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Scientists report that they visualized the three-dimensional structure of an essential membrane channel in the control of blood pressure. Their results ("Structure of the human epithelial sodium channel by cryoelectronic microscopy"), published in eLife, represents the first time that the human epithelial sodium channel has been shown so precisely since it was isolated for the first time and described by cloning expression in 1993, explains lead author Isabelle Baconguis. , Ph.D., Assistant Professor at the University) Vollum Institute.
Lead author Sigrid Noreng, a graduate student from Dr. Baconguis' laboratory, adds that the discovery provides a starting point for the development of better treatments for a range of diseases associated with the channel. "It will certainly move the field forward," said Dr. Baconguis.
"The epithelial sodium channel (ENaC), a member of the ENaC / DEG superfamily, regulates the homeostasis of Na + and water. ENaCs assemble as heterotrimeric channels harboring protease sensitive domains critical for channel synchronization. Here we present the structure of human ENaC in the uncleaved state determined by single particle cryoelectronic microscopy. The ion channel is composed of a large extracellular domain and a narrow transmembrane domain, "the researchers write.
"The structure reveals that ENaC assembles with 1: 1: 1 stoichiometry α: β: γ subunits arranged in the opposite direction of the needles of a clock. The shape of each subunit is reminiscent of one hand, with the main trigger areas of a "finger" and a "thumb". The elusive, protease-sensitive domain of inhibition is placed between these domains to regulate the conformational changes of the "finger" and the "thumb"; thus, the structure provides the first view of the architecture of ENaC inhibition.
The channel allows sodium ions to be absorbed into the tissues of the entire body, including the kidney. As such, it is a crucial aspect of human health by regulating the balance of sodium, blood volume and blood pressure. "We could not have left the ocean without him," said Richard Posert, a co-author of the thesis, a graduate student from Dr. Baconguis' laboratory.
The dysfunction of ENaC can lead to severe forms of hypertension, such as Liddle's syndrome or neonatal salt loss syndrome. The discovery answers fundamental biophysical questions about the specific architecture of the canal, which could lead to the development of drugs 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 linked to many diseases," says Dr. Baconguis. "As soon as you disrupt this membrane protein, everything downstream is also disrupted."
Noreng notes that the discovery may be particularly useful in developing targeted drugs to control high blood pressure. "There are no good drugs that specifically target this protein.To discover the structure of this channel will be very important for the development of new and better drugs for blood pressure."
The researchers made this discovery through the use of a cryo-electron electron microscope installed in the Robertson Life Sciences Building building of the OHSU. The Cryo-EM technology is part of a new national center intended to expand the use of a technique focused on structural biology. The technique allows scientists to visualize biological molecules at the atomic scale and see them in their natural state.
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