Project Details
Projekt
Investigating the molecular mechanisms of sodium self-inhibition of epithelial sodium channel isoforms
Subject Area
Biophysics
Animal Physiology and Biochemistry
Animal Physiology and Biochemistry
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 538564058
The epithelial sodium channel (ENaC) is a sodium-selective ion channel that plays a key role in the regulation of salt and water balance in tetrapod vertebrates. In humans, dysfunctions in ENaC activity are associated with important diseases such as hypertension, cystic fibrosis, pulmonary edema, or nephrotic syndrome. ENaCs can be composed of four subunits (alpha, beta, gamma and delta) and form heterotrimeric "alpha-beta-gamma" or "delta-beta-gamma" channel isoforms. The constitutively active ENaCs are isoform-specifically throttled in activity by extracellular sodium ions. This mechanism is termed sodium self-inhibition and plays a critical role in the control of channel activity because key regulatory stimuli influence channel activity via enhancement or reduction of sodium self-inhibition. The molecular and structural basis of sodium self-inhibition is largely unknown. In this project, in particular, by using a combination of electrophysiological techniques (two-electrode voltage-clamp and patch-clamp), binding analyses (microscale thermophoresis) and computational modeling (atomic high performance simulations), the molecular and structural mechanisms of sodium self-inhibition of ENaC isoforms will be explored. Not only specific protein domains at the interfaces of neighboring ENaC subunits are investigated for their contribution to sodium self-inhibition, but also structural mechanisms of important regulatory stimuli (chloride inhibition and mechanosensitivity) of ENaC isoforms are elucidated. This will increase knowledge on the basic molecular physiology and structure-function relationships of these important ion channels, and provide the basis for further research approaches, in particular to elucidate the physiological function of ENaC isoforms, as well as to develop isoform-specific ENaC modulators.
DFG Programme
Research Grants
International Connection
Denmark, USA
Cooperation Partners
Isabelle Baconguis, Ph.D.; Professor Dr. Stephan Alexander Pless
