Our goals
Ion channels are integral membrane proteins that act as molecular switches of electrochemical signaling in the central nervous system. We would like to better understand the mechanisms that underly functional and pharmacological properties of ion channels. We use X-ray crystallography and electrophysiology to study ion channels both at the structural and functional level. We have currently set up a GFP-based pipeline for expression and detergent screening of ion channels from bacteria and eukaryotes. Our targets are the following classes of ion channels:
Cys-loop receptors
Cys-loop receptors are a class of pentameric ligand-gated ion channels, which includes the nicotinic acetylcholine receptor, GABA-A receptor, Glycine receptor and 5-HT3 receptor. These receptors are the molecular targets for a wide diversity of clinically important drugs, including tranquilizers and anticonvulsants like benzodiazepines, curare-like muscle relaxants and anti-emetics such as ondansetron. Several auto-immune diseases (e.g. myasthenia gravis) or mental illnesses (epilepsy, schizophrenia) are caused by the abnormal function of ligand-gated ion channels. We are pursuing crystal structures of recently identified molluscan and bacterial homologs of cys-loop receptors. This work is carried out in collaboration with several partners from the NeuroCypres FP7-consortium, including Guus Smit (VU, Amsterdam), Sarah Lummis (Cambridge, UK), Daniel Bertrand (Geneva), Pierre-Jean Corringer (Pasteur, Paris) and Werner Sieghart (Vienna, Austria).
TRP channels
In collaboration with the Laboratory for Ion Channel Research from Bernd Nilius and Thomas Voets we are studying an intensely investigated class of ion channels which are gated by a wide variety of chemical and physical stimuli, including voltage- or temperature change and ligand binding. TRP channels are the molecular sensors in the central nervous system of heat and cold temperatures. The cold-activated TRP channel is also activated by binding of menthol, which explains the fresh sensation of toothpaste and cough medication. The heat-activated TRP channel is activated by binding of capsaicine, the compound that produces the hot sensation of chili peppers.
Ion channels from bacteria
In collaboration with the Laboratory of Toxicology from Jan Tytgat we are studying 2 families of ion channels in bacteria that are activated by voltage changes across the membrane and/or intracellular concentrations of second messengers. We are specifically interested in bacterial homologs of human ion channels involved in disease and drug therapy. Our aim is to describe functional properties of these bacterial channels using electrophysiological techniques. In addition, we are trying to identify peptide toxins and find suitable candidates for large-scale expression and X-ray crystallography.
