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 Ca2+-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 wildtype 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 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)P-3 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.

Impaired permeability to Ins(1,4,5)P-3 in a mutant connexin underlies recessive hereditary deafness

Pozzan T;Mammano F
2005

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 Ca2+-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 wildtype 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 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)P-3 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.
2005
Connexin 26
Ca2+
Gap-junction channels
HeLa cells
hereditary diseases
Charcot Marie Tooth (CMTX)
hearing impairment
lens cataracts
skin disorders
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.14243/314194
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