987;51:851–80.

    Article  CAS  PubMed  Google Scholar 

  67. Shaw RM, Fay AJ, Puthenveedu MA, von Zastrow M, Jan YN, Jan LY. Microtubule plus-end-tracking proteins target gap junctions directly from the cell interior to adherens junctions. Cell. 2007;128:547–60.

    Article  CAS  PubMed  Google Scholar 

  68. Giepmans BN, Verlaan I, Hengeveld T, Janssen H, Calafat J, Falk MM, Moolenaar WH. Gap junction protein connexin-43 interacts directly with microtubules. Curr Biol. 2001;11:1364–8.

    Article  CAS  PubMed  Google Scholar 

  69. Wei CJ, Francis R, Xu X, Lo CW. Connexin43 associated with an N-cadherin-containing multiprotein complex is required for gap junction formation in NIH3T3 cells. J Biol Chem. 2005;280: 19925–36.

    Article  CAS  PubMed  Google Scholar 

  70. Kojima T, Kokai Y, Chiba H, Yamamoto M, Mochizuki Y, Sawada N. Cx32 but not Cx26 is associated with tight junctions in primary cultures of rat hepatocytes. Exp Cell Res. 2001;263:193–201.

    Article  CAS  PubMed  Google Scholar 

  71. Nagasawa K, Chiba H, Fujita H, Kojima T, Saito T, Endo T, Sawada N. Possible involvement of gap junctions in the barrier function of tight junctions of brain and lung endothelial cells. J Cell Physiol. 2006;208:123–32.

    Article  CAS  PubMed  Google Scholar 

  72. Singh D, Solan JL, Taffet SM, Javier R, Lampe PD. Connexin 43 interacts with zona occludens-1 and -2 proteins in a cell cycle stage-specific manner. J Biol Chem. 2005;280:30416–21.

    Article  CAS  PubMed  Google Scholar 

  73. Hunter AW, Barker RJ, Zhu C, Gourdie RG. Zonula occludens-1 alters connexin43 gap junction size and organization by influencing channel accretion. Mol Biol Cell. 2005;16:5686–98.

    Article  CAS  PubMed  Google Scholar 

  74. Zhu C, Barker RJ, Hunter AW, Zhang Y, Jourdan J, Gourdie RG. Quantitative analysis of ZO-1 co-localization with Cx43 gap junction plaques in cultures of rat neonatal cardiomyocytes. Microsc Microanal. 2005;11:244–8.

    CAS  PubMed  Google Scholar 

  75. Akoyev V, Takemoto DJ. ZO-1 is required for protein kinase C γ-driven disassembly of connexin 43. Cell Signal. 2007;19:958–67.

    Article  CAS  PubMed  Google Scholar 

  76. Butkevich E, Hulsmann S, Wenzel D, Shirao T, Duden R, Majoul I. Drebrin is a novel connexin-43 binding partner that links gap junctions to the submembrane cytoskeleton. Curr Biol. 2004;14:650–8.

    Article  CAS  PubMed  Google Scholar 

  77. Li W, Nagy JI. Connexin43 phosphorylation state and intercellular communication in cultured astrocytes following hypoxia and protein phosphatase inhibition. Eur J Neurosci. 2000;12:2644–50.

    Article  CAS  PubMed  Google Scholar 

  78. Li WE, Ochalski PA, Hertzberg EL, Nagy JI. Immunorecognition, ultrastructure and phosphorylation status of astrocytic gap junctions and connexin43 in rat brain after cerebral focal ischaemia. Eur J Neurosci. 1998;10:2444–63.

    Article  CAS  PubMed  Google Scholar 

  79. Cooper CD, Lampe PD. Casein kinase 1 regulates connexin43 gap junction assembly. J Biol Chem. 2002;277:44962–8.

    Article  CAS  PubMed  Google Scholar 

  80. Lampe PD, Cooper CD, King TJ, Burt JM. Analysis of connexin43 phosphorylated at S325, S328 and S330 in normoxic and ischemic heart. J Cell Sci. 2006;119:3435–42.

    Article  CAS  PubMed  Google Scholar 

  81. Doble BW, Dang X, Ping P, Fandrich RR, Nickel BE, Jin Y, Cattini PA, Kardami E. Phosphorylation of serine 262 in the gap junction protein connexin-43 regulates DNA synthesis in cell-cell contact forming cardiomyocytes. J Cell Sci. 2004;117:507–14.

    Article  CAS  PubMed  Google Scholar 

  82. Lampe PD, TenBroek EM, Burt JM, Kurata WE, Johnson RG, Lau AF. Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication. J Cell Biol. 2000;126:1503–12.

    Article  Google Scholar 

  83. Berthoud VM, Rook M, Hertzberg EL, Sáez JC. On the mechanism of cell uncoupling induced by a tumor promotor phorbol ester in clone 9 cells, a rat liver epithelial cell line. Eur J Cell Biol. 1993;62:384–96.

    CAS  PubMed  Google Scholar 

  84. Reynhout JK, Lampe PD, Johnson RG. An activator of protein kinase C inhibits gap junction communication between cultured bovine lens cells. Exp Cell Res. 1992;198:337–42.

    Article  CAS  PubMed  Google Scholar 

  85. Peracchia C, Sotkis A, Wang XG, Peracchia LL, Persechini A. Calmodulin directly gates gap junction channels. J Biol Chem. 2000;275:26220–4.

    Article  CAS  PubMed  Google Scholar 

  86. Torok K, Stauffer K, Evans WH. Connexin 32 of gap junctions contains two cytoplasmic calmodulin-binding domains. Biochem J. 1997;326:479–83.

    CAS  PubMed  Google Scholar 

  87. Zhang X, Qi Y. Role of intramolecular interaction in connexin50: mediating the Ca2+ dependent binding of calmodulin to gap junction. Arch Biochem Biophys. 2005;440:111–7.

    Article  CAS  PubMed  Google Scholar 

  88. Burr GS, Mitchell CK, Keflemariam YJ, Heidelberger R, O'Brien J. Calcium-dependent binding of calmodulin to neuronal gap junction proteins. Biochem Biophys Res Commun. 2005;335:1191–8.

    Article  CAS  PubMed  Google Scholar 

  89. Loo LW, Kanemitsu MY, Lau AF. In vivo association of pp60v-src and the gap-junction protein connexin 43 in v-src-transformed fibroblasts. Mol Carcinogen. 1999;25:187–95.

    Article  CAS  Google Scholar 

  90. Giepmans BN, Hengeveld T, Postma FR, Moolenaar WH. Interaction of c-Src with gap junction protein connexin-43. Role in the regulation of cell-cell communication. J Biol Chem. 2001;276:8544–9.

    Article  CAS  PubMed  Google Scholar 

  91. Toyofuku T, Akamatsu Y, Zhang H, Kuzuya T, Tada M, Hori M. c-Src regulates the interaction between connexin-43 and ZO-1 in cardiac myocytes. J Biol Chem. 2001;276:1780–8.

    Article  CAS  PubMed  Google Scholar 

  92. Lin R, Warn-Cramer BJ, Kurata WE, Lau AF. v-Src phosphorylation of connexin 43 on Tyr247 and Tyr265 disrupts gap junctional communication. J Cell Biol. 2001;154:815–27.

    Article  CAS  PubMed  Google Scholar 

  93. Sorgen PL, Duffy HS, Sahoo P, Coombs W, Delmar M, Spray DC. Structural changes in the carboxyl terminus of the gap junction protein connexin43 indicates signaling between binding domains for c-Src and zonula occludens-1. J Biol Chem. 2004;279:54695–701.

    Article  CAS  PubMed  Google Scholar 

  94. Duffy HS, Ashton AW, O'Donnell P, Coombs W, Taffet SM, Delmar M, Spray DC. Regulation of connexin43 protein complexes by intracellular acidification. Circ Res. 2004;94:215–22.

    Article  CAS  PubMed  Google Scholar 

  95. Cottrell GT, Lin R, Warn-Cramer BJ, Lau AF, Burt JM. Mechanism of v-Src- and mitogen-activated protein kinase-induced reduction of gap junction communication. Am J Physiol Cell Physiol. 2003;284:C511–20.

    CAS  PubMed  Google Scholar 

  96. Zhou L, Kasperek EM, Nicholson BJ. Dissection of the molecular basis of pp60(v-src) induced gating of connexin 43 gap junction channels. J Cell Biol. 1999;144:1033–45.

    Article  CAS  PubMed  Google Scholar 

  97. Warn-Cramer BJ, Cottrell GT, Burt JM, Lau AF. Regulation of connexin-43 gap junctional intercellular communication by mitogen-activated protein kinase. J Biol Chem. 1998;273:9188–96.

    Article  CAS  PubMed  Google Scholar 

  98. Polontchouk L, Ebelt B, Jackels M, Dhein S. Chronic effects of endothelin 1 and angiotensin II on gap junctions and intercellular communication in cardiac cells. FASEB J. 2002;16:87–9.

    CAS  PubMed  Google Scholar 

  99. Petrich BG, Gong X, Lerner DL, Wang X, Brown JH, Saffitz JE, Wang Y. c-Jun N-terminal kinase activation mediates downregulation of connexin43 in cardiomyocytes. Circ Res. 2002;91:640–7.

    Article  CAS  PubMed  Google Scholar 

  100. Cameron SJ, Malik S, Akaike M, Lerner-Marmarosh N, Yan C, Lee JD, Abe J, Yang J. Regulation of epidermal growth factor-induced connexin 43 gap junction communication by big mitogen-activated protein kinase1/ERK5 but not ERK1/2 kinase activation. J Biol Chem. 2003;278:18682–8.

    Article  CAS  PubMed  Google Scholar 

  101. Yamamoto T, Kojima T, Murata M, Takano K, Go M, Hatakeyama N, Chiba H, Sawada N. p38 MAP-kinase regulates function of gap and tight junctions during regeneration of rat hepatocytes. J Hepatol. 2005;42:707–18.

    Article  CAS  PubMed  Google Scholar 

  102. Qin H, Shao Q, Igdoura SA, Alaoui-Jamali MA, Laird DW. Lysosomal and proteasomal degradation play distinct roles in the life cycle of Cx43 in gap junctional intercellular communication-deficient and -competent breast tumor cells. J Biol Chem. 2003;278:30005–14.

    Article  CAS  PubMed  Google Scholar 

  103. Thomas MA, Zosso N, Scerri I, Demaurex N, Chanson M, Staub O. A tyrosine-based sorting signal is involved in connexin43 stability and gap junction turnover. J Cell Sci. 2003;116:2213–22.

    Article  CAS  PubMed  Google Scholar 

  104. Leykauf K, Salek M, Bomke J, Frech M, Lehmann WD, Durst M, Alonso A. Ubiquitin protein ligase Nedd4 binds to connexin43 by a phosphorylation-modulated process. J Cell Sci. 2006;119:3634–42.

    Article  CAS  PubMed  Google Scholar 

  105. Lan Z, Kurata WE, Martyn KD, Jin C, Lau AF. Novel rab GAP-like protein, CIP85, interacts with connexin43 and induces its degradation. Biochemistry 2005;44:2385–96.

    Article  CAS  PubMed  Google Scholar 

  106. Xie H, Laird DW, Chang T-H, Hu VW. A mitosis-specific phosphorylation of the gap junction protein connexin43 in human vascular cells: biochemical characterization and localization. J Cell Biol. 1997;137:203–10.

    Article  CAS  PubMed  Google Scholar 

  107. Lampe PD, Kurata WE, Warn-Cramer B, Lau AF. Formation of a distinct connexin43 phosphoisoform in mitotic cells is dependent upon p34cdc2 kinase. J Cell Sci. 1998;111:833–41.

    CAS  PubMed  Google Scholar 

  108. Kanemitsu MY, Jiang W, Eckhart W. Cdc2-mediated phosphorylation of the gap junction protein, connexin43, during mitosis. Cell Growth Differ. 1998;9:13–21.

    CAS  PubMed  Google Scholar 

  109. Yin X, Gu S, Jiang JX. The development-associated cleavage of lens connexin 45.6 by caspase-3-like protease is regulated by casein kinase II-mediated phosphorylation. J Biol Chem. 2001;276:34567–72.

    Article  CAS  PubMed  Google Scholar 

  110. Yin X, Jedrzejewski PT, Jiang JX. Casein kinase II phosphorylates lens connexin 45.6 and is involved in its degradation. J Biol Chem. 2000;275:6850–6.

    Article  CAS  PubMed  Google Scholar 

  111. Hertlein B, Butterweck A, Haubrich S, Willecke K, Traub O. Phosphorylated carboxy-terminal serine residues stabilize the mouse gap junction protein connexin45 against degradation. J Membrane Biol. 1998;162:247–57.

    Article  CAS  Google Scholar 

  112. Squecco R, Sassoli C, Nuti F, Martinesi M, Chellini F, Nosi D, Zecchi-Orlandini S, Francini F, Formigli L, Meacci E. Sphingosine 1-phosphate induces myoblast differentiation through Cx43 protein expression: a role for a gap junction-dependent and -independent function. Mol Biol Cell. 2006;17:4896–910.

    Article  CAS  PubMed  Google Scholar 

  113. Gellhaus A, Dong X, Propson S, Maass K, Klein-Hitpass L, Kibschull M, Traub O, Willecke K, Perbal B, Lye SJ, Winterhager E. Connexin43 interacts with NOV: a possible mechanism for negative regulation of cell growth in choriocarcinoma cells. J Biol Chem. 2004;279:36931–42.

    Article  CAS  PubMed  Google Scholar 

  114. Balda MS, Garrett MD, Matter K. The ZO-1-associated Y-box factor ZONAB regulates epithelial cell proliferation and cell density. J Cell Biol. 2003;160:423–32.

    Article  CAS  PubMed  Google Scholar 

  115. Ciolofan C, Li XB, Olson C, Kamasawa N, Gebhardt BR, Yasumura T, Morita M, Rash JE, Nagy JI. Association of connexin36 and zonula occludens-1 with zonula occludens-2 and the transcription factor zonula occludens-1-associated nucleic acid-binding protein at neuronal gap junctions in rodent retina. Neuroscience. 2006;140:433–51.

    Article  CAS  PubMed  Google Scholar 

  116. Lagree V, Brunschwig K, Lopez P, Gilula NB, Richard G, Falk MM. Specific amino-acid residues in the N-terminus and M3 implicated in channel function and oligomerization compatibility of connexin43. J Cell Sci. 2003;116:3189–201.

    Article  CAS  PubMed  Google Scholar 

  117. Harris AL. Emerging issues of connexin channels: biophysics fills the gap. Q Rev Biophys. 2001;34:325–472.

    CAS  PubMed  Google Scholar 

  118. White TW, Paul DL, Goodenough DA, Bruzzone R. Functional analysis of selective interactions among rodent connexins. Mol Biol Cell. 1995;6:459–70.

    CAS  PubMed  Google Scholar 

  119. Foote CI, Zhou L, Zhu X, Nicholson BJ. 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. 1998;140:1187–97.

    Article  CAS  PubMed  Google Scholar 

  120. Bao X, Chen Y, Reuss L, Altenberg GA. Functional expression in Xenopus oocytes of gap-junctional hemichannels formed by a cysteine-less connexin 43. J Biol Chem. 2004;279:9689–92.

    Article  CAS  PubMed  Google Scholar 

  121. Shibayama J, Guti~rrez C, Gonzalez D, Kieken F, Seki A, Carrion JR, Sorgen PL, Taffet SM, Barrio LC, Delmar M. Effect of charge substitutions at residue his-142 on voltage-gating of connexin43 channels. Biophys J. 2006;91:4054–63.

    Article  CAS  PubMed  Google Scholar 

  122. Kanemitsu MY, Loo LW, Simon S, Lau AF, Eckhart W. Tyrosine phosphorylation of connexin 43 by v-src is mediated by SH2 and SH3 domain interactions. J Biol Chem. 1997;272:22824–31.

    Article  CAS  PubMed  Google Scholar 

  123. Giepmans BN, Feiken E, Gebbink MF, Moolenaar WH. Association of connexin43 with a receptor protein tyrosine phosphatase. Cell Commun Adhes. 2003;10:201–5.

    CAS  PubMed  Google Scholar 

  124. Wang XG, Peracchia C. Positive charges of the initial C-terminus domain of Cx32 inhibit gap junction gating sensitivity to CO2. Biophys J. 1997;73:798–806.

    Article  CAS  PubMed  Google Scholar 

  125. Giepmans BN, Moolenaar WH. The gap junction protein connexin43 interacts with the second PDZ domain of the zona occludens-1 protein. Curr Biol. 1998;8:931–4.

    Article  CAS  PubMed  Google Scholar 

  126. Toyofuku T, Yabuki M, Otsu K, Kuzuya T, Hori M, Tada M. Direct association of the gap junction protein connexin-43 with ZO-1 in cardiac myocytes. J Biol Chem. 1998;273:12725–31.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The work performed in the authors’ lab reviewed here was supported by National Institutes of Health (NIH) grant GM55632.

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  1. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M5C800 Box 19024, Seattle, WA 98109, US

    Paul D. Lampe

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  1. Joell L. Solan
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Correspondence to Paul D. Lampe .

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  1. New Jersey Medical School UMDNJ, Newark, NJ, USA

    Andrew L. Harris  & Darren Locke  & 

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Solan, J.L., Lampe, P.D. (2009). Biochemistry of Connexins. In: Harris, A.L., Locke, D. (eds) Connexins. Humana Press. https://doi.org/10.1007/978-1-59745-489-6_11

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