Análisis del represor transcripcional DREAM

DREAM/calsenilin/ KChIP-3 is a multifunctional neuronal calcium sensor with specific functions in different subcellular compartments. In the nucleus, the Ca²⁺-free form of DREAM binds tightly to DRE sequences in the DNA and controls the expression of several genes related to Ca²⁺ homeostasis, neuronal excitability and neuronal survival. As an auxiliary protein in the plasma membrane, DREAM interacts with and regulates gating of Kv4 potassium channels, voltage-dependent Ca²⁺ channels, and N-methyl-D-aspartate receptors. Calcium binding to functional EF-hands in the DREAM protein triggers a conformational change that prevents binding to DNA and modifies its affinity for some interacting proteins e.g. CREM, CREB and GRK2, but not for others e.g. Kv4 potassium and Cav1.2 calcium channels. Importantly, changes in the protein conformation of DREAM and other members of the neuronal calcium sensor superfamily are also induced upon binding of small molecules, like arachidonic acid, which modifies their protein-protein interacting properties.  The project will explore the functional consequences of the binding of these molecules to DREAM and the potential use of these inhibitors to treat pathologies where DREAM activity is modified.