Epithelial sodium channels play a major role in high blood pressure or hypertension, often referred to as the ‘silent killer’. Image credit: Lori Vaskalis, Jason Cole (CC BY 4.0)
The bodies of humans and other animals contain many different fluids that play vital roles in the body, such as blood, saliva and the fluids that surround cells in organs. These fluids all contain particles called ions, which can affect the flow of water into and out of cells and alter the activity of proteins. Therefore, in order to survive, an animal must tightly regulate the levels of ions in its body.
Epithelial cells line the surface of organs, and the inside of the digestive system and other cavities in the human body. A channel known as ENaC is found on the surface of epithelial cells and controls the volume of the fluid surrounding cells, blood pressure and the volume of liquid in the airways. This channel spans the membrane surrounding each epithelial cell and allows sodium ions to pass into the cell. To promote the opening of the channel, enzymes remove portions of the ENaC called extracellular domain, which sits on the outside surface of an epithelial cell. Three components (or ‘subunits’) called alpha, beta and gamma are needed to form an ENaC, but it is not clear how they fit together to form a single working unit.
Noreng et al. used a technique called cryo-electron microscopy to study the three-dimensional structure of the human ENaC. This revealed that a single channel contains one alpha, one beta and one gamma subunit, which sit next to each other to form a narrow tube through the membrane and a large extracellular domain. When viewed from the outside of the cell the subunits form a narrow ring in a counter-clockwise manner.
Further analysis of the structure suggested that when enzymes remove pieces of the extracellular domain of ENaC, it becomes easier for the rest of the channel to adopt a shape that allows sodium ions to move through the pore. A next step will be to study the three-dimensional structure of ENaC when it takes on different shapes to better understand how it works.
