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J Biol Chem. 2014 Aug 1;289(31):21519-32. doi: 10.1074/jbc.M114.578757. Epub 2014 Jun 17.

Altered inhibition of Cx26 hemichannels by pH and Zn2+ in the A40V mutation associated with keratitis-ichthyosis-deafness syndrome.

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  • 1From the Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461.
  • 2the Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322, and.
  • 3the Department of Biological Sciences, SUNY College of Optometry, New York, New York 10036.
  • 4From the Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461,


Excessive opening of undocked Cx26 hemichannels in the plasma membrane is associated with disease pathogenesis in keratitis-ichthyosis-deafness (KID) syndrome. Thus far, excessive opening of KID mutant hemichannels has been attributed, almost solely, to aberrant inhibition by extracellular Ca(2+). This study presents two new possible contributing factors, pH and Zn(2+). Plasma pH levels and micromolar concentrations of Zn(2+) inhibit WT Cx26 hemichannels. However, A40V KID mutant hemichannels show substantially reduced inhibition by these factors. Using excised patches, acidification was shown to be effective from either side of the membrane, suggesting a protonation site accessible to H(+) flux through the pore. Sensitivity to pH was not dependent on extracellular aminosulfonate pH buffers. Single channel recordings showed that acidification did not affect unitary conductance or block the hemichannel but rather promoted gating to the closed state with transitions characteristic of the intrinsic loop gating mechanism. Examination of two nearby KID mutants in the E1 domain, G45E and D50N, showed no changes in modulation by pH or Zn(2+). N-bromo-succinimide, but not thiol-specific reagents, attenuated both pH and Zn(2+) responses. Individually mutating each of the five His residues in WT Cx26 did not reveal a key His residue that conferred sensitivity to pH or Zn(2+). From these data and the crystal structure of Cx26 that suggests that Ala-40 contributes to an intrasubunit hydrophobic core, the principal effect of the A40V mutation is probably a perturbation in structure that affects loop gating, thereby affecting multiple factors that act to close Cx26 hemichannels via this gating mechanism.

© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.


Connexin; Gating; Hearing; Hemichannels; Syndromic Deafness; Zinc; pH Regulation

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