Gap-junctional channel and hemichannel activity of two recently identified connexin 26 mutants associated with deafness
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Gap-junction channels (GJCs) are formed by head-to-head association of two hemichannels (HCs, connexin hexamers). HCs and GJCs are permeable to ions and hydrophilic molecules of up to Mr ~1 kDa. Hearing impairment of genetic origin is common, and mutations of connexin 26 (Cx26) are its major cause. We recently identified two novel Cx26 mutations in hearing-impaired subjects, L10P and G109V. L10P forms functional GJCs with slightly altered voltage dependence and HCs with decrease ATP/cationic dye selectivity. G109V does not form functional GJCs, but forms functional HCs with enhanced extracellular Ca2+ sensitivity and subtle alterations in voltage dependence and ATP/cationic dye selectivity. Deafness associated with G109V could result from decreased GJCs activity, whereas deafness associated to L10P may have a more complex mechanism that involves changes in HC permeability.
KeywordsDeafness Hemichannels Connexins Gap-junction channels Ion channel Mutation
This work was supported by the Fondecyt  and Anillo [ACT 1104] to M.A.R., National Institutes of Health grants [R01 GM79629, 3R01 GM079629-03S1], and American Heart Association, Texas Affiliate Inc. Grant-in-Aid [14GRNT18750014] to G.A.A.
- 1.Anselmi F, Hernandez VH, Crispino G, Seydel A, Ortolano S, Roper SD, Kessaris N, Richardson W, Rickheit G, Filippov MA, Monyer H, Mammano F (2008) ATP release through connexin hemichannels and gap junction transfer of second messengers propagate Ca2+ signals across the inner ear. Proc Natl Acad Sci U S A 105:18770–18775CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Dalamón V, Lotersztein V, Béhèran A, Lipovsek M, Diamante F, Pallares N, Francipane L, Frechtel G, Paoli B, Mansilla E, Diamante V, Elgoyhen AB (2010) GJB2 and GJB6 genes: molecular study and identification of novel GJB2 mutations in the hearing-impaired Argentinean population. Audiol Neuro Otol 15:194–202CrossRefGoogle Scholar
- 12.Figueroa VA, Retamal MA, Cea LA, Salas JD, Vargas AA, Verdugo CA, Jara O, Martínez AD, Sáez JC (2014) Extracellular gentamicin reduces the activity of connexin hemichannels and interferes with purinergic Ca(2+) signaling in HeLa cells. Front Cell Neurosci 8:265CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Kudo T, Kure S, Ikeda K, Xia AP, Katori Y, Suzuki M, Kojima K, Ichinohe A, Suzuki Y, Aoki Y, Kobayashi T, Matsubara Y (2003) Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness. Hum Mol Genet 12:995–1004CrossRefPubMedGoogle Scholar
- 42.Terrinoni A, Codispoti A, Serra V, Didona B, Bruno E, Nisticò R, Giustizieri M, Alessandrini M, Campione E, Melino G (2010) Connexin 26 (GJB2) mutations, causing KID Syndrome, are associated with cell death due to calcium gating deregulation. Biochem Biophys Res Commun 394:909–914CrossRefPubMedGoogle Scholar