Gap junction-mediated intercellular biochemical coupling in cochlear supporting cells is required for normal cochlear functions.
Dysfunction of gap junctions (GJs) caused by mutations in connexin26 (Cx26) and Cx30 accounts for nearly half of all cases of hereditary nonsyndromic deafness cases. Although it is widely held that GJs connecting supporting cells in the organ of Corti mainly provide ionic pathways for rapid removal of K+ around the base of hair cells, the function of GJs in the cochlea remains unknown. Here we show that GJs were not assembled in the supporting cells of the organ of Corti until 3 days after birth in mice and then gradually matured to connect supporting cells before the onset of hearing. In organotypic cochlear cultures that were confirmed to express GJs, GJs mediated the propagation of intracellular Ca2+ concentration waves in supporting cells by allowing intercellular diffusion of inositol 1,4,5-trisphosphate. We found that a subset of structurally mild Cx26 mutations located at the second transmembrane region (V84L, V95M, and A88S) and a Cx30 mutation located at the first cytoplasmic segment (T5M) specifically affect the intercellular exchange of larger molecules but leave the ionic permeability intact. Our results indicated that Cx26 and Cx30 mutations that are linked to sensorineural deafness retained ionic coupling but were deficient in biochemical permeability. Therefore, GJ-mediated intercellular exchange of biochemically important molecules is required for normal cochlear functions.
Zhang
Yanping
Y
Department of Otolaryngology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322-3030, USA.
Tang
Wenxue
W
Ahmad
Shoab
S
Sipp
James A
JA
Chen
Ping
P
Lin
Xi
X
D000818:Animals; D000831:Animals, Newborn; D020013:Calcium Signaling / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D002460:Cell Line; D003051:Cochlea / Q000166:cytology* / Q000254:growth & development* / Q000502:physiology; D000072259:Connexin 26; D000075302:Connexin 30; D017630:Connexins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D018408:Patch-Clamp Techniques; D010539:Permeability; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D000075302:Connexin 30; D017630:Connexins; D005456:Fluorescent Dyes; C000607042:GJB2 protein, human; C100629:Gjb6 protein, mouse; D011993:Recombinant Fusion Proteins; D000072259:Connexin 26