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IP3 spreads to elicit Ca2+ peaks via wild-type (top), but not mutant (bottom), connexins. MAMMANO/MACMILLAN

A miniscule change in a pore protein can mean the difference between hearing and deafness, say Martina Beltramello, Valeria Piazza, Fabio Mammano (Venetian Institute of Molecular Medicine, Padua, Italy), and colleagues. They have characterized a mutant connexin from the inner ear that allows the passage of ions and a dye, but not of the intracellular messenger inositol 1,4,5-trisphosphate (IP₃). The result is a failure in hearing.The connexin is expressed in supporting cells in the organ of Corti (http://www.vimm.it/cochlea). These cells are thought to ferry K⁺ away from sensory cells, thus preventing opening of channels in these cells that would admit toxic levels of Ca²⁺.

Most connexin mutations associated with deafness yield missorted or nonfunctional channel proteins. The Italian group focused on the V84L mutant, which is correctly sorted and, as they show, forms channels with normal unitary conductance and open channel probabilities. Ions and the higher molecular weight dye Lucifer yellow can pass through these channels.

But IP₃ introduced into cells expressing V84L mutant connexins did not, as in wild type, generate Ca²⁺ waves in adjacent cells. Failure to spread this message may be the basis for a failure in K⁺ scavenging and thus sensory cell death.

Thus the addition of a single CH₂ unit can determine the difference between conductance and nonconductance of IP₃. The detailed structure of the relevant connexin is not yet known, but the minimal structural difference may be amplified if the residue in question pokes into the channel that is formed by 6 connexin subunits.

Reference:

Beltramello, M., et al. 2004. Nat. Cell Biol. doi:10.1038/ncb1205.

William A. Wells

wellsw{at}rockefeller.edu

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This Article PDF (Full Text) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wells, W. A. Search for Related Content PubMed Articles by Wells, W. A. Social Bookmarking                      What's this?