Identification and Validation of Novel Inotropy-Enhancing Molecular Targets

In this project molecular targets in a novel positive inotropic pathway coupling M2 muscarinic receptors to RhoA/Rho-kinase in heart failure are characterized and validated. The so far identified targets are the Regulator of G-protein signaling RGS3, the RhoGTPase-actvating protein p190RhoGAP and the guanine nucleotide exchange factor Tiam1. Depending on the expression level of RGS3 this proteins allow for a switch of the coupling of M2 muscarinic receptors to a Rho-kinase dependent positive inotropic response in cardiac myocytes. Therefore, all three proteins are putative molecular targets for novel therapies in heart failure.