1. From Hyperactive Connexin26 Hemichannels to Impairments in Epidermal Calcium Gradient and Permeability Barrier in the Keratitis-Ichthyosis-Deafness Syndrome 
Isaac E. García, Felicitas Bosen, Paula Mujica, Amaury Pupo, Carolina Flores-Muñoz, Oscar Jara, Carlos González, Klaus Willecke, Agustín D. Martínez 
Journal of Investigative Dermatology 
Volume 136, Issue 3, Pages (March 2016)
DOI: /j.jid
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2. Figure 1
Most KID-related mutations in Cx26 hemichannel are associated with channel pore domain. (a) Topology of Cx26 with labeling (red) of amino acid residues linked to KID. Structural model of Cx26 HC produced with crystallographic data from Maeda et al. (2009). Missing residues of human Cx26 were inserted using the Modeller program. This was performed by generating models of human Cx26 structure, using the full sequence of human Cx26 as target, and the structure of Cx26 (pdb: 2ZW3) as template. Ten models were generated and the one with the lowest discrete optimized protein energy (DOPE) score was selected. Cartoon representation of the (b) lateral, (c) extracellular, and (d) cytoplasmic views of Cx26 HC pore surfaces. Subunit A is colored in a blue-green gradient from the N- to the C-terminus. The other subunits are semitransparent. The nine residues (G11, G12, N14, S17, A40, G45, D50, A88, and F142) affected by mutations associated with the KID syndrome are colored in red. Residues A40, G45, and D50 are indicated as red spots facing the pore from the extracellular side (b and c), whereas G12 and N14 are depicted as red spots facing the pore from the intracellular side (b and d). Cx, connexin; EL, extracellular loop; HC, hemichannel; IL, intracellular loop; KID, keratitis-ichthyosis-deafness; TM, transmembrane region.
Journal of Investigative Dermatology  , DOI: ( /j.jid )
Copyright © 2015 The Authors Terms and Conditions

3. Figure 2
Working hypothesis for the molecular mechanism of the KID syndrome in the skin. KID mutant Cx26 proteins (green) lead to hyperactive HCs with either wtCx26 (orange) or wtCx43 (red). This may change the ionic homeostasis of the keratinocytes and lead to Ca2+ overload by (a) increased release of ATP causing opening of P2X channels and/or (b) direct diffusion of Ca2+ through opened HCs. The change in Ca2+ homeostasis may trigger a disturbance of the epidermal Ca2+ gradient leading to an aberrant lipid processing and barrier defect. This barrier defect may be compensated by hyperproliferation of the basal epidermal layer causing hyperkeratosis of the KID syndrome. Cx, connexin; GJCs, gap junction channels; HC, hemichannel; KID, keratitis-ichthyosis-deafness syndrome; wt, wild type.
Modified from García et al. (2015).
Journal of Investigative Dermatology  , DOI: ( /j.jid )
Copyright © 2015 The Authors Terms and Conditions