Grant: Operating Grant

Ligand-gated ion channels are membrane proteins stimulated by chemical compounds. They consist of two modules responsible for the binding to the ligand and the ion conduction, respectively. While binding and ion conduction are well understood, little is known how the different modules interact and regulate each other, a process called "chemomechanical coupling". The importance of the coupling between the gating modules and the pore lies in its relation to many hereditary diseases. Defects in genes encoding for the coupling elements "tune" the channels' function. This tuning capability also makes the coupling region interesting as a pharmacological target. In our research program, we will investigate defects related to Olmsted syndrome, a severe dermatological disorder, metatropic dysplasia, a developmental disorder leading to skeletal deformation and dwarfism, and familial episodic pain disorder. We will study two ligand-gated ion channels, ionotropic glutamate receptors (iGluR) and transient receptor potential (TRP) channels. iGluRs are the most abundantly expressed excitatory neurotransmitter receptors in the brain. TRP channels are responsible for different senses including noxious heat and cold, pH, pungent compounds (wasabi, pepper) as well as chemical compounds. In both channels, we will establish the mechanisms of chemomechanical coupling on the atomic level. We will also identify the molecular binding site for blockers of the TRPA1 channel, which is suspected to play a key role in the development of migraine, one of the most burdensome diseases, affecting 1-2% of the general population. This will help to develop more effective drugs to alleviate the symptoms of migraine. Technically, we will use voltage-clamp fluorometry (i.e. simultaneous measurements of function and structural rearrangements), single molecule fluorescence and fluorescent unnatural amino acids in combination with molecular biology to establish links between structural and functional data