The calcium-activated cation TRPM4 channel is predominantly expressed in cells of the cardiovascular and immune system, pancreas and kidney. TRPM4 seems to be involved in many calcium-dependent cellular processes, such as insulin secretion or mast cells degranulation. There is a strong link between mutated TRPM4 channels and fatal forms of cardiac arrhythmias. Although TRPM4 is a promising drug target for treating cardiac arrhythmias, hypertension, or immunological disorders, its physiologic role in many tissues ist still unclear.

We first will elucidate the mutation-induced functional alterations of TRPM4 genetic variants found in patients with cardiac conduction defects. Other patients with cardiac arrhythmias will also be screened for TRPM4 mutations.

Later, we will study TRPM4 regulation by ubiquitin and ubiquitin-like proteins and search for proteins interacting with TRPM4. Virtual screening based on ligand similarity (see project 10A) should lead to novel TRPM4 ligands which will be then pharmacologically tested in vitro and in vivo.