Scientists report that they have visualized the three-dimensional structure of a membrane channel that's critical in controlling blood pressure. Their findings (“Structure of the human epithelial sodium channel by cryo-electron microscopy”), published in eLife, represent the first time the human epithelial sodium channel has been shown so precisely since it was first isolated and described through expression cloning in 1993, says senior author Isabelle Baconguis, Ph.D., assistant professor in the Oregon Health and Science University (OHSU) Vollum Institute.
Lead author Sigrid Noreng, a graduate student in Dr. Baconguis' lab, adds that the discovery provides a starting point for the development of better treatments for a range of diseases associated with the channel. “It's definitely going to move the field forward,” Dr. Baconguis agreed.
“The epithelial sodium channel (ENaC), a member of the ENaC/DEG superfamily, regulates Na+ and water homeostasis. ENaCs assemble as heterotrimeric channels that harbor protease-sensitive domains critical for gating the channel. Here we present the structure of human ENaC in the uncleaved state determined by single-particle cryo-electron microscopy. The ion channel is composed of a large extracellular domain and a narrow transmembrane domain,” write the investigators.
“The structure reveals that ENaC assembles with a 1:1:1 stoichiometry of α:β:γ subunits arranged in a counter-clockwise manner. The shape of each subunit is reminiscent of a hand, with key gating domains of a 'finger' and a 'thumb'. Wedged between these domains is the elusive protease-sensitive inhibitory domain poised to regulate conformational changes of the 'finger' and 'thumb'; thus, the structure provides the first view of the architecture of inhibition of ENaC.”
The channel enables sodium ions to be absorbed into tissues throughout the body, including the kidney. As such, it is a crucial aspect of human health by regulating sodium balance, blood volume, and blood pressure. “We wouldn't have been able to leave the ocean without it,” quipps co-author Richard Posert, a graduate student in Dr. Baconguis' lab.
Dysfunction of the ENaC can lead to severe forms of hypertension such as Liddle syndrome or neonatal salt-wasting disorder. The discovery answers fundamental biophysical questions about the specific architecture of the channel, which ultimately could lead to the development of medications to improve the treatment of diseases such as severe hypertension, heart failure, and nephrotic syndrome, according to the researchers.
“This is the first visual representation of a protein that is connected to many diseases,” Dr. Baconguis says. “As soon as you perturb this membrane protein, everything downstream becomes disrupted as well.”
Noreng notes the discovery may be especially helpful in developing targeted medications to control high blood pressure. “There are no good medications that target this protein specifically. Discovering the structure of this channel will be very important toward the development of new and better blood pressure medications.”
The researchers made the discovery through the use of a cryo-electron microscope housed in OHSU's Robertson Life Sciences Building. Cryo-EM technology is part of a newly designated national center intended to widen the use of a technique that is focused on structural biology. The technique enables scientists to visualize biological molecules at an atomic scale and to see them in their natural state.