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First published online 25 November 2008
doi: 10.1242/jcs.033373

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Molecular reorganization of Cx43, Zo-1 and Src complexes during the endocytosis of gap junction plaques in response to a non-genomic carcinogen

Jérome Gilleron^1,2, Céline Fiorini^1,2, Diane Carette^1,2, Christiane Avondet^1,2,*, Matthias M. Falk³, Dominique Segretain^1,2 and Georges Pointis^1,2,

¹ INSERM U 895, Team 5 Physiopathologic control of germ cell proliferation: genomic and non genomic mechanisms, Université Paris Descartes, 45 rue des Saint-Pères, 75006, Paris, France
² Centre de Mediterranéen de Médecine Moléculaire (C3M), 151 route Saint-Antoine de Ginestière BP 2 3194, 06204 Nice cedex 3, France
³ Department of Biological Sciences, Lehigh University, 111 Research Drive, Iacocca Hall, Bethlehem, PA 18015, USA

Author for correspondence (e-mail: pointis{at}unice.fr)

Accepted 18 September 2008

The gap junction protein connexin 43 (Cx43) exhibits dynamic trafficking that is altered in most tumor cells and in response to carcinogen exposure. A number of connexin (Cx)-binding proteins are known to be involved in endocytic internalization of gap junctions. Here, we analyzed the discrete molecular interactions that occur between Src, ZO-1 and Cx43 during Cx43 internalization in response to the non-genomic carcinogen -hexachlorocyclohexane (HCH). Internalization of the Cx43 gap junction plaque was significantly accelerated in Cx43-GFP transfected 42GPA9 Sertoli cells that were exposed to the carcinogen. HCH induced the rapid recruitment of Src to the plasma membrane, activation of Src within 3 minutes and the efficient inhibition of gap junctional coupling, but had no effect in the presence of the Src inhibitor PP2. Immunoprecipitation experiments demonstrated that HCH increased Cx43-Src interaction and concomitantly decreased Cx43–ZO-1 association. ZO-1 was detected on both sides of the gap junction plaques in untreated cells, but appeared to be mainly localized on one side during HCH-induced internalization. The dissociation of ZO-1 from Cx43 appears to occur specifically on the side of the plaque to which Src was recruited. These findings provide mechanistic evidence by which internalization of the Cx43 gap junction plaque might be initiated, suggesting that Src-mediated dissociation of ZO-1 from one side of the plaque initiates endocytic internalization of gap junctions and that this process is amplified in response to exposure to HCH.

Key words: GJA1, Cx43 gap junction plaque, Endocytosis, Src, ZO-1, Carcinogen

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