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Mechanism of deafness caused by mutations of the cochlear Cx26

        The inner ear provides sensory information related to hearing and balance. The mechano-transduction of sound waves into electrical impulses occurs in the cochlea, which houses the organ of Corti, a narrow spiral of epithelial sensory cells (hair cells).
        Most cells that have gap junctions express more than one connexin isoform, and as a result a variety of gap-junctional channel and hemichannel compositions can exist. Hemichannels formed by one or more connexin isoforms are called homomeric and heteromeric, respectively.


Schematic representation of Cx26, gap junction and gap-junctional hemichannels. A. Cx26. The transmembrane segments (M1-M4), the extracellular loops (EC1 and EC2), the intracellular loop (IC loop) and the C-terminal (CT) region are displayed. B. Gap-junctions. Gap junctions consist of clusters of gap-junctional channels, each formed by docking of two hemichannels, one from each of the adjacent cells. C. Homomeric and heteromeric hemichannels (illustrated by all black and mix of gray and black connexin subunits, respectively). Modified from Bruzzone et al.

       
        The cochlear gap-junctional communication network is essential for hearing, and in most cells of the normal cochlea, gap-junctional channels and hemichannels are formed by Cx26 and Cx30 (heteromeric, heterotypic). Profound hearing loss of genetic origin is common (~1 in 2,000 children) and mutations of Cx26 are the major cause. Our long-term objective is to elucidate at the molecular level the mechanisms by which connexin mutations cause deafness. Understanding the molecular mechanism of deafness caused by expression of Cx26 mutants will serve as a basis for rational therapeutic approaches to treat or prevent the disorder.

The major efforts of our current research are aimed at determining:

  1. The effects of subunit composition on the permeability properties of wild-type heteromeric Cx26/Cx30 gap-junctional hemichannels.
  2. The mechanisms of the alterations of gap-junctional communication by selected Cx26 mutants associated with deafness.

        Our basic approach is to compare the permeability properties of heteromeric hemichannels with varying Cx26/Cx30 proportions with those of homomeric Cx26 and Cx30 hemichannels and determine how variations in the subunit composition alters Cx26/Cx30 hemichannel permeability. To address this aim, we perform studies of gap-junctional channels and hemichannels expressed in frog oocytes, as well as studies of purified hemichannels. We carry out experiments that span from single-hemichannel recordings using the patch-clamp technique, to permeability studies of purified hemichannels containing known numbers of mutant subunits.



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