Connexin30 mutations responsible for hidrotic ectodermal dysplasia cause abnormal hemichannel activity

Clouston syndrome or hidrotic ectodermal dysplasia (HED) is a rare dominant genodermatosis characterized by palmoplantar hyperkeratosis, generalized alopecia and nail defects. The disease is caused by mutations in the human GJB6 gene which encodes the gap junction protein connexin30 (Cx30). To gain insight into the molecular mechanisms underlying HED, we have analyzed the consequences of two of these mutations (G11R Cx30 and A88V Cx30) on the functional properties of the connexons they form. Here, we show that the distribution of Cx30 is similar in affected palmoplantar skin and in normal epidermis. We further demonstrate that the presence of the wild-type protein (wt Cx30) improves the trafficking of mutated Cx30 to the plasma membrane where both G11R and A88V Cx30 co-localize with wt Cx30 and form functional intercellular channels. The electrophysiological properties of channels made of G11R and A88V Cx30 differ slightly from those of wt Cx30 but allow for dye transfer between transfected HeLa cells. Finally, we document a gain of function of G11R and A88V Cx30, which form functional hemichannels at the cell surface and, when expressed in HeLa cells, generate a leakage of ATP into the extracellular medium. Such increased ATP levels might act as a paracrine messenger that, by altering the epidermal factors which control the proliferation and differentiation of keratinocytes, may play an important role in the pathophysiological processes leading to the HED phenotyp

Connexin30 mutations responsible for hidrotic ectodermal dysplasia cause abnormal hemichannel activity

Clouston syndrome or hidrotic ectodermal dysplasia (HED) is a rare dominant genodermatosis characterized by palmoplantar hyperkeratosis, generalized alopecia and nail defects. The disease is caused by mutations in the human GJB6 gene which encodes the gap junction protein connexin30 (Cx30). To gain insight into the molecular mechanisms underlying HED, we have analyzed the consequences of two of these mutations (G11R Cx30 and A88V Cx30) on the functional properties of the connexons they form. Here, we show that the distribution of Cx30 is similar in affected palmoplantar skin and in normal epidermis. We further demonstrate that the presence of the wild-type protein (wt Cx30) improves the trafficking of mutated Cx30 to the plasma membrane where both G11R and A88V Cx30 co-localize with wt Cx30 and form functional intercellular channels. The electrophysiological properties of channels made of G11R and A88V Cx30 differ slightly from those of wt Cx30 but allow for dye transfer between transfected HeLa cells. Finally, we document a gain of function of G11R and A88V Cx30, which form functional hemichannels at the cell surface and, when expressed in HeLa cells, generate a leakage of ATP into the extracellular medium. Such increased ATP levels might act as a paracrine messenger that, by altering the epidermal factors which control the proliferation and differentiation of keratinocytes, may play an important role in the pathophysiological processes leading to the HED phenotype. © Oxford University Press 2004; all rights reserved.link_to_subscribed_fulltex

Molecular Mechanisms for the Lithiation of Ruthenium Oxide Nanoplates as Lithium-Ion Battery Anode Materials: An Experimentally Motivated Computational Study

First-principles computational studies were used to calculate discharge curves for lithium in RuO₂ and to understand the molecular mechanism of lithium sorption into crystalline bulk RuO₂. These studies were complemented by experiments to provide new insights into the molecular mechanisms for the first and subsequent discharges of RuO₂ anodes in lithium ion batteries. RuO₂ nanoplates show slow fading of capacity over multiple cycles, retaining 76% of their original capacity after 20 cycles. The calculated discharge curves for lithium in RuO₂ lattice show qualitative agreement with experimental discharge curves for RuO₂ nanoplates. The molecular level analysis shows that an intercalation mechanism is operational until a 1:1 Li:Ru ratio is reached, which is followed by a conversion mechanism into Ru metal and Li₂O. Furthermore, in agreement with experiment, the computations predict superstoichiometric capacity of RuO₂, i.e., accommodation of lithium well beyond the stoichiometric limit of 4:1 Li:Ru ratio, and show that the additional lithium atoms reside at the interface of the Ru metal and Li₂O. This shows that the extra capacity can be explained without invoking electrolyte or solvent–electrolyte interface effects