Cedric Vallee
Academic and research departments
Leverhulme Quantum Biology Doctoral Training Centre (QB-DTC), School of Veterinary Medicine, School of Biosciences, Faculty of Health and Medical Sciences.About
My research project
Exploration of ion selectivity in the ENaC/DEG FamilyIon channels in living cells are examples of where quantum effects can play a role in biology. These proteins provide a selective conduction of ions across cellular membranes, which is crucial for cell survival. They are so important that they rank as the second most important target for the development of pharmaceutical drugs. However, the mechanisms behind their selectivity - e.g. how these proteins can perfectly discriminate between ions - is not entirely understood.
The aim of this exciting PhD is to investigate selectivity of sodium (Na+) within a specific channel family: the Epithelial Sodium Channel/Degenerin (ENaC/DEG) Family. Studies will be driven by two different but related approaches: simulation via computer modelling and experiments via electrophysiology. I will mainly be focused on the selectivity filter of the channels, which is generally the narrowest part of the pore and where the channel can discriminate different ions, even those of identical charge, allowing only the right one to pass through (in this case Na+). The motif in the ENaC/DEG Family is (G/S)XS, where X is a non-conserved residue within this ion channel family.
It has been stated that residues of the selectivity filter create an energy barrier that ions have to cross. The aim of my project is to simulate the ion flow through these energy barriers, whilst experimentally measuring electrophysiological currents. To investigate the mechanism, several parameters can be tested: different ions (Li+, K+, Ca2+), isotopes (6Li, 40K, 43Ca, 44Ca, heavy water), flow direction and phospholipid composition of the membrane.
Supervisors
Ion channels in living cells are examples of where quantum effects can play a role in biology. These proteins provide a selective conduction of ions across cellular membranes, which is crucial for cell survival. They are so important that they rank as the second most important target for the development of pharmaceutical drugs. However, the mechanisms behind their selectivity - e.g. how these proteins can perfectly discriminate between ions - is not entirely understood.
The aim of this exciting PhD is to investigate selectivity of sodium (Na+) within a specific channel family: the Epithelial Sodium Channel/Degenerin (ENaC/DEG) Family. Studies will be driven by two different but related approaches: simulation via computer modelling and experiments via electrophysiology. I will mainly be focused on the selectivity filter of the channels, which is generally the narrowest part of the pore and where the channel can discriminate different ions, even those of identical charge, allowing only the right one to pass through (in this case Na+). The motif in the ENaC/DEG Family is (G/S)XS, where X is a non-conserved residue within this ion channel family.
It has been stated that residues of the selectivity filter create an energy barrier that ions have to cross. The aim of my project is to simulate the ion flow through these energy barriers, whilst experimentally measuring electrophysiological currents. To investigate the mechanism, several parameters can be tested: different ions (Li+, K+, Ca2+), isotopes (6Li, 40K, 43Ca, 44Ca, heavy water), flow direction and phospholipid composition of the membrane.
My qualifications
Pharmacological characterization of CDX, a Candoxin-inspired antagonist of nicotinic acetylcholine receptors.
Supervisor: Prof. Kini R. Manjunatha
Publications
The Epithelial Sodium Channel/Degenerin (ENaC/DEG) family is a superfamily of sodium-selective channels that play diverse and important physiological roles in a wide variety of animal species. Despite their differences, they share a high homology in the pore region in which the ion discrimination takes place. Although ion selectivity has been studied for decades, the mechanisms underlying this selectivity for trimeric channels, and particularly for the ENaC/DEG family, are still poorly understood. This systematic review follows PRISMA guidelines and aims to determine the main components that govern ion selectivity in the ENaC/DEG family. In total, 27 papers from three online databases were included according to specific exclusion and inclusion criteria. It was found that the G/SxS selectivity filter (glycine/serine, non-conserved residue, serine) and other well conserved residues play a crucial role in ion selectivity. Depending on the ion type, residues with different properties are involved in ion permeability. For lithium against sodium, aromatic residues upstream of the selectivity filter seem to be important, whereas for sodium against potassium, negatively charged residues downstream of the selectivity filter seem to be important. This review provides new perspectives for further studies to unravel the mechanisms of ion selectivity.