Project Details
Projekt
Molecular mechanisms involved in the modulation of ion channels of the ENaC/Degenerin family by amphiphilic substances
Applicant
Professorin Dr. Silke Härteis
Subject Area
Anatomy and Physiology
Term
from 2014 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 265081537
The epithelial sodium channel (ENaC)/degenerin (DEG) superfamily encompasses a large number of ion channels with various (patho-)physiological functions. Members include the epithelial sodium channel (ENaC), the acid-sensing ion channels (ASICs) activated by protons and the bile acid-sensitive ion channel (BASIC). The so-called DEG region localized close to the channel pore is a hallmark of channels belonging to the ENaC/DEG family and is important for channel gating. Starting point of the present project proposal is the hypothesis that the DEG region is a potential target for modulator molecules (bile acids and possibly other natural occurring amphiphilic substances) that may contribute to the regulation of ion channels of the ENaC/DEG family under physiological and pathophysiological conditions. However, their identity and mode of action are still largely unknown. Interestingly, in the published crystal structure of ASIC1, the n-dodecyl-β-D-maltoside molecule was cocrystallized within the pore region of the channel in close proximity to the DEG region. In preliminary work, we could show that maltoside shows a similar stimulatory effect on the ENaC/DEG ion channels as bile acids. This suggests that the DEG region of the ENaC/DEG ion channels represents a potential binding site for other amphiphilic substances including naturally occurring molecules. Therefore, this project focusses on the systematic characterization of chemical properties of amphiphilic modulators that bind to the DEG region and may alter the function of the ENaC/DEG ion channels. This characterization will allow the subsequent search for endogenous amphiphilic substances that regulate ENaC, ASIC and BASIC in a similar way as bile acids. In this project, a combination of computer simulations and experimental electrophysiological methods will be used to identify such substances. In summary, the aim of the proposed project is a detailed investigation of the novel regulatory mechanism of ENaC/DEG ion channels by amphiphilic substances as described in our previous work. To elucidate the underlying mechanisms is of fundamental interest for a better understanding of the regulation of these ion channels at the molecular level. Furthermore, the proposed studies may establish the DEG region as potential "drug target" and identify so far unknown tissue specific amphiphilic modulators of ENaC/DEG ion channels with potential (patho-)physiological relevance.
DFG Programme
Research Grants
