Connexin 43: Key roles in the skin (Review)
- Authors:
- Xiao‑Fei Zhang
- Xiaofeng Cui
-
Affiliations: Department of Biological Sciences and Biotechnology, School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, Wuhan, Hubei 430070, P.R. China - Published online on: May 3, 2017 https://doi.org/10.3892/br.2017.903
- Pages: 605-611
This article is mentioned in:
Abstract
![]() |
Proksch E, Brandner JM and Jensen JM: The skin: An indispensable barrier. Exp Dermatol. 17:1063–1072. 2008. View Article : Google Scholar : PubMed/NCBI | |
Kanitakis J: Anatomy, histology and immunohistochemistry of normal human skin. Eur J Dermatol. 12:390–399; quiz 400–401. 2002.PubMed/NCBI | |
Martin PE, Easton JA, Hodgins MB and Wright CS: Connexins: Sensors of epidermal integrity that are therapeutic targets. FEBS Lett. 588:1304–1314. 2014. View Article : Google Scholar : PubMed/NCBI | |
Söhl G and Willecke K: Gap junctions and the connexin protein family. Cardiovasc Res. 62:228–232. 2004. View Article : Google Scholar : PubMed/NCBI | |
Söhl G and Willecke K: An update on connexin genes and their nomenclature in mouse and man. Cell Commun Adhes. 10:173–180. 2003. View Article : Google Scholar : PubMed/NCBI | |
Kumar NM and Gilula NB: The gap junction communication channel. Cell. 84:381–388. 1996. View Article : Google Scholar : PubMed/NCBI | |
Alexander DB and Goldberg GS: Transfer of biologically important molecules between cells through gap junction channels. Curr Med Chem. 10:2045–2058. 2003. View Article : Google Scholar : PubMed/NCBI | |
Hervé JC, Derangeon M, Bahbouhi B, Mesnil M and Sarrouilhe D: The connexin turnover, an important modulating factor of the level of cell-to-cell junctional communication: Comparison with other integral membrane proteins. J Membr Biol. 217:21–33. 2007. View Article : Google Scholar : PubMed/NCBI | |
Berthoud VM, Minogue PJ, Laing JG and Beyer EC: Pathways for degradation of connexins and gap junctions. Cardiovasc Res. 62:256–267. 2004. View Article : Google Scholar : PubMed/NCBI | |
Kretz M, Euwens C, Hombach S, Eckardt D, Teubner B, Traub O, Willecke K and Ott T: Altered connexin expression and wound healing in the epidermis of connexin-deficient mice. J Cell Sci. 116:3443–3452. 2003. View Article : Google Scholar : PubMed/NCBI | |
Di WL, Rugg EL, Leigh IM and Kelsell DP: Multiple epidermal connexins are expressed in different keratinocyte subpopulations including connexin 31. J Invest Dermatol. 117:958–964. 2001. View Article : Google Scholar : PubMed/NCBI | |
Risek B, Klier FG and Gilula NB: Multiple gap junction genes are utilized during rat skin and hair development. Development. 116:639–651. 1992.PubMed/NCBI | |
Wu M, Moh MC and Schwarz H: HepaCAM associates with connexin 43 and enhances its localization in cellular junctions. Sci Rep. 6:362182016. View Article : Google Scholar : PubMed/NCBI | |
Garcia IE, Maripillán J, Jara O, Ceriani R, Palacios-Muñoz A, Ramachandran J, Olivero P, Perez-Acle T, González C, Sáez JC, et al: Keratitis-ichthyosis-deafness syndrome-associated Cx26 mutants produce nonfunctional gap junctions but hyperactive hemichannels when co-expressed with wild type Cx43. J Invest Dermatol. 135:1338–1347. 2015. View Article : Google Scholar : PubMed/NCBI | |
Shuja Z, Li L, Gupta S, Mese G and White TW: Connexin26 mutations causing palmoplantar keratoderma and deafness interact with connexin43, modifying gap junction and hemichannel properties. J Invest Dermatol. 136:225–235. 2016. View Article : Google Scholar : PubMed/NCBI | |
Geimonen E, Jiang W, Ali M, Fishman GI, Garfield RE and Andersen J: Activation of protein kinase C in human uterine smooth muscle induces connexin-43 gene transcription through an AP-1 site in the promoter sequence. J Biol Chem. 271:23667–23674. 1996. View Article : Google Scholar : PubMed/NCBI | |
Geimonen E, Boylston E, Royek A and Andersen J: Elevated connexin-43 expression in term human myometrium correlates with elevated c-Jun expression and is independent of myometrial estrogen receptors. J Clin Endocrinol Metab. 83:1177–1185. 1998. View Article : Google Scholar : PubMed/NCBI | |
van der Heyden MA, Rook MB, Hermans MM, Rijksen G, Boonstra J, Defize LH and Destrée OH: Identification of connexin43 as a functional target for Wnt signalling. J Cell Sci. 111:1741–1749. 1998.PubMed/NCBI | |
Bao X, Lee SC, Reuss L and Altenberg GA: Change in permeant size selectivity by phosphorylation of connexin 43 gap-junctional hemichannels by PKC. Proc Natl Acad Sci USA. 104:pp. 4919–4924. 2007; View Article : Google Scholar : PubMed/NCBI | |
Riquelme MA, Burra S, Kar R, Lampe PD and Jiang JX: Mitogen-activated protein kinase (MAPK) activated by prostaglandin E2 phosphorylates connexin 43 and closes osteocytic hemichannels in response to continuous flow shear stress. J Biol Chem. 290:28321–28328. 2015. View Article : Google Scholar : PubMed/NCBI | |
Pahujaa M, Anikin M and Goldberg GS: Phosphorylation of connexin43 induced by Src: Regulation of gap junctional communication between transformed cells. Exp Cell Res. 313:4083–4090. 2007. View Article : Google Scholar : PubMed/NCBI | |
Cooper CD and Lampe PD: Casein kinase 1 regulates connexin-43 gap junction assembly. J Biol Chem. 277:44962–44968. 2002. View Article : Google Scholar : PubMed/NCBI | |
TenBroek EM, Lampe PD, Solan JL, Reynhout JK and Johnson RG: Ser364 of connexin43 and the upregulation of gap junction assembly by cAMP. J Cell Biol. 155:1307–1318. 2001. View Article : Google Scholar : PubMed/NCBI | |
Kjenseth A, Fykerud T, Rivedal E and Leithe E: Regulation of gap junction intercellular communication by the ubiquitin system. Cell Signal. 22:1267–1273. 2010. View Article : Google Scholar : PubMed/NCBI | |
Kjenseth A, Fykerud TA, Sirnes S, Bruun J, Yohannes Z, Kolberg M, Omori Y, Rivedal E and Leithe E: The gap junction channel protein connexin 43 is covalently modified and regulated by SUMOylation. J Biol Chem. 287:15851–15861. 2012. View Article : Google Scholar : PubMed/NCBI | |
Giepmans BN, Verlaan I and Moolenaar WH: Connexin-43 interactions with ZO-1 and alpha- and beta-tubulin. Cell Commun Adhes. 8:219–223. 2001. View Article : Google Scholar : PubMed/NCBI | |
Giepmans BN, Verlaan I, Hengeveld T, Janssen H, Calafat J, Falk MM and Moolenaar WH: Gap junction protein connexin-43 interacts directly with microtubules. Curr Biol. 11:1364–1368. 2001. View Article : Google Scholar : PubMed/NCBI | |
Shaw RM, Fay AJ, Puthenveedu MA, von Zastrow M, Jan YN and Jan LY: Microtubule plus-end-tracking proteins target gap junctions directly from the cell interior to adherens junctions. Cell. 128:547–560. 2007. View Article : Google Scholar : PubMed/NCBI | |
Plante I, Stewart MK, Barr K, Allan AL and Laird DW: Cx43 suppresses mammary tumor metastasis to the lung in a Cx43 mutant mouse model of human disease. Oncogene. 30:1681–1692. 2011. View Article : Google Scholar : PubMed/NCBI | |
Kim MO, Ryu JM, Suh HN, Park SH, Oh YM, Lee SH and Han HJ: cAMP promotes cell migration through cell junctional complex dynamics and actin cytoskeleton remodeling: Implications in skin wound healing. Stem Cells Dev. 24:2513–2524. 2015. View Article : Google Scholar : PubMed/NCBI | |
Wang H, Cao X, Lin Z, Lee M, Jia X, Ren Y, Dai L, Guan L, Zhang J, Lin X, et al: Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome. Hum Mol Genet. 24:243–250. 2015. View Article : Google Scholar : PubMed/NCBI | |
Sargen MR, Gormley RH, Pasha TL, Yum S, Acs G, Xu X and Zhang PJ: Melanocytic tumors express connexin 43 but not 26: Immunohistochemical analysis with potential significance in melanocytic oncogenesis. Am J Dermatopathol. 35:813–817. 2013. View Article : Google Scholar : PubMed/NCBI | |
Rezze GG, Fregnani JH, Duprat J and Landman G: Cell adhesion and communication proteins are differentially expressed in melanoma progression model. Hum Pathol. 42:409–418. 2011. View Article : Google Scholar : PubMed/NCBI | |
Shaw TJ and Martin P: Wound repair at a glance. J Cell Sci. 122:3209–3213. 2009. View Article : Google Scholar : PubMed/NCBI | |
Falanga V: Wound healing and its impairment in the diabetic foot. Lancet. 366:1736–1743. 2005. View Article : Google Scholar : PubMed/NCBI | |
Janis JE, Kwon RK and Lalonde DH: A practical guide to wound healing. Plast Reconstr Surg. 125:230e–244e. 2010. View Article : Google Scholar : PubMed/NCBI | |
Dunn CA and Lampe PD: Injury-triggered Akt phosphorylation of Cx43: A ZO-1-driven molecular switch that regulates gap junction size. J Cell Sci. 127:455–464. 2014. View Article : Google Scholar : PubMed/NCBI | |
Cogliati B, Vinken M, Silva TC, Araújo CM, Aloia TP, Chaible LM, Mori CM and Dagli ML: Connexin 43 deficiency accelerates skin wound healing and extracellular matrix remodeling in mice. J Dermatol Sci. 79:50–56. 2015. View Article : Google Scholar : PubMed/NCBI | |
Ghatnekar GS, O'Quinn MP, Jourdan LJ, Gurjarpadhye AA, Draughn RL and Gourdie RG: Connexin43 carboxyl-terminal peptides reduce scar progenitor and promote regenerative healing following skin wounding. Regen Med. 4:205–223. 2009. View Article : Google Scholar : PubMed/NCBI | |
Mori R, Power KT, Wang CM, Martin P and Becker DL: Acute downregulation of connexin43 at wound sites leads to a reduced inflammatory response, enhanced keratinocyte proliferation and wound fibroblast migration. J Cell Sci. 119:5193–5203. 2006. View Article : Google Scholar : PubMed/NCBI | |
Wang HH, Su CH, Wu YJ, Li JY, Tseng YM, Lin YC, Hsieh CL, Tsai CH and Yeh HI: Reduction of connexin43 in human endothelial progenitor cells impairs the angiogenic potential. Angiogenesis. 16:553–560. 2013. View Article : Google Scholar : PubMed/NCBI | |
Gartner C, Ziegelhöffer B, Kostelka M, Stepan H, Mohr FW and Dhein S: Knock-down of endothelial connexins impairs angiogenesis. Pharmacol Res. 65:347–357. 2012. View Article : Google Scholar : PubMed/NCBI | |
Gottrup F: A specialized wound-healing center concept: Importance of a multidisciplinary department structure and surgical treatment facilities in the treatment of chronic wounds. Am J Surg. 187 Suppl 5A:38S–43S. 2004. View Article : Google Scholar : PubMed/NCBI | |
Reiber GE, Lipsky BA and Gibbons GW: The burden of diabetic foot ulcers. Am J Surg. 176 Suppl 2A:5S–10S. 1998. View Article : Google Scholar : PubMed/NCBI | |
Wang CM, Lincoln J, Cook JE and Becker DL: Abnormal connexin expression underlies delayed wound healing in diabetic skin. Diabetes. 56:2809–2817. 2007. View Article : Google Scholar : PubMed/NCBI | |
Mendoza-Naranjo A, Cormie P, Serrano AE, Wang CM, Thrasivoulou C, Sutcliffe JE, Gilmartin DJ, Tsui J, Serena TE, Phillips AR and Becker DL: Overexpression of the gap junction protein Cx43 as found in diabetic foot ulcers can retard fibroblast migration. Cell Biol Int. 36:661–667. 2012. View Article : Google Scholar : PubMed/NCBI | |
Vinnik IuS, Salmina AB, Tepliakova OV, Drobushevskaia AI, Malinovskaia NA, Pozhilenkova EA, Morgun AV and Gitlina AG: Dynamics of local expression of connexin-43 and basic fibroblast growth factor receptors in patients with skin and soft-tissue infections against the background of diabetes mellitus type II. Vestn Khir Im I I Grek. 173:47–52. 2014.(In Russian). PubMed/NCBI | |
Mendoza-Naranjo A, Cormie P, Serrano AE, Hu R, O'Neill S, Wang CM, Thrasivoulou C, Power KT, White A, Serena T, et al: Targeting Cx43 and N-cadherin, which are abnormally upregulated in venous leg ulcers, influences migration, adhesion and activation of Rho GTPases. PLoS One. 7:e373742012. View Article : Google Scholar : PubMed/NCBI | |
Paznekas WA, Boyadjiev SA, Shapiro RE, Daniels O, Wollnik B, Keegan CE, Innis JW, Dinulos MB, Christian C, Hannibal MC and Jabs EW: Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am J Hum Genet. 72:408–418. 2003. View Article : Google Scholar : PubMed/NCBI | |
Kogame T, Dainichi T, Shimomura Y, Tanioka M, Kabashima K and Miyachi Y: Palmoplantar keratosis in oculodentodigital dysplasia with a GJA1 point mutation out of the C-terminal region of connexin 43. J Dermatol. 41:1095–1097. 2014. View Article : Google Scholar : PubMed/NCBI | |
van Steensel MA, Spruijt L, van der Burgt I, Bladergroen RS, Vermeer M, Steijlen PM and van Geel M: 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. 2005. View Article : Google Scholar : PubMed/NCBI | |
Boyden LM, Craiglow BG, Zhou J, Hu R, Loring EC, Morel KD, Lauren CT, Lifton RP and Bilguvar K: Yale Center for Mendelian Genomics et al. Dominant de novo mutations in GJA1 cause erythrokeratodermia variabilis et progressiva, without features of oculodentodigital dysplasia. J Invest Dermatol. 135:1540–1547. 2015. View Article : Google Scholar : PubMed/NCBI | |
Mou YY, Zhao GQ, Lin JY, Zhao J, Lin H, Hu LT, Xu Q, Wang Q and Sun WR: Expression of connexin 43 and E-cadherin in choroidal melanoma. Int J Ophthalmol. 4:156–161. 2011.PubMed/NCBI | |
Lin JH, Takano T, Cotrina ML, Arcuino G, Kang J, Liu S, Gao Q, Jiang L, Li F, Lichtenberg-Frate H, et al: Connexin 43 enhances the adhesivity and mediates the invasion of malignant glioma cells. J Neurosci. 22:4302–4311. 2002.PubMed/NCBI | |
Schiffner S, Zimara N, Schmid R and Bosserhoff AK: p54nrb is a new regulator of progression of malignant melanoma. Carcinogenesis. 32:1176–1182. 2011. View Article : Google Scholar : PubMed/NCBI | |
Wang WK, Chen MC, Leong HF, Kuo YL, Kuo CY and Lee CH: Connexin 43 suppresses tumor angiogenesis by down-regulation of vascular endothelial growth factor via hypoxic-induced factor-1α. Int J Mol Sci. 16:439–451. 2014. View Article : Google Scholar : PubMed/NCBI | |
Tittarelli A, Guerrero I, Tempio F, Gleisner MA, Avalos I, Sabanegh S, Ortíz C, Michea L, López MN, Mendoza-Naranjo A and Salazar-Onfray F: Overexpression of connexin 43 reduces melanoma proliferative and metastatic capacity. Br J Cancer. 113:259–267. 2015. View Article : Google Scholar : PubMed/NCBI | |
Lomas A, Leonardi-Bee J and Bath-Hextall F: A systematic review of worldwide incidence of nonmelanoma skin cancer. Br J Dermatol. 166:1069–1080. 2012. View Article : Google Scholar : PubMed/NCBI | |
Stelkovics E, Kiszner G, Meggyeshazi N, Korom I, Varga E, Nemeth I, Molnar J and Marczinovits I: Selective in situ protein expression profiles correlate with distinct phenotypes of basal cell carcinoma and squamous cell carcinoma of the skin. Histol Histopathol. 28:941–954. 2013.PubMed/NCBI | |
Tada J and Hashimoto K: Ultrastructural localization of gap junction protein connexin 43 in normal human skin, basal cell carcinoma, and squamous cell carcinoma. J Cutan Pathol. 24:628–635. 1997. View Article : Google Scholar : PubMed/NCBI | |
Arita K, Akiyama M, Tsuji Y, McMillan JR, Eady RA and Shimizu H: Changes in gap junction distribution and connexin expression pattern during human fetal skin development. J Histochem Cytochem. 50:1493–1500. 2002. View Article : Google Scholar : PubMed/NCBI | |
Choudhry R, Pitts JD and Hodgins MB: Changing patterns of gap junctional intercellular communication and connexin distribution in mouse epidermis and hair follicles during embryonic development. Dev Dyn. 210:417–430. 1997. View Article : Google Scholar : PubMed/NCBI | |
Goliger JA and Paul DL: Expression of gap junction proteins Cx26, Cx31.1, Cx37, and Cx43 in developing and mature rat epidermis. Dev Dyn. 200:1–13. 1994. View Article : Google Scholar : PubMed/NCBI | |
Butterweck A, Elfgang C, Willecke K and Traub O: Differential expression of the gap junction proteins connexin45,−43, −40, −31, and −26 in mouse skin. Eur J Cell Biol. 65:152–163. 1994.PubMed/NCBI | |
Ackert CL, Gittens JE, O'Brien MJ, Eppig JJ and Kidder GM: Intercellular communication via connexin43 gap junctions is required for ovarian folliculogenesis in the mouse. Dev Biol. 233:258–270. 2001. View Article : Google Scholar : PubMed/NCBI | |
Dyce PW, Li D, Barr KJ and Kidder GM: Connexin43 is required for the maintenance of multipotency in skin-derived stem cells. Stem Cells De. 23:1636–1646. 2014. View Article : Google Scholar | |
Lorraine C, Wright CS and Martin PE: Connexin43 plays diverse roles in co-ordinating cell migration and wound closure events. Biochem Soc Trans. 43:482–488. 2015. View Article : Google Scholar : PubMed/NCBI | |
Moore K, Ghatnekar G, Gourdie RG and Potts JD: Impact of the controlled release of a connexin 43 peptide on corneal wound closure in an STZ model of type I diabetes. PLoS One. 9:e865702014. View Article : Google Scholar : PubMed/NCBI | |
Gilmartin DJ, Soon A, Thrasivoulou C, Phillips AR, Jayasinghe SN and Becker DL: Sustained release of Cx43 antisense oligodeoxynucleotides from coated collagen scaffolds promotes wound healing. Adv Healthc Mater. 5:1786–1799. 2016. View Article : Google Scholar : PubMed/NCBI | |
Qiu C, Coutinho P, Frank S, Franke S, Law LY, Martin P, Green CR and Becker DL: Targeting connexin43 expression accelerates the rate of wound repair. Curr Biol. 13:1697–1703. 2003. View Article : Google Scholar : PubMed/NCBI | |
Boitano S, Dirksen ER and Evans WH: Sequence-specific antibodies to connexins block intercellular calcium signaling through gap junctions. Cell Calcium. 23:1–9. 1998. View Article : Google Scholar : PubMed/NCBI | |
Oviedo-Orta E, Hoy T and Evans WH: Intercellular communication in the immune system: Differential expression of connexin40 and 43, and perturbation of gap junction channel functions in peripheral blood and tonsil human lymphocyte subpopulations. Immunology. 99:578–590. 2000. View Article : Google Scholar : PubMed/NCBI | |
Wang N, de Vuyst E, Ponsaerts R, Boengler K, Palacios-Prado N, Wauman J, Lai CP, de Bock M, Decrock E, Bol M, et al: Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury. Basic Res Cardiol. 108:3092013. View Article : Google Scholar : PubMed/NCBI | |
Wright CS, van Steensel MA, Hodgins MB and Martin PE: Connexin mimetic peptides improve cell migration rates of human epidermal keratinocytes and dermal fibroblasts in vitro. Wound Repair Regen. 17:240–249. 2009. View Article : Google Scholar : PubMed/NCBI | |
Kandyba EE, Hodgins MB and Martin PE: A murine living skin equivalent amenable to live-cell imaging: Analysis of the roles of connexins in the epidermis. J Invest Dermatol. 128:1039–1049. 2008. View Article : Google Scholar : PubMed/NCBI | |
Ongstad EL, O'Quinn MP, Ghatnekar GS, Yost MJ and Gourdie RG: A Connexin43 mimetic peptide promotes regenerative healing and improves mechanical properties in skin and heart. Adv Wound Care (New Rochelle). 2:55–62. 2013. View Article : Google Scholar : PubMed/NCBI | |
Contreras JE, Sanchez HA, Eugenin EA, Speidel D, Theis M, Willecke K, Bukauskas FF, Bennett MV and Sáez JC: 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:pp. 495–500. 2002; View Article : Google Scholar : PubMed/NCBI | |
Goldberg GS, Moreno AP, Bechberger JF, Hearn SS, Shivers RR, MacPhee DJ, Zhang YC and Naus CC: Evidence that disruption of connexon particle arrangements in gap junction plaques is associated with inhibition of gap junctional communication by a glycyrrhetinic acid derivative. Exp Cell Res. 222:48–53. 1996. View Article : Google Scholar : PubMed/NCBI | |
Davidson JS and Baumgarten IM: Glycyrrhetinic acid derivatives: A novel class of inhibitors of gap-junctional intercellular communication. Structure-activity relationships. J Pharmacol Exp Ther. 246:1104–1107. 1988.PubMed/NCBI | |
Pollok S, Pfeiffer AC, Lobmann R, Wright CS, Moll I, Martin PE and Brandner JM: Connexin 43 mimetic peptide Gap27 reveals potential differences in the role of Cx43 in wound repair between diabetic and non-diabetic cells. J Cell Mol Med. 15:861–873. 2011. View Article : Google Scholar : PubMed/NCBI | |
Wright CS, Berends RF, Flint DJ and Martin PE: Cell motility in models of wounded human skin is improved by Gap27 despite raised glucose, insulin and IGFBP-5. Exp Cell Res. 319:390–401. 2013. View Article : Google Scholar : PubMed/NCBI | |
Ishido M and Kasuga N: Characteristics of the localization of connexin 43 in satellite cells during skeletal muscle regeneration in vivo. Acta Histochem Cytochem. 48:53–60. 2015. View Article : Google Scholar : PubMed/NCBI | |
Schulz R, Görge PM, Gorbe A, Ferdinandy P, Lampe PD and Leybaert L: Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection. Pharmacol Ther. 153:90–106. 2015. View Article : Google Scholar : PubMed/NCBI | |
Elbadawy HM, Mirabelli P, Xeroudaki M, Parekh M, Bertolin M, Breda C, Cagini C, Ponzin D, Lagali N and Ferrari S: Effect of Connexin 43 inhibition by the mimetic peptide Gap27 on corneal wound healing, inflammation and neovascularization. Br J Pharmacol. 173:2880–2893. 2016. View Article : Google Scholar : PubMed/NCBI | |
Becker DL, Phillips AR, Duft BJ, Kim Y and Green CR: Translating connexin biology into therapeutics. Semin Cell Dev Biol. 50:49–58. 2016. View Article : Google Scholar : PubMed/NCBI |