title: Impaired permeability to Ins(1,4,5)P3 in a mutant connexin underlies recessive hereditary deafness.
abstract: Connexins are membrane proteins that assemble into gap-junction channels and are responsible for direct, electrical and metabolic coupling between connected cells. Here we describe an investigation of the properties of a recombinantly expressed recessive mutant of connexin 26 (Cx26), the V84L mutant, associated with deafness. Unlike other Cx26 mutations, V84L affects neither intracellular sorting nor electrical coupling, but specifically reduces permeability to the Ca(2+)-mobilizing messenger inositol 1,4,5-trisphosphate (Ins(1,4,5)P(3)). Both the permeability to Lucifer Yellow and the unitary channel conductance of V84L-mutant channels are indistinguishable from those of the wild-type Cx26. Injection of Ins(1,4,5)P(3) into supporting cells of the rat organ of Corti, which abundantly express Cx26, ensues in a regenerative wave of Ca(2+) throughout the tissue. Blocking the gap junction communication abolishes wave propagation. We propose that the V84L mutation reduces metabolic coupling mediated by Ins(1,4,5)P(3) to an extent sufficient to impair the propagation of Ca(2+) waves and the formation of a functional syncytium. Our data provide the first demonstration of a specific defect of metabolic coupling and offer a mechanistic explanation for the pathogenesis of an inherited human disease.
authors.affiliation: Venetian Institute of Molecular Medicine, via G. Orus 2, 35129 Padua, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Beltramello
authors.forename: Valeria
authors.initials: V
authors.lastname: Piazza
authors.forename: Feliksas F
authors.initials: FF
authors.lastname: Bukauskas
authors.forename: Tullio
authors.initials: T
authors.lastname: Pozzan
authors.forename: Fabio
authors.initials: F
authors.lastname: Mammano
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001693:Biological Transport, Active / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D002450:Cell Communication / Q000187:drug effects / Q000235:genetics; D002463:Cell Membrane Permeability / Q000235:genetics; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D003638:Deafness / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism*; D005808:Genes, Recessive / Q000235:genetics; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism* / Q000494:pharmacology; D007760:Labyrinth Supporting Cells / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009924:Organ Culture Techniques; D009925:Organ of Corti / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems / Q000235:genetics*
chemical_list: D017630:Connexins; C000607042:GJB2 protein, human; C000607044:Gjb2 protein, rat; D000072259:Connexin 26; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium