Skip to main content
SpringerLink
Log in

Posttranslational Modifications in Connexins and Pannexins

  • Published:
The Journal of Membrane Biology Aims and scope Submit manuscript

Abstract

Posttranslational modification is a common cellular process that is used by cells to ensure a particular protein function. This can happen in a variety of ways, e.g., from the addition of phosphates or sugar residues to a particular amino acid, ensuring proper protein life cycle and function. In this review, we assess the evidence for ubiquitination, glycosylation, phosphorylation, S-nitrosylation as well as other modifications in connexins and pannexin proteins. Based on the literature, we find that posttranslational modifications are an important component of connexin and pannexin regulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Ambrosi C, Gassmann O, Pranskevich JN, Boassa D, Smock A, Wang J, Dahl G, Steinem C, Sosinsky GE (2010) Pannexin1 and pannexin2 channels show quaternary similarities to connexons and different oligomerization numbers from each other. J Biol Chem 285:24420–24431

    Article  PubMed  CAS  Google Scholar 

  • Andrade-Rozental AF, Rozental R, Hopperstad MG, Wu JK, Vrionis FD, Spray DC (2000) Gap junctions: the “kiss of death” and the “kiss of life”. Brain Res Brain Res Rev 32:308–315

    Article  PubMed  CAS  Google Scholar 

  • Bao L, Locovei S, Dahl G (2004a) Pannexin membrane channels are mechanosensitive conduits for ATP. FEBS Lett 572:65–68

    Article  PubMed  CAS  Google Scholar 

  • Bao X, Reuss L, Altenberg GA (2004b) Regulation of purified and reconstituted connexin 43 hemichannels by protein kinase C-mediated phosphorylation of serine 368. J Biol Chem 279:20058–20066

    Article  PubMed  CAS  Google Scholar 

  • Bao X, Lee SC, Reuss L, Altenberg GA (2007) Change in permeant size selectivity by phosphorylation of connexin 43 gap-junctional hemichannels by PKC. Proc Natl Acad Sci USA 104:4919–4924

    Article  PubMed  CAS  Google Scholar 

  • Barbe MT, Monyer H, Bruzzone R (2006) Cell–cell communication beyond connexins: the pannexin channels. Physiology (Bethesda) 21:103–114

    Article  CAS  Google Scholar 

  • Bargiotas P, Krenz A, Hormuzdi SG, Ridder DA, Herb A, Barakat W, Penuela S, von Engelhardt J, Monyer H, Schwaninger M (2011) Pannexins in ischemia-induced neurodegeneration. Proc Natl Acad Sci USA 108:20772–20777

    Article  PubMed  CAS  Google Scholar 

  • Beardslee MA, Laing JG, Beyer EC, Saffitz JE (1998) Rapid turnover of connexin43 in the adult rat heart. Circ Res 83:629–635

    Article  PubMed  CAS  Google Scholar 

  • Beardslee MA, Lerner DL, Tadros PN, Laing JG, Beyer EC, Yamada KA, Kleber AG, Schuessler RB, Saffitz JE (2000) Dephosphorylation and intracellular redistribution of ventricular connexin43 during electrical uncoupling induced by ischemia. Circ Res 87:656–662

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Billaud M, Lohman AW, Straub AC, Looft-Wilson R, Johnstone SR, Araj CA, Best AK, Chekeni FB, Ravichandran KS, Penuela S, Laird DW, Isakson BE (2011) Pannexin1 regulates alpha1-adrenergic receptor- mediated vasoconstriction. Circ Res 109:80–85

    Article  PubMed  CAS  Google Scholar 

  • Boassa D, Ambrosi C, Qiu F, Dahl G, Gaietta G, Sosinsky G (2007) Pannexin1 channels contain a glycosylation site that targets the hexamer to the plasma membrane. J Biol Chem 282:31733–31743

    Article  PubMed  CAS  Google Scholar 

  • Boassa D, Qiu F, Dahl G, Sosinsky G (2008) Trafficking dynamics of glycosylated pannexin 1 proteins. Cell Commun Adhes 15:119–132

    Article  PubMed  CAS  Google Scholar 

  • Boitano S, Evans WH (2000) Connexin mimetic peptides reversibly inhibit Ca2+ signaling through gap junctions in airway cells. Am J Physiol Lung Cell Mol Physiol 279:L623–L630

    PubMed  CAS  Google Scholar 

  • Brill LM, Xiong W, Lee KB, Ficarro SB, Crain A, Xu Y, Terskikh A, Snyder EY, Ding S (2009) Phosphoproteomic analysis of human embryonic stem cells. Cell Stem Cell 5:204–213

    Article  PubMed  CAS  Google Scholar 

  • Bunse S, Schmidt M, Prochnow N, Zoidl G, Dermietzel R (2010) Intracellular cysteine 346 is essentially involved in regulating Panx1 channel activity. J Biol Chem 285:38444–38452

    Article  PubMed  CAS  Google Scholar 

  • Bunse S, Schmidt M, Hoffmann S, Engelhardt K, Zoidl G, Dermietzel R (2011) Single cysteines in the extracellular and transmembrane regions modulate pannexin 1 channel function. J Membr Biol 244:21–33

    Article  PubMed  CAS  Google Scholar 

  • Burt JM, Nelson TK, Simon AM, Fang JS (2008) Connexin 37 profoundly slows cell cycle progression in rat insulinoma cells. Am J Physiol Cell Physiol 295:C1103–C1112

    Article  PubMed  CAS  Google Scholar 

  • Chandrasekhar A, Bera AK (2012) Hemichannels: permeants and their effect on development, physiology and death. Cell Biochem Funct 30:89–100

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Chen VC, Gouw JW, Naus CC, Foster LJ (2012) Connexin multi-site phosphorylation: mass spectrometry-based proteomics fills the gap. Biochim Biophys Acta. doi:10.1016/j.bbamem.2012.02.028

  • Contreras JE, Sanchez HA, Eugenin EA, Speidel D, Theis M, Willecke K, Bukauskas FF, Bennett MV, Saez JC (2002) Metabolic inhibition induces opening of unapposed connexin 43 gap junction hemichannels and reduces gap junctional communication in cortical astrocytes in culture. Proc Natl Acad Sci USA 99:495–500

    Article  PubMed  CAS  Google Scholar 

  • Cooper CD, Lampe PD (2002) Casein kinase 1 regulates connexin-43 gap junction assembly. J Biol Chem 277:44962–44968

    Article  PubMed  CAS  Google Scholar 

  • Cooper CD, Solan JL, Dolejsi MK, Lampe PD (2000) Analysis of connexin phosphorylation sites. Methods 20:196–204

    Article  PubMed  CAS  Google Scholar 

  • Cottrell GT, Lin R, Warn-Cramer BJ, Lau AF, Burt JM (2003) Mechanism of v-Src- and mitogen-activated protein kinase-induced reduction of gap junction communication. Am J Physiol Cell Physiol 284:C511–C520

    PubMed  CAS  Google Scholar 

  • Crow DS, Beyer EC, Paul DL, Kobe SS, Lau AF (1990) Phosphorylation of connexin43 gap junction protein in uninfected and Rous sarcoma virus-transformed mammalian fibroblasts. Mol Cell Biol 10:1754–1763

    PubMed  CAS  Google Scholar 

  • Dando R, Roper SD (2009) Cell-to-cell communication in intact taste buds through ATP signalling from pannexin 1 gap junction hemichannels. J Physiol 587:5899–5906

    Article  PubMed  CAS  Google Scholar 

  • Das Sarma J, Meyer RA, Wang F, Abraham V, Lo CW, Koval M (2001) Multimeric connexin interactions prior to the trans-Golgi network. J Cell Sci 114:4013–4024

    PubMed  CAS  Google Scholar 

  • Davis FP (2011) Phosphorylation at the interface. Structure 19:1726–1727

    Article  PubMed  CAS  Google Scholar 

  • De Vuyst E, Decrock E, De Bock M, Yamasaki H, Naus CC, Evans WH, Leybaert L (2007) Connexin hemichannels and gap junction channels are differentially influenced by lipopolysaccharide and basic fibroblast growth factor. Mol Biol Cell 18:34–46

    Article  PubMed  CAS  Google Scholar 

  • del Castillo FJ, Cohen-Salmon M, Charollais A, Caille D, Lampe PD, Chavrier P, Meda P, Petit C (2009) Consortin, a trans-Golgi network cargo receptor for the plasma membrane targeting and recycling of connexins. Hum Mol Genet 19:262–275

    Article  PubMed  CAS  Google Scholar 

  • Doble BW, Dang X, Ping P, Fandrich RR, Nickel BE, Jin Y, Cattini PA, Kardami E (2004) Phosphorylation of serine 262 in the gap junction protein connexin-43 regulates DNA synthesis in cell–cell contact forming cardiomyocytes. J Cell Sci 117:507–514

    Article  PubMed  CAS  Google Scholar 

  • Dunn CA, Su V, Lau AF, Lampe PD (2012) Activation of Akt, not connexin 43 protein ubiquitination, regulates gap junction stability. J Biol Chem 287:2600–2607

    Article  PubMed  CAS  Google Scholar 

  • Ek-Vitorin JF, King TJ, Heyman NS, Lampe PD, Burt JM (2006) Selectivity of connexin 43 channels is regulated through protein kinase C-dependent phosphorylation. Circ Res 98:1498–1505

    Article  PubMed  CAS  Google Scholar 

  • Falk MM, Gilula NB (1998) Connexin membrane protein biosynthesis is influenced by polypeptide positioning within the translocon and signal peptidase access. J Biol Chem 273:7856–7864

    Article  PubMed  CAS  Google Scholar 

  • Falk MM, Buehler LK, Kumar NM, Gilula NB (1997) Cell-free synthesis and assembly of connexins into functional gap junction membrane channels. EMBO J 16:2703–2716

    Article  PubMed  CAS  Google Scholar 

  • Freeze HH, Sharma V (2010) Metabolic manipulation of glycosylation disorders in humans and animal models. Semin Cell Dev Biol 21:655–662

    Article  PubMed  CAS  Google Scholar 

  • Gehi R, Shao Q, Laird DW (2011) Pathways regulating the trafficking and turnover of pannexin1 protein and the role of the C-terminal domain. J Biol Chem 286:27639–27653

    Article  PubMed  CAS  Google Scholar 

  • Geiss-Friedlander R, Melchior F (2007) Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 8:947–956

    Article  PubMed  CAS  Google Scholar 

  • Girao H, Pereira P (2007) The proteasome regulates the interaction between Cx43 and ZO-1. J Cell Biochem 102:719–728

    Article  PubMed  CAS  Google Scholar 

  • Girao H, Catarino S, Pereira P (2009) Eps15 interacts with ubiquitinated Cx43 and mediates its internalization. Exp Cell Res 315:3587–3597

    Article  PubMed  CAS  Google Scholar 

  • Godecke S, Roderigo C, Rose CR, Rauch BH, Godecke A, Schrader J (2012) Thrombin-induced ATP release from human umbilical vein endothelial cells. Am J Physiol Cell Physiol 302:C915–C923

    Article  PubMed  CAS  Google Scholar 

  • He LQ, Cai F, Liu Y, Liu MJ, Tan ZP, Pan Q, Fang FY, de Liang S, Wu LQ, Long ZG, Dai HP, Xia K, Xia JH, Zhang ZH (2005) Cx31 is assembled and trafficked to cell surface by ER–Golgi pathway and degraded by proteasomal or lysosomal pathways. Cell Res 15:455–464

    Article  PubMed  CAS  Google Scholar 

  • Hertlein B, Butterweck A, Haubrich S, Willecke K, Traub O (1998) Phosphorylated carboxy terminal serine residues stabilize the mouse gap junction protein connexin45 against degradation. J Membr Biol 162:247–257

    Article  PubMed  CAS  Google Scholar 

  • Hess DT, Stamler JS (2012) Regulation by S-nitrosylation of protein posttranslational modification. J Biol Chem 287:4411–4418

    Article  PubMed  CAS  Google Scholar 

  • Hunter AW, Barker RJ, Zhu C, Gourdie RG (2005) Zonula occludens-1 alters connexin43 gap junction size and organization by influencing channel accretion. Mol Biol Cell 16:5686–5698

    Article  PubMed  CAS  Google Scholar 

  • Huttlin EL, Jedrychowski MP, Elias JE, Goswami T, Rad R, Beausoleil SA, Villen J, Haas W, Sowa ME, Gygi SP (2010) A tissue-specific atlas of mouse protein phosphorylation and expression. Cell 143:1174–1189

    Article  PubMed  CAS  Google Scholar 

  • Iglesias R, Dahl G, Qiu F, Spray DC, Scemes E (2009) Pannexin 1: the molecular substrate of astrocyte “hemichannels”. J Neurosci 29:7092–7097

    Article  PubMed  CAS  Google Scholar 

  • Jin C, Martyn KD, Kurata WE, Warn-Cramer BJ, Lau AF (2004) Connexin43 PDZ2 binding domain mutants create functional gap junctions and exhibit altered phosphorylation. Cell Commun Adhes 11:67–87

    Article  PubMed  CAS  Google Scholar 

  • John SA, Kondo R, Wang SY, Goldhaber JI, Weiss JN (1999) Connexin-43 hemichannels opened by metabolic inhibition. J Biol Chem 274:236–240

    Article  PubMed  CAS  Google Scholar 

  • Johnson LN, Koval M (2009) Cross-talk between pulmonary injury, oxidant stress, and gap junctional communication. Antioxid Redox Signal 11:355–367

    Article  PubMed  CAS  Google Scholar 

  • Johnson GL, Vaillancourt RR (1994) Sequential protein kinase reactions controlling cell growth and differentiation. Curr Opin Cell Biol 6:230–238

    Article  PubMed  CAS  Google Scholar 

  • Johnson RG, Reynhout JK, TenBroek EM, Quade BJ, Yasumura T, Davidson KG, Sheridan JD, Rash JE (2012) Gap junction assembly: roles for the formation plaque and regulation by the C-terminus of connexin43. Mol Biol Cell 23:71–86

    Article  PubMed  CAS  Google Scholar 

  • Johnstone SR, Ross J, Rizzo MJ, Straub AC, Lampe PD, Leitinger N, Isakson BE (2009) Oxidized phospholipid species promote in vivo differential cx43 phosphorylation and vascular smooth muscle cell proliferation. Am J Pathol 175:916–924

    Article  PubMed  CAS  Google Scholar 

  • Johnstone SR, Kroncke BM, Straub AC, Best AK, Dunn CA, Mitchell LA, Peskova Y, Nakamoto RK, Koval M, Lo CW, Lampe PD, Columbus L, Isakson BE (2012) MAPK phosphorylation of connexin 43 promotes binding of cyclin E and smooth muscle cell proliferation. Circ Res

  • Kameritsch P, Khandoga N, Nagel W, Hundhausen C, Lidington D, Pohl U (2005) Nitric oxide specifically reduces the permeability of Cx37-containing gap junctions to small molecules. J Cell Physiol 203:233–242

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Kelsell DP, Di WL, Houseman MJ (2001) Connexin mutations in skin disease and hearing loss. Am J Hum Genet 68:559–568

    Article  PubMed  CAS  Google Scholar 

  • Kim DY, Kam Y, Koo SK, Joe CO (1999) Gating connexin 43 channels reconstituted in lipid vesicles by mitogen-activated protein kinase phosphorylation. J Biol Chem 274:5581–5587

    Article  PubMed  CAS  Google Scholar 

  • Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP (2011) Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol Cell 44:325–340

    Article  PubMed  CAS  Google Scholar 

  • Kjenseth A, Fykerud TA, Sirnes S, Bruun J, Kolberg M, Yohannes Z, Omori Y, Rivedal E, Leithe E (2012) The gap junction channel protein connexin43 is covalently modified and regulated by SUMOylation. J Biol Chem 287:15851–15861

    Article  PubMed  CAS  Google Scholar 

  • Kondo RP, Wang SY, John SA, Weiss JN, Goldhaber JI (2000) Metabolic inhibition activates a non-selective current through connexin hemichannels in isolated ventricular myocytes. J Mol Cell Cardiol 32:1859–1872

    Article  PubMed  CAS  Google Scholar 

  • Koval M (2006) Pathways and control of connexin oligomerization. Trends Cell Biol 16:159–166

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Kwak BR, Jongsma HJ (1996) Regulation of cardiac gap junction channel permeability and conductance by several phosphorylating conditions. Mol Cell Biochem 157:93–99

    Article  PubMed  CAS  Google Scholar 

  • Kwak BR, Hermans MM, De Jonge HR, Lohmann SM, Jongsma HJ, Chanson M (1995) Differential regulation of distinct types of gap junction channels by similar phosphorylating conditions. Mol Biol Cell 6:1707–1719

    PubMed  CAS  Google Scholar 

  • Lai A, Le DN, Paznekas WA, Gifford WD, Jabs EW, Charles AC (2006) Oculodentodigital dysplasia connexin43 mutations result in non-functional connexin hemichannels and gap junctions in C6 glioma cells. J Cell Sci 119:532–541

    Article  PubMed  CAS  Google Scholar 

  • Laing JG, Beyer EC (1995) The gap junction protein connexin43 is degraded via the ubiquitin proteasome pathway. J Biol Chem 270:26399–26403

    Article  PubMed  CAS  Google Scholar 

  • Laird DW (2005) Connexin phosphorylation as a regulatory event linked to gap junction internalization and degradation. Biochim Biophys Acta 1711:172–182

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Lampe PD, Lau AF (2004) The effects of connexin phosphorylation on gap junctional communication. Int J Biochem Cell Biol 36:1171–1186

    Article  PubMed  CAS  Google Scholar 

  • Lampe PD, Kurata WE, Warn-Cramer BJ, Lau AF (1998) Formation of a distinct connexin43 phosphoisoform in mitotic cells is dependent upon p34cdc2 kinase. J Cell Sci 111(pt 6):833–841

    PubMed  CAS  Google Scholar 

  • Lampe PD, TenBroek EM, Burt JM, Kurata WE, Johnson RG, Lau AF (2000) Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication. J Cell Biol 149:1503–1512

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Leithe E, Rivedal E (2004) Ubiquitination and down-regulation of gap junction protein connexin-43 in response to 12-O-tetradecanoylphorbol 13-acetate treatment. J Biol Chem 279:50089–50096

    Article  PubMed  CAS  Google Scholar 

  • Leithe E, Rivedal E (2007) Ubiquitination of gap junction proteins. J Membr Biol 217:43–51

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Leykauf K, Salek M, Bomke J, Frech M, Lehmann WD, Durst M, Alonso A (2006) Ubiquitin protein ligase Nedd4 binds to connexin43 by a phosphorylation-modulated process. J Cell Sci 119:3634–3642

    Article  PubMed  CAS  Google Scholar 

  • Li YF, Wang X (2010) The role of the proteasome in heart disease. Biochim Biophys Acta 1809:141–149

    PubMed  Google Scholar 

  • Lichtenstein A, Minogue PJ, Beyer EC, Berthoud VM (2011) Autophagy: a pathway that contributes to connexin degradation. J Cell Sci 124:910–920

    Article  PubMed  CAS  Google Scholar 

  • Locke D, Harris AL (2009) Connexin channels and phospholipids: association and modulation. BMC Biol 7:52

    Article  PubMed  CAS  Google Scholar 

  • Locke D, Liu J, Harris AL (2005) Lipid rafts prepared by different methods contain different connexin channels, but gap junctions are not lipid rafts. Biochemistry 44:13027–13042

    Article  PubMed  CAS  Google Scholar 

  • Locke D, Koreen IV, Harris AL (2006) Isoelectric points and posttranslational modifications of connexin26 and connexin32. FASEB J 20:1221–1223

    Article  PubMed  CAS  Google Scholar 

  • Locovei S, Bao L, Dahl G (2006) Pannexin 1 in erythrocytes: function without a gap. Proc Natl Acad Sci USA 103:7655–7659

    Article  PubMed  CAS  Google Scholar 

  • Lohman AW, Billaud M, Straub AC, Johnstone SR, Best AK, Lee MY, Barr K, Penuela S, Laird DW, Isakson BE (2012) Expression of pannexin isoforms in the systemic murine arterial network. J Vasc Res (in press)

  • Marquez-Rosado L, Solan JL, Dunn CA, Norris RP, Lampe PD (2011) Connexin43 phosphorylation in brain, cardiac, endothelial and epithelial tissues. Biochim Biophys Acta

  • Martin PE, Evans WH (2004) Incorporation of connexins into plasma membranes and gap junctions. Cardiovasc Res 62:378–387

    Article  PubMed  CAS  Google Scholar 

  • Martinez AD, Hayrapetyan V, Moreno AP, Beyer EC (2003) A carboxyl terminal domain of connexin43 is critical for gap junction plaque formation but not for homo- or hetero-oligomerization. Cell Commun Adhes 10:323–328

    PubMed  CAS  Google Scholar 

  • McKinnon RL, Lidington D, Bolon M, Ouellette Y, Kidder GM, Tyml K (2006) Reduced arteriolar conducted vasoconstriction in septic mouse cremaster muscle is mediated by nNOS-derived NO. Cardiovasc Res 69:236–244

    Article  PubMed  CAS  Google Scholar 

  • McKinnon RL, Bolon ML, Wang HX, Swarbreck S, Kidder GM, Simon AM, Tyml K (2009) Reduction of electrical coupling between microvascular endothelial cells by NO depends on connexin37. Am J Physiol Heart Circ Physiol 297:H93–H101

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Musil LS, Goodenough DA (1991) Biochemical analysis of connexin43 intracellular transport, phosphorylation, and assembly into gap junctional plaques. J Cell Biol 115:1357–1374

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Musil LS, Cunningham BA, Edelman GM, Goodenough DA (1990) Differential phosphorylation of the gap junction protein connexin43 in junctional communication-competent and -deficient cell lines. J Cell Biol 111:2077–2088

    Article  PubMed  CAS  Google Scholar 

  • Musil LS, Le AC, VanSlyke JK, Roberts LM (2000) Regulation of connexin degradation as a mechanism to increase gap junction assembly and function. J Biol Chem 275:25207–25215

    Article  PubMed  CAS  Google Scholar 

  • Nishi H, Hashimoto K, Panchenko AR (2011) Phosphorylation in protein–protein binding: effect on stability and function. Structure 19:1807–1815

    Article  PubMed  CAS  Google Scholar 

  • Norris RP, Freudzon M, Mehlmann LM, Cowan AE, Simon AM, Paul DL, Lampe PD, Jaffe LA (2008) Luteinizing hormone causes MAP kinase-dependent phosphorylation and closure of connexin 43 gap junctions in mouse ovarian follicles: one of two paths to meiotic resumption. Development 135:3229–3238

    Article  PubMed  CAS  Google Scholar 

  • Pahujaa M, Anikin M, Goldberg GS (2007) Phosphorylation of connexin43 induced by Src: regulation of gap junctional communication between transformed cells. Exp Cell Res 313:4083–4090

    Article  PubMed  CAS  Google Scholar 

  • Palatinus JA, Gourdie RG (2007) Xin and the art of intercalated disk maintenance. Am J Physiol Heart Circ Physiol 293:H2626–H2628

    Article  PubMed  CAS  Google Scholar 

  • Palatinus JA, Rhett JM, Gourdie RG (2011a) The connexin43 carboxyl terminus and cardiac gap junction organization. Biochim Biophys Acta 1818:1831–1843

    PubMed  Google Scholar 

  • Palatinus JA, Rhett JM, Gourdie RG (2011b) Enhanced PKCepsilon mediated phosphorylation of connexin43 at serine 368 by a carboxyl-terminal mimetic peptide is dependent on injury. Channels (Austin) 5:236–240

    Article  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Park HS, Yu JW, Cho JH, Kim MS, Huh SH, Ryoo K, Choi EJ (2004) Inhibition of apoptosis signal-regulating kinase 1 by nitric oxide through a thiol redox mechanism. J Biol Chem 279:7584–7590

    Article  PubMed  CAS  Google Scholar 

  • Paulson AF, Lampe PD, Meyer RA, TenBroek E, Atkinson MM, Walseth TF, Johnson RG (2000) Cyclic AMP and LDL trigger a rapid enhancement in gap junction assembly through a stimulation of connexin trafficking. J Cell Sci 113(pt 17):3037–3049

    PubMed  CAS  Google Scholar 

  • Pearson RA, Dale N, Llaudet E, Mobbs P (2005) ATP released via gap junction hemichannels from the pigment epithelium regulates neural retinal progenitor proliferation. Neuron 46:731–744

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Penuela S, Celetti SJ, Bhalla R, Shao Q, Laird DW (2008) Diverse subcellular distribution profiles of pannexin 1 and pannexin 3. Cell Commun Adhes 15:133–142

    Article  PubMed  CAS  Google Scholar 

  • Penuela S, Bhalla R, Nag K, Laird DW (2009) Glycosylation regulates pannexin intermixing and cellular localization. Mol Biol Cell 20:4313–4323

    Article  PubMed  CAS  Google Scholar 

  • Penuela S, Gehi R, Laird DW (2012) The biochemistry and function of pannexin channels. Biochim Biophys Acta (in press)

  • Pinho SS, Seruca R, Gartner F, Yamaguchi Y, Gu J, Taniguchi N, Reis CA (2011) Modulation of E-cadherin function and dysfunction by N-glycosylation. Cell Mol Life Sci 68:1011–1020

    Article  PubMed  CAS  Google Scholar 

  • Puranam KL, Laird DW, Revel JP (1993) Trapping an intermediate form of connexin43 in the Golgi. Exp Cell Res 206:85–92

    Article  PubMed  CAS  Google Scholar 

  • Rahman S, Carlile G, Evans WH (1993) Assembly of hepatic gap junctions. Topography and distribution of connexin 32 in intracellular and plasma membranes determined using sequence-specific antibodies. J Biol Chem 268:1260–1265

    PubMed  CAS  Google Scholar 

  • Ray A, Zoidl G, Weickert S, Wahle P, Dermietzel R (2005) Site-specific and developmental expression of pannexin1 in the mouse nervous system. Eur J Neurosci 21:3277–3290

    Article  PubMed  Google Scholar 

  • Reis CA, Osorio H, Silva L, Gomes C, David L (2010) Alterations in glycosylation as biomarkers for cancer detection. J Clin Pathol 63:322–329

    Article  PubMed  CAS  Google Scholar 

  • Remo BF, Qu J, Volpicelli FM, Giovannone S, Shin D, Lader J, Liu FY, Zhang J, Lent DS, Morley GE, Fishman GI (2011) Phosphatase-resistant gap junctions inhibit pathological remodeling and prevent arrhythmias. Circ Res 108:1459–1466

    Article  PubMed  CAS  Google Scholar 

  • Retamal MA, Cortes CJ, Reuss L, Bennett MV, Saez JC (2006) S-nitrosylation and permeation through connexin 43 hemichannels in astrocytes: induction by oxidant stress and reversal by reducing agents. Proc Natl Acad Sci USA 103:4475–4480

    Article  PubMed  CAS  Google Scholar 

  • Retamal MA, Yin S, Altenberg GA, Reuss L (2009) Modulation of Cx46 hemichannels by nitric oxide. Am J Physiol Cell Physiol 296:C1356–C1363

    Article  PubMed  CAS  Google Scholar 

  • Rhett JM, Jourdan J, Gourdie RG (2011) Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1. Mol Biol Cell 22:1516–1528

    Article  PubMed  CAS  Google Scholar 

  • Richards TS, Dunn CA, Carter WG, Usui ML, Olerud JE, Lampe PD (2004) Protein kinase C spatially and temporally regulates gap junctional communication during human wound repair via phosphorylation of connexin43 on serine368. J Cell Biol 167:555–562

    Article  PubMed  CAS  Google Scholar 

  • Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, Stokes M, Sullivan L, Mitchell J, Wetzel R, Macneill J, Ren JM, Yuan J, Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb MJ (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131:1190–1203

    Article  PubMed  CAS  Google Scholar 

  • Roth J, Zuber C, Park S, Jang I, Lee Y, Kysela KG, Le Fourn V, Santimaria R, Guhl B, Cho JW (2010) Protein N-glycosylation, protein folding, and protein quality control. Mol Cells 30:497–506

    Article  PubMed  CAS  Google Scholar 

  • Saez JC, Nairn AC, Czernik AJ, Spray DC, Hertzberg EL, Greengard P, Bennett MV (1990) Phosphorylation of connexin 32, a hepatocyte gap-junction protein, by cAMP-dependent protein kinase, protein kinase C and Ca2+/calmodulin-dependent protein kinase II. Eur J Biochem 192:263–273

    Article  PubMed  CAS  Google Scholar 

  • Saez JC, Martinez AD, Branes MC, Gonzalez HE (1998) Regulation of gap junctions by protein phosphorylation. Braz J Med Biol Res 31:593–600

    Article  PubMed  CAS  Google Scholar 

  • Saez JC, Berthoud VM, Branes MC, Martinez AD, Beyer EC (2003) Plasma membrane channels formed by connexins: their regulation and functions. Physiol Rev 83:1359–1400

    PubMed  CAS  Google Scholar 

  • Sandilos JK, Chiu YH, Chekeni FB, Armstrong AJ, Walk SF, Ravichandran KS, Bayliss DA (2012) Pannexin 1, an ATP release channel, is activated by caspase cleavage of its pore-associated C terminal autoinhibitory region. J Biol Chem (in press)

  • Schalper KA, Riquelme MA, Branes MC, Martinez AD, Vega JL, Berthoud VM, Bennett MV, Saez JC (2012) Modulation of gap junction channels and hemichannels by growth factors. Mol BioSyst 8:685–698

    Article  PubMed  CAS  Google Scholar 

  • Schulz R, Heusch G (2004) Connexin 43 and ischemic preconditioning. Cardiovasc Res 62:335–344

    Article  PubMed  CAS  Google Scholar 

  • Segretain D, Falk MM (2004) Regulation of connexin biosynthesis, assembly, gap junction formation, and removal. Biochim Biophys Acta 1662:3–21

    Article  PubMed  CAS  Google Scholar 

  • Segretain D, Fiorini C, Decrouy X, Defamie N, Prat JR, Pointis G (2004) A proposed role for ZO-1 in targeting connexin 43 gap junctions to the endocytic pathway. Biochimie 86:241–244

    Article  PubMed  CAS  Google Scholar 

  • Seul KH, Kang KY, Lee KS, Kim SH, Beyer EC (2004) Adenoviral delivery of human connexin37 induces endothelial cell death through apoptosis. Biochem Biophys Res Commun 319:1144–1151

    Article  PubMed  CAS  Google Scholar 

  • Silverman WR, de Rivero Vaccari JP, Locovei S, Qiu F, Carlsson SK, Scemes E, Keane RW, Dahl G (2009) The pannexin 1 channel activates the inflammasome in neurons and astrocytes. J Biol Chem 284:18143–18151

    Article  PubMed  CAS  Google Scholar 

  • Singh D, Solan JL, Taffet SM, Javier R, Lampe PD (2005) Connexin 43 interacts with zona occludens-1 and -2 proteins in a cell cycle stage-specific manner. J Biol Chem 280:30416–30421

    Article  PubMed  CAS  Google Scholar 

  • Solan JL, Lampe PD (2005) Connexin phosphorylation as a regulatory event linked to gap junction channel assembly. Biochim Biophys Acta 1711:154–163

    Article  PubMed  CAS  Google Scholar 

  • Solan JL, Lampe PD (2007) Key connexin 43 phosphorylation events regulate the gap junction life cycle. J Membr Biol 217:35–41

    Article  PubMed  CAS  Google Scholar 

  • Solan JL, Lampe PD (2008) Connexin 43 in LA-25 cells with active v-src is phosphorylated on Y247, Y265, S262, S279/282, and S368 via multiple signaling pathways. Cell Commun Adhes 15:75–84

    Article  PubMed  CAS  Google Scholar 

  • Solan JL, Lampe PD (2009) Connexin43 phosphorylation: structural changes and biological effects. Biochem J 419:261–272

    Article  PubMed  CAS  Google Scholar 

  • Solan JL, Fry MD, TenBroek EM, Lampe PD (2003) Connexin43 phosphorylation at S368 is acute during S and G2/M and in response to protein kinase C activation. J Cell Sci 116:2203–2211

    Article  PubMed  CAS  Google Scholar 

  • Solan JL, Marquez-Rosado L, Sorgen PL, Thornton PJ, Gafken PR, Lampe PD (2007) Phosphorylation at S365 is a gatekeeper event that changes the structure of Cx43 and prevents down-regulation by PKC. J Cell Biol 179:1301–1309

    Article  PubMed  CAS  Google Scholar 

  • Sridharan M, Adderley SP, Bowles EA, Egan TM, Stephenson AH, Ellsworth ML, Sprague RS (2010) Pannexin 1 is the conduit for low oxygen tension-induced ATP release from human erythrocytes. Am J Physiol Heart Circ Physiol 299:H1146–H1152

    Article  PubMed  CAS  Google Scholar 

  • Srisakuldee W, Jeyaraman MM, Nickel BE, Tanguy S, Jiang ZS, Kardami E (2009) Phosphorylation of connexin-43 at serine 262 promotes a cardiac injury-resistant state. Cardiovasc Res 83:672–681

    Article  PubMed  CAS  Google Scholar 

  • Stamler JS, Simon DI, Osborne JA, Mullins ME, Jaraki O, Michel T, Singel DJ, Loscalzo J (1992) S-nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds. Proc Natl Acad Sci USA 89:444–448

    Article  PubMed  CAS  Google Scholar 

  • Straub AC, Johnstone SR, Heberlein KR, Rizzo MJ, Best AK, Boitano S, Isakson BE (2009) Site-specific connexin phosphorylation is associated with reduced heterocellular communication between smooth muscle and endothelium. J Vasc Res 47:277–286

    Article  PubMed  CAS  Google Scholar 

  • Straub AC, Billaud M, Johnstone SR, Best AK, Yemen S, Dwyer ST, Looft-Wilson R, Lysiak JJ, Gaston B, Palmer L, Isakson BE (2011) Compartmentalized connexin 43 S-nitrosylation/denitrosylation regulates heterocellular communication in the vessel wall. Arterioscler Thromb Vasc Biol 31:399–407

    Article  PubMed  CAS  Google Scholar 

  • Su V, Nakagawa R, Koval M, Lau AF (2010) Ubiquitin-independent proteasomal degradation of endoplasmic reticulum-localized connexin43 mediated by CIP75. J Biol Chem 285:40979–40990

    Article  PubMed  CAS  Google Scholar 

  • Swayne LA, Sorbara CD, Bennett SA (2010) Pannexin 2 is expressed by postnatal hippocampal neural progenitors and modulates neuronal commitment. J Biol Chem 285:24977–24986

    Article  PubMed  CAS  Google Scholar 

  • TenBroek EM, Lampe PD, Solan JL, Reynhout JK, Johnson RG (2001) Ser364 of connexin43 and the upregulation of gap junction assembly by cAMP. J Cell Biol 155:1307–1318

    Article  PubMed  CAS  Google Scholar 

  • Toyofuku T, Yabuki M, Otsu K, Kuzuya T, Hori M, Tada M (1998) Direct association of the gap junction protein connexin-43 with ZO-1 in cardiac myocytes. J Biol Chem 273:12725–12731

    Article  PubMed  CAS  Google Scholar 

  • Toyofuku T, Akamatsu Y, Zhang H, Kuzuya T, Tada M, Hori M (2001) c-Src regulates the interaction between connexin-43 and ZO-1 in cardiac myocytes. J Biol Chem 276:1780–1788

    Article  PubMed  CAS  Google Scholar 

  • Traub O, Look J, Dermietzel R, Brummer F, Hulser D, Willecke K (1989) Comparative characterization of the 21-kD and 26-kD gap junction proteins in murine liver and cultured hepatocytes. J Cell Biol 108:1039–1051

    Article  PubMed  CAS  Google Scholar 

  • van Rijen HV, van Veen TA, Hermans MM, Jongsma HJ (2000) Human connexin40 gap junction channels are modulated by cAMP. Cardiovasc Res 45:941–951

    Article  PubMed  Google Scholar 

  • van Veen TA, van Rijen HV, Jongsma HJ (2000) Electrical conductance of mouse connexin45 gap junction channels is modulated by phosphorylation. Cardiovasc Res 46:496–510

    Article  PubMed  Google Scholar 

  • Voges D, Zwickl P, Baumeister W (1999) The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu Rev Biochem 68:1015–1068

    Article  PubMed  CAS  Google Scholar 

  • Vogt A, Hormuzdi SG, Monyer H (2005) Pannexin1 and pannexin2 expression in the developing and mature rat brain. Brain Res Mol Brain Res 141:113–120

    Article  PubMed  CAS  Google Scholar 

  • Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C (2011) A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Mol Cell Proteomics 10:M111.013284

    Google Scholar 

  • Wang Y, Mehta PP (1995) Facilitation of gap-junctional communication and gap-junction formation in mammalian cells by inhibition of glycosylation. Eur J Cell Biol 67:285–296

    PubMed  CAS  Google Scholar 

  • Wang Y, Rose B (1995) Clustering of Cx43 cell-to-cell channels into gap junction plaques: regulation by cAMP and microfilaments. J Cell Sci 108(pt 11):3501–3508

    PubMed  CAS  Google Scholar 

  • Wang Y, Mehta PP, Rose B (1995) Inhibition of glycosylation induces formation of open connexin-43 cell-to-cell channels and phosphorylation and triton X-100 insolubility of connexin-43. J Biol Chem 270:26581–26585

    Article  PubMed  CAS  Google Scholar 

  • Warn-Cramer BJ, Cottrell GT, Burt JM, Lau AF (1998) Regulation of connexin-43 gap junctional intercellular communication by mitogen-activated protein kinase. J Biol Chem 273:9188–9196

    Article  PubMed  CAS  Google Scholar 

  • Wayakanon P, Bhattacharjee R, Nakahama KI, Morita I (2012) The role of the Cx43 C-terminus in GJ plaque formation and internalization. Biochem Biophys Res Commun 420:456–461

    Article  PubMed  CAS  Google Scholar 

  • Whalen EJ, Foster MW, Matsumoto A, Ozawa K, Violin JD, Que LG, Nelson CD, Benhar M, Keys JR, Rockman HA, Koch WJ, Daaka Y, Lefkowitz RJ, Stamler JS (2007) Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2. Cell 129:511–522

    Article  PubMed  CAS  Google Scholar 

  • Willis MS, Townley-Tilson WH, Kang EY, Homeister JW, Patterson C (2010) Sent to destroy: the ubiquitin proteasome system regulates cell signaling and protein quality control in cardiovascular development and disease. Circ Res 106:463–478

    Article  PubMed  CAS  Google Scholar 

  • Wisniewski JR, Nagaraj N, Zougman A, Gnad F, Mann M (2010) Brain phosphoproteome obtained by a FASP-based method reveals plasma membrane protein topology. J Proteome Res 9:3280–3289

    Article  PubMed  CAS  Google Scholar 

  • Xia J, Lim JC, Lu W, Beckel JM, Macarak EJ, Laties AM, Mitchell CH (2012) Neurons respond directly to mechanical deformation with pannexin-mediated ATP release and autostimulation of P2X7 receptors. J Physiol 590(pt 10):2285–2304

    PubMed  CAS  Google Scholar 

  • Xie H, Laird DW, Chang TH, Hu VW (1997) A mitosis-specific phosphorylation of the gap junction protein connexin43 in human vascular cells: biochemical characterization and localization. J Cell Biol 137:203–210

    Article  PubMed  CAS  Google Scholar 

  • Yasukawa T, Tokunaga E, Ota H, Sugita H, Martyn JA, Kaneki M (2005) S-nitrosylation-dependent inactivation of Akt/protein kinase B in insulin resistance. J Biol Chem 280:7511–7518

    Article  PubMed  CAS  Google Scholar 

  • Yin X, Gu S, Jiang JX (2001) 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 276:34567–34572

    Article  PubMed  CAS  Google Scholar 

  • Yin X, Liu J, Jiang JX (2008) Lens fiber connexin turnover and caspase-3-mediated cleavage are regulated alternately by phosphorylation. Cell Commun Adhes 15:1–11

    Article  PubMed  CAS  Google Scholar 

  • Zhang L, Deng T, Sun Y, Liu K, Yang Y, Zheng X (2008) Role for nitric oxide in permeability of hippocampal neuronal hemichannels during oxygen glucose deprivation. J Neurosci Res 86:2281–2291

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This study was supported by National Institutes of Health grants HL088554 and HL107963 (to B. E. I.), an American Heart Association Scientist Development Grant (to B. E. I.), American Heart Association postdoctoral fellowships (to M. B. and S. R. J.) and a National Institutes of Health Cardiovascular Training Grant (to A. W. L.).

Author information

Authors and Affiliations

  1. Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA

    Scott R. Johnstone, Marie Billaud, Alexander W. Lohman & Brant E. Isakson

  2. Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, PO Box 801394, Charlottesville, VA, 22908, USA

    Alexander W. Lohman & Brant E. Isakson

  3. Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA

    Evan P. Taddeo

Authors
  1. Scott R. Johnstone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marie Billaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexander W. Lohman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Evan P. Taddeo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Brant E. Isakson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Brant E. Isakson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Johnstone, S.R., Billaud, M., Lohman, A.W. et al. Posttranslational Modifications in Connexins and Pannexins. J Membrane Biol 245, 319–332 (2012). https://doi.org/10.1007/s00232-012-9453-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00232-012-9453-3

Keywords

Search

Navigation