Grant: Operating Grant

Cardiac myxomas are tumors that can cause stroke and/or heart failure. These cardiovascular disorders, and others including acute ischemic stress, are associated with a defective reading of the signal transmitted in the cell by a second messenger called cyclic adenosine monophosphate or cAMP. The translation of the cAMP signal plays a critical role also in the development of bradycardia (i.e. life-threatening low heart rates) and epilepsy. The long-term goal of this project is to elucidate the structural and dynamical changes that translate the cAMP signal into a specific biological response necessary for the survival of the cell. We will use Nuclear Magnetic Resonance (NMR) Spectroscopy to investigate how, under physiological solution conditions, the cAMP second messenger interacts with and modifies two of its most important target proteins, the cAMP-dependent protein kinase A (PKA) and the hyperpolarization-activated and cyclic nucleotide-gated channels (HCN). The effect of the cAMP second messenger on the PKA and HCN proteins is currently poorly understood at a structural level and NMR has only very recently been used to investigate this at atomic resolution. NMR will reveal not only the structural changes in PKA and HCN caused by cAMP, but will also characterize how the dynamics of PKA and HCN is affected by cAMP. Knowledge of both structure and dynamics on both proteins is required in order to fully understand at a molecular level how cAMP works in the human heart and brain. The elucidation of the structural and dynamical changes associated with cAMP-binding is expected to help define general rules applicable to the design of drugs for cardiovascular and neurological disorders.