Nature Cell Biology
7, 63 - 69 (2004)
Published online: 12 December 2004; | doi:10.1038/ncb1205
Impaired permeability to Ins(1,4,5)P3 in a mutant connexin underlies recessive hereditary deafnessMartina Beltramello1, 5, Valeria Piazza1, 5, Feliksas F. Bukauskas2, Tullio Pozzan1, 3
& Fabio Mammano1, 41
Venetian Institute of Molecular Medicine, via G. Orus 2, 35129 Padua, Italy. 2
Department of Neuroscience, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA. 3
Department of Biomedical Sciences and Consiglio Nazionale delle Ricerche Institute of Neuroscience, University of Padua, viale G. Colombo 3, 35121 Padua, Italy. 4
Department of Physics, University, of Padua, via Marzolo 8, 35132 Padua, Italy. 5
These authors contributed equally to this work.
Correspondence should be addressed to Fabio Mammano fabio.mammano@unipd.itConnexins 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 Ca2+-mobilizing messenger inositol 1,4,5-trisphosphate (Ins(1,4,5)P3). 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)P3 into supporting cells of the rat organ of Corti, which abundantly express Cx26, ensues in a regenerative wave of Ca2+ 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)P3 to an extent sufficient to impair the propagation of Ca2+ 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.
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