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Biogenesis and Degradation of Gap Junctions

  • Chapter
Connexins

Abstract

The dynamic regulation of gap junction biogenesis and degradation is a key element in the control of intercellular communication. This regulation starts in the endoplasmic reticulum, in which a large fraction of newly synthesized connexin molecules can be degraded. Multisubunit assembly of endogenously expressed connexins is first detected in the trans-Golgi network, as opposed to the endoplasmic reticulum wherein most other integral membrane proteins oligomerize. Gap junction plaques grow, at least in part, by lateral diffusion of plasma membrane connexin hemichannels to the periphery of the plaques. Connexins have a half-life of a few hours, being turned over within the endoplasmic reticulum by the ubiquitin/proteasome system and after transport to the cell surface via the lysosome. Although some aspects of gap junction biogenesis and degradation are relatively well understood, several intriguing unanswered questions remain.

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References

  1. Valiunas V, Bukauskas FF, Weingart R. Conductances and selective permeability of connexin43 gap junction channels examined in neonatal rat heart cells. Circ Res. 1997;80:708–19.

    CAS  PubMed  Google Scholar 

  2. Castro C, Gomez-Hernandez JM, Silander K, Barrio LC. Altered formation of hemichannels and gap junction channels caused by C-terminal connexin-32 mutations. J Neurosci. 1999;19:3752–60.

    CAS  PubMed  Google Scholar 

  3. Zhang JT, Chen M, Foote CI, Nicholson BJ. Membrane integration of in vitro-translated gap junctional proteins: co- and posttranslational mechanisms. Mol Biol Cell. 1996;7:471–82.

    CAS  PubMed  Google Scholar 

  4. Falk MM, Buehler LK, Kumar NM, Gilula NB. Cell-free synthesis and assembly of connexins into functional gap junction membrane channels. EMBO J. 1997;16:2703–16.

    Article  CAS  PubMed  Google Scholar 

  5. Falk MM, Kumar NM, Gilula NB. Membrane insertion of gap junction connexins: polytopic channel-forming membrane proteins. J Cell Biol. 1994;127:343–55.

    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. Meusser B, Hirsch C, Jarosch E, Sommer T. ERAD: the long road to destruction. Nat Cell Biol. 2005;7:766–72.

    Article  CAS  PubMed  Google Scholar 

  8. Glickman MH, Ciechanover A. The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev. 2002;82:373–428.

    CAS  PubMed  Google Scholar 

  9. Jarosch E, Lenk U, Sommer T. Endoplasmic reticulum-associated protein degradation. Int Rev Cytol. 2003;223:39–81.

    Article  CAS  PubMed  Google Scholar 

  10. Groll M, Huber R. Inhibitors of the eukaryotic 20S proteasome core particle: a structural approach. Biochim Biophys Acta. 2004;1695:33–44.

    Article  CAS  PubMed  Google Scholar 

  11. 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 

  12. Kelly SM, Vanslyke JK, Musil LS. Regulation of ubiquitin-proteasome system-mediated degradation by cytosolic stress. Mol Biol Cell. 2007;18:4279–91.

    Article  CAS  PubMed  Google Scholar 

  13. Goldberg GS, Lampe PD, Nicholson BJ. Selective transfer of endogenous metabolites through gap junctions composed of different connexins. Nat Cell Biol. 1999;1:457–9.

    Article  CAS  PubMed  Google Scholar 

  14. Nakamura TY, Yamamoto I, Kanno Y, Shiba Y, Goshima K. Metabolic coupling of glutathione between mouse and quail cardiac myocytes and its protective role against oxidative stress. Circ Res. 1994;74:806–16.

    CAS  PubMed  Google Scholar 

  15. Laing JG, Tadros PN, Green K, Saffitz JE, Beyer EC. Proteolysis of connexin43-containing gap junctions in normal and heat-stressed cardiac myocytes. Cardiovasc Res. 1998;38:711–8.

    Article  CAS  PubMed  Google Scholar 

  16. Hamada N, Kodama S, Suzuki K, Watanabe M. Gap junctional intercellular communication and cellular response to heat stress. Carcinogenesis. 2003;24:1723–8.

    Article  CAS  PubMed  Google Scholar 

  17. Mitra S, Annamalai L, Chakraborty S, Johnson K, Song X, Batra S, Mehta, P. Androgen-regulated formation and degradation of gap junctions in androgen-responsive human prostate cancer cells. Mol Biol Cell. 2006;17:5400–16.

    Article  CAS  PubMed  Google Scholar 

  18. Kang SW, Rane NS, Kim SJ, Garrison JL, Taunton J, Hegde RS. Substrate-specific translocational attenuation during ER stress defines a pre-emptive quality control pathway. Cell. 2006;127:999–1013.

    Article  CAS  PubMed  Google Scholar 

  19. Musil LS, Goodenough DA. Multisubunit assembly of an integral plasma membrane channel protein, gap junction connexin43, occurs after exit from the ER. Cell. 1993;74:1065–77.

    Article  CAS  PubMed  Google Scholar 

  20. Koval M, Harley JE, Hick E, Steinberg TH. Connexin46 is retained as monomers in a trans-Golgi compartment of osteoblastic cells. J Cell Biol. 1997;137:847–57.

    Article  CAS  PubMed  Google Scholar 

  21. Sarma JD, Wang F, Koval M. Targeted gap junction protein constructs reveal connexin-specific differences in oligomerization. J Biol Chem. 2002;277:20911–8.

    Article  PubMed  Google Scholar 

  22. Maza J, Das Sarma J, Koval M. Defining a minimal motif required to prevent connexin oligomerization in the endoplasmic reticulum. J Biol Chem. 2005;280:21115–21.

    Article  CAS  PubMed  Google Scholar 

  23. VanSlyke JK, Musil LS. Exogenous overexpression of connexins induces premature assembly of connexons in the ER J. Cell Commun Adhes. 2005;12:86.

    Google Scholar 

  24. Omori Y, Mesnil M, Yamasaki H. Connexin 32 mutations from X-linked Charcot-Marie-Tooth disease patients: functional defects and dominant-negative effects. Mol Biol Cell. 1996;7:907–16.

    CAS  PubMed  Google Scholar 

  25. Kumar NM, Gilula NB. Molecular biology and genetics of gap junction channels. Semin Cell Biol. 1992;3:3–16.

    Article  CAS  PubMed  Google Scholar 

  26. Koch AW, Farooq A, Shan W, Zeng L, Colman DR, Zhou MM. Structure of the neural (N-) cadherin prodomain reveals a cadherin extracellular domain-like fold without adhesive characteristics. Structure. 2004;12:793–805.

    Article  CAS  PubMed  Google Scholar 

  27. 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 

  28. Thomas T, Jordan K, Simek J, Shao Q, Jedeszko C, Walton P, Laird DW. Mechanisms of Cx43 and Cx26 transport to the plasma membrane and gap junction regeneration. J Cell Sci. 2005;118:4451–62.

    Article  CAS  PubMed  Google Scholar 

  29. George CH, Kendall JM, Evans WH. Intracellular trafficking pathways in the assembly of connexins into gap junctions. J Biol Chem. 1999;274:8678–85.

    Article  CAS  PubMed  Google Scholar 

  30. Lauf U, Lopez P, Falk MM. Expression of fluorescently tagged connexins: a novel approach to rescue function of oligomeric DsRed-tagged proteins. FEBS Lett. 2001;498:11–5.

    Article  CAS  PubMed  Google Scholar 

  31. Sáez JC, Retamal MA, Basilio D, Bukauskas FF, Bennett MVL. Connexin-based gap junction hemichannels: gating mechanisms. Biochim Biophys Acta. 2005;1711:215–24.

    Article  CAS  PubMed  Google Scholar 

  32. Ebihara L. New roles for connexons. News Physiol Sci. 2003;18:100–3.

    CAS  PubMed  Google Scholar 

  33. Goodenough DA, Paul DL. Beyond the gap: functions of unpaired connexon channels. Nat Rev Mol Cell Biol. 2003;4:285–94.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  35. Lauf U, Giepmans BN, Lopez P, Braconnot S, Chen SC, Falk MM. Dynamic trafficking and delivery of connexons to the plasma membrane and accretion to gap junctions in living cells. Proc Natl Acad Sci USA. 2002;99:10446–51.

    Google Scholar 

  36. Gaietta G, Deerinck DT, Adams SR, Bouwer J, Tour O, Laird DW, Sosinsky GE, Tsien RY, Ellisman MH. Multicolor and electron microscopic imaging of connexin trafficking. Science. 2002;296:503–7.

    Article  CAS  PubMed  Google Scholar 

  37. 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 

  38. Guerrier A, Fonlupt P, Morand I, Rabilloud R, Audebet C, Krutovskikh V,Gros D, Rousset B, Munari-Silem Y. Gap junctions and cell polarity: connexin32 and connexin43 expressed in polarized thyroid epithelial cells assemble into separate gap junctions, which are located in distinct regions of the lateral plasma membrane domain. J Cell Sci. 1995;108:2609–17.

    CAS  PubMed  Google Scholar 

  39. Wang Y, Rose B. An inhibition of gap-junctional communication by cadherins. J Cell Sci. 1997;110:301–9.

    CAS  PubMed  Google Scholar 

  40. Johnson RG, Meyer RA, Lampe PD. Gap junction formation: a self-assembly model involving membrane domains of lipid and protein. In: Sperelakis N, Cole WC, editors. Cell interactions and gap junctions. Boca Raton, FL: CRC Press; 1989. pp. 159–79.

    Google Scholar 

  41. Traub O, Look J, Dermietzel R, Brummer F, Hülser D, Willecke K. Comparative characterization of the 21-kD and 26-kD gap junction proteins in murine liver and cultured hepatocytes. J Cell Biol. 1989;108:1039–51.

    Article  CAS  PubMed  Google Scholar 

  42. Musil LS, Le AC, VanSlyke JK, Roberts LM. Regulation of connexin degradation as a mechanism to increase gap junction assembly and function. J Biol Chem. 2000;275:25207–15.

    Article  CAS  PubMed  Google Scholar 

  43. Beardslee MA, Laing JG, Beyer EC, Saffitz JE. Rapid turnover of connexin43 in the adult rat heart. Circ Res. 1998;83:629–35.

    CAS  PubMed  Google Scholar 

  44. 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 

  45. 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 

  46. Fallon RF, Goodenough DA. Five-hour half-life of mouse liver gap-junction protein. J Cell Biol. 1981;90:521–6.

    Article  CAS  PubMed  Google Scholar 

  47. Fishman GI, Gao Y, Hertzberg EL, Spray DC. Reversible intercellular coupling by regulated expression of a gap junction channel gene. Cell Adhes Commun. 1995;3:353–65.

    Article  CAS  PubMed  Google Scholar 

  48. Jordan K, Chodock R, Hand AR, Laird DW. The origin of annular junctions: a mechanism of gap junction internalization. J Cell Sci. 2001;114:763–73.

    CAS  PubMed  Google Scholar 

  49. McNeil PL, Steinhardt RA. Plasma membrane disruption: repair, prevention, adaptation. Annu Rev Cell Dev Biol. 2003;19:697–731.

    Google Scholar 

  50. 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 

  51. Larsen WJ, Tung HN. Origin and fate of cytoplasmic gap junction vesicles in rabbit granulosa cells. Tissue Cell. 1978;10:585–598.

    CAS  PubMed  Google Scholar 

  52. 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 

  53. Laing JG, Tadros PN, Westphale EM, Beyer EC. Degradation of connexin43 gap junctions involves both the proteasome and the lysosome. Exp Cell Res. 1997;236:482–92.

    Article  CAS  PubMed  Google Scholar 

  54. Tsukamoto T, Nigam SK. Cell-cell dissociation upon epithelial cell scattering requires a step mediated by the proteasome. J Biol Chem. 1999;274:24579–84.

    Article  CAS  PubMed  Google Scholar 

  55. Longva KE, Blystad FD, Stang E, Larsen AM, Johannessen LE, Madshus IH. Ubiquitination and proteasomal activity is required for transport of the EGF receptor to inner membranes of multivesicular bodies. J Cell Biol. 2002;156:843–54.

    Article  CAS  PubMed  Google Scholar 

  56. Younger JM, Ren HY, Chen L, Fan CY, Fields A, Patterson C, Cyr DM. A foldable CFTRδF508 biogenic intermediate accumulates upon inhibition of the Hsc70-CHIP E3 ubiquitin ligase. J Cell Biol. 2004;167:1075–85.

    Article  CAS  PubMed  Google Scholar 

  57. Johnson R, Hammer M, Sheridan J, Revel JP. Gap junction formation between reaggregated Novikoff hepatoma cells. Proc Natl Acad Sci USA. 1974;71:4536–40.

    Google Scholar 

  58. 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 

  59. 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 

  60. Ahmad S, Tang W, Chang Q, Qu Y, Hibshman J, Li Y, Söhl G, Willecke K, Chen P, Lin X. Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness. Proc Natl Acad Sci USA. 2007;104:1337–41.

    Google Scholar 

  61. Mesnil M, Crespin S, Avanzo JL, Zaidan-Dagli ML. Defective gap junctional intercellular communication in the carcinogenic process. Biochim Biophys Acta. 2005;1719:125–45.

    Article  CAS  PubMed  Google Scholar 

  62. Mesnil M. Connexins and cancer. Biol Cell. 2002;94:493–500.

    Article  CAS  PubMed  Google Scholar 

  63. Mesnil M, Yamasaki H. Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy: role of gap-junctional intercellular communication. Cancer Res. 2000;60:3989–99.

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by National Institutes of Health (NIH) grants R01 NS40740-01 and R01 EY014622.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology L224, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, US

    Linda S. Musil

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  1. Linda S. Musil
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Correspondence to Linda S. Musil .

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Editors and Affiliations

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

    Andrew L. Harris  & Darren Locke  & 

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Musil, L.S. (2009). Biogenesis and Degradation of Gap Junctions. In: Harris, A.L., Locke, D. (eds) Connexins. Humana Press. https://doi.org/10.1007/978-1-59745-489-6_9

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