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J Biol Chem
2014 Aug 01;28931:21519-32. doi: 10.1074/jbc.M114.578757.
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Altered inhibition of Cx26 hemichannels by pH and Zn2+ in the A40V mutation associated with keratitis-ichthyosis-deafness syndrome.
Sanchez HA
,
Bienkowski R
,
Slavi N
,
Srinivas M
,
Verselis VK
.
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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.
Anselmi,
ATP release through connexin hemichannels and gap junction transfer of second messengers propagate Ca2+ signals across the inner ear.
2008, Pubmed
Anselmi,
ATP release through connexin hemichannels and gap junction transfer of second messengers propagate Ca2+ signals across the inner ear.
2008,
Pubmed
Beahm,
Hemichannel and junctional properties of connexin 50.
2002,
Pubmed
,
Xenbase
Bevans,
Regulation of connexin channels by pH. Direct action of the protonated form of taurine and other aminosulfonates.
1999,
Pubmed
Bukauskas,
Gap junction channel gating.
2004,
Pubmed
Chappell,
Histidine suppresses zinc modulation of connexin hemichannels.
2004,
Pubmed
,
Xenbase
Dermietzel,
Molecular and functional diversity of neural connexins in the retina.
2000,
Pubmed
,
Xenbase
Di,
Multiple epidermal connexins are expressed in different keratinocyte subpopulations including connexin 31.
2001,
Pubmed
Ebihara,
Properties of a nonjunctional current expressed from a rat connexin46 cDNA in Xenopus oocytes.
1993,
Pubmed
,
Xenbase
Frederickson,
Concentrations of extracellular free zinc (pZn)e in the central nervous system during simple anesthetization, ischemia and reperfusion.
2006,
Pubmed
Gerido,
Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness.
2007,
Pubmed
,
Xenbase
Gossman,
Hemichannel-mediated inositol 1,4,5-trisphosphate (IP3) release in the cochlea: a novel mechanism of IP3 intercellular signaling.
2008,
Pubmed
Harris,
Kinetic properties of a voltage-dependent junctional conductance.
1981,
Pubmed
Hombach,
Functional expression of connexin57 in horizontal cells of the mouse retina.
2004,
Pubmed
Karlin,
Substituted-cysteine accessibility method.
1998,
Pubmed
Klaassen,
Connexin hemichannel mediated ephaptic inhibition in the retina.
2012,
Pubmed
Kumar,
Zinc and skin: a brief summary.
2012,
Pubmed
Lee,
An update of the defensive barrier function of skin.
2006,
Pubmed
Lee,
Connexin-26 mutations in deafness and skin disease.
2009,
Pubmed
Lee,
Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in Xenopus oocytes.
2009,
Pubmed
,
Xenbase
Levit,
Pathological hemichannels associated with human Cx26 mutations causing Keratitis-Ichthyosis-Deafness syndrome.
2012,
Pubmed
,
Xenbase
Locke,
Mechanism for modulation of gating of connexin26-containing channels by taurine.
2011,
Pubmed
Long,
Voltage sensor of Kv1.2: structural basis of electromechanical coupling.
2005,
Pubmed
Lopez,
Insights on the mechanisms of Ca(2+) regulation of connexin26 hemichannels revealed by human pathogenic mutations (D50N/Y).
2013,
Pubmed
,
Xenbase
Maeda,
Structure of the connexin 26 gap junction channel at 3.5 A resolution.
2009,
Pubmed
Mese,
The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome.
2011,
Pubmed
Mhaske,
The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity.
2013,
Pubmed
,
Xenbase
Miles,
Modification of histidyl residues in proteins by diethylpyrocarbonate.
1977,
Pubmed
Nakagawa,
Structural and functional studies of gap junction channels.
2010,
Pubmed
Ripps,
Properties of connexin26 hemichannels expressed in Xenopus oocytes.
2004,
Pubmed
,
Xenbase
Rubinos,
Mechanism of inhibition of connexin channels by the quinine derivative N-benzylquininium.
2012,
Pubmed
,
Xenbase
Sanchez,
The D50N mutation and syndromic deafness: altered Cx26 hemichannel properties caused by effects on the pore and intersubunit interactions.
2013,
Pubmed
,
Xenbase
Sánchez,
Differentially altered Ca2+ regulation and Ca2+ permeability in Cx26 hemichannels formed by the A40V and G45E mutations that cause keratitis ichthyosis deafness syndrome.
2010,
Pubmed
,
Xenbase
Scott,
Connexins in epidermal homeostasis and skin disease.
2012,
Pubmed
,
Xenbase
Spande,
Selective cleavage and modification of peptides and proteins.
1970,
Pubmed
Spray,
Equilibrium properties of a voltage-dependent junctional conductance.
1981,
Pubmed
,
Xenbase
Stefaniak,
International guidelines for the in vivo assessment of skin properties in non-clinical settings: part 1. pH.
2013,
Pubmed
Stong,
A novel mechanism for connexin 26 mutation linked deafness: cell death caused by leaky gap junction hemichannels.
2006,
Pubmed
Sun,
Zinc modulation of hemi-gap-junction channel currents in retinal horizontal cells.
2009,
Pubmed
Tao,
Biochemical requirements for inhibition of Connexin26-containing channels by natural and synthetic taurine analogs.
2004,
Pubmed
Terrinoni,
Connexin 26 (GJB2) mutations, causing KID Syndrome, are associated with cell death due to calcium gating deregulation.
2010,
Pubmed
Tombola,
How does voltage open an ion channel?
2006,
Pubmed
Trexler,
Voltage gating and permeation in a gap junction hemichannel.
1996,
Pubmed
,
Xenbase
Trexler,
Rapid and direct effects of pH on connexins revealed by the connexin46 hemichannel preparation.
1999,
Pubmed
,
Xenbase
Trexler,
The first extracellular loop domain is a major determinant of charge selectivity in connexin46 channels.
2000,
Pubmed
,
Xenbase
Wangemann,
Supporting sensory transduction: cochlear fluid homeostasis and the endocochlear potential.
2006,
Pubmed
Xu,
The role of connexins in ear and skin physiology - functional insights from disease-associated mutations.
2013,
Pubmed
Zhao,
Gap junctional hemichannel-mediated ATP release and hearing controls in the inner ear.
2005,
Pubmed
Zoidl,
Molecular cloning and functional expression of zfCx52.6: a novel connexin with hemichannel-forming properties expressed in horizontal cells of the zebrafish retina.
2004,
Pubmed
,
Xenbase
