Grant: Operating Grant

Most of the drugs currently used to treat heart failure and related diseases (including beta-blockers) are directed against the largest family of cell surface receptors (which transduce signals outside of the cell into activity inside the cell), the so-called G protein-coupled receptors or GPCRs. These drugs target ligand-binding sites, i.e. the site where endogenous compounds interact with the receptor. Drugs thus act as either agonists, mimicking the effects of the natural ligand or as antagonists, which block the effects of the natural ligand. The problem is that all of these drugs produce significant side effects. This, in part is due to the fact that targetting the ligand binding site may not be specific or selective enough to elicit or block only the desired effect. This is likely due to the nature of the receptor and how it's downstream signalling pathways are organized. These receptors do not as previously believed interact with their signalling partners in a random fashion as a result of agonist stimulation. Recent data has shown that 1) each single receptor can be coupled to multiple signalling pathways in the same cell ; 2) receptors are physically and stably associated with their signalling pathways even before agonist stimulation and 3) these complexes form during biosynthesis, i.e. before the receptor gets to it's final destination in the cell membrane. How then, can we make drugs that are more specific and have less side effects? This project is aimed at characterizing individual receptor signalling complexes, their organization and specificity and how they are assembled. Once we know 1) what is in any given signalling complex and 2) how it is assembled and localized in the cell we can in principle, we can thus reduce the number of side effects seen with current therapeutic approaches to diseases such as heart failure.