Cryo-EM studies of heteromeric epithelial sodium channels
EMSL Project ID
50423
Abstract
Epithelial sodium channels (ENaCs) are members of the ENaC/DEG superfamily of trimeric voltage-independent, Na+-selective and amiloride-sensitive ion channels. ENaCs assemble as heterotrimers that harbor an exquisitely Na+-selective pore that is critical in the fine-tuning of Na+ and K+ balance. Abnormal regulation in the functional activity of ENaCs contributes importantly to human disease, and especially to hypertension (high blood pressure), a condition that affects about 1 billion people worldwide. Despite such clinical importance, detail into the mechanism of ENaC function at the molecular level has remained elusive and the lack of structures of ENaC has been a barrier to progress in the field. The objective of this research proposal is to resolve molecular mechanisms underlying ENaC gating, ion permeation, and pore block utilizing methods of cryo-electron microscopy, electrophysiology, and other biochemical and biophysical assays. Central to this proposal is to determine structures of ENaC at different phsyiological states and these studies will demonstrate how excision of the autoinhibitory peptide tracts from the extracellular domain is coupled to the opening of its Na+-selective ion channel, a novel mechanism of ion channel gating that is without precedent. This work will not only provide the molecular basis of ENaC function, more broadly, it will advance our understanding of whole body salt and water homeostasis.
Project Details
Start Date
2019-01-14
End Date
2021-03-17
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members