Mutations of connexin 26 at position 75 and dominant deafness: Essential role of arginine for the generation of functional gap-junctional channels

• Published in: Hearing research Vol. 220; no. 1; pp. 87 - 94
• Main Authors: Deng, Yanqin, Chen, Yongyue, Reuss, Luis, Altenberg, Guillermo A.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.10.2006; Elsevier
• Subjects: Amino Acids, Aromatic - physiology; Analysis of Variance; Animals; Arginine - genetics; Arginine - physiology; Aromatic amino acids; Biological and medical sciences; Connexins - chemistry; Connexins - genetics; Cx26; Deafness - genetics; Ear and associated structures. Auditory pathways and centers. Hearing. Vocal organ. Phonation. Sound production. Echolocation; Ear, auditive nerve, cochleovestibular tract, facial nerve: diseases, semeiology; Fundamental and applied biological sciences. Psychology; Gap junction; Gap Junctions - physiology; Genetic disease; Hemichannels; Ion Channel Gating; Medical sciences; Mutagenesis, Site-Directed; Mutation; Non tumoral diseases; Oocytes - metabolism; Otorhinolaryngology. Stomatology; Skin disease; Vertebrates: nervous system and sense organs; Xenopus laevis; G j; I j; Hemichannels; Skin disease; G GJH,Gap-junctional hemichannel conductance; Aromatic amino acids; Cx26; WT; Gap junction; Genetic disease; Tyrosine; Alanine; Corti organ; Cell junction; Auditory disorder; Sound; Inner ear; Organ of hearing; Hearing loss; Connexin; Arginine; Gap; Asparagine; Cochlea; ENT disease; Transduction; Mutation
• ISSN: 0378-5955; 1878-5891
• DOI: 10.1016/j.heares.2006.07.004

Gap-junctional channels are large intercellular aqueous pores formed by head-to-head association of two gap-junctional hemichannels (connexin hexamers), one from each of the adjacent cells. The mechano-transduction of sound waves into electrical impulses occurs in the cochlea, which houses the organ of Corti. Hereditary deafness is frequent and mutations of connexin 26, the predominant connexin of the cochlea, are its most frequent cause. Mutations of R75 cause deafness and disrupt gap-junctional communication. Here, we determined the effects of substitutions of R75 with different residues (alanine, asparagine, aspartic acid, lysine, phenylalanine, tyrosine or tryptophan) on formation of gap-junctional channels and hemichannels. We show that connexin 26 R75 is essential for the formation of gap-junctional channels. Substitution of R75 with aromatic residues yields functional hemichannels that display altered voltage dependence, whereas substitution with other residues yields non-functional hemichannels. The expression of R75 mutants has a dominant negative effect on gap-junctional communication mediated by wild-type connexin 26, independently of the ability of the mutants to form functional gap-junctional hemichannels. Our results show that the arginine located at position 75 of connexin 26 is essential for function, and cannot be replaced by other residues.