Computational investigation of drug action on human-induced stem cell-derived cardiomyocytes.

We compare experimental and computational results for the actions of the cardioactive drugs Lidocaine, Verapamil, Veratridine, and Bay K 8644 on a tissue monolayer consisting of mainly fibroblasts and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSc-CM). The choice of the computational models is justified and literature data is collected to model drug action as accurately as possible. The focus of this work is to evaluate the validity and capability of existing models for native human cells with respect to the simulation of pharmaceutical treatment of monolayers and hiPSc-CM.

cAMP-dependent activation of CFTR inhibits the epithelial sodium channel (ENaC) without affecting its surface expression.

The cystic fibrosis transmembrane conductance regulator (CFTR) is thought to modulate epithelial sodium channel (ENaC) function in various preparations. However, the molecular nature and (patho-)physiological significance of the CFTR/ENaC interaction is still unclear and may vary in different tissues. Co-expression experiments in Xenopus laevis oocytes are a popular approach to investigate a possible functional interaction of CFTR and ENaC but have revealed controversial results.

The role of individual Nedd4-2 (KIAA0439) WW domains in binding and regulating epithelial sodium channels.

The amiloride-sensitive epithelial sodium channel (ENaC) is essential for fluid and electrolyte homeostasis. ENaC consists of alpha, beta, and gamma subunits, each of which contains a PPxY motif that interacts with the WW domains of the ubiquitin-protein ligases Nedd4 and Nedd4-2. Disruption of this interaction, as in Liddle's syndrome in which mutations delete or alter the PPxY motif of either the beta or the gamma subunits, results in increased ENaC activity.

Cystic fibrosis transmembrane conductance regulator-dependent up-regulation of Kir1.1 (ROMK) renal K+ channels by the epithelial sodium channel.

The epithelial sodium channel (ENaC) and the secretory potassium channel (Kir1.1/ROMK) are expressed in the apical membrane of renal collecting duct principal cells where they provide the rate-limiting steps for Na(+) absorption and K(+) secretion. The cystic fibrosis transmembrane conductance regulator (CFTR) is thought to regulate the function of both ENaC and Kir1.