Grant: Project Grant

G protein coupled receptors (GPCR) are the main target of existing pharmacological agents.These receptors signal via coupling mechanisms involving either g-proteins or beta arrestins-mediated mechanisms. Previous research by our group has identified a lithium sensitive beta arrestin mediated cell signaling mechanism for the dopamine D2 receptor, a GPCR targeted by psycho-active drugs. Activation of D2R leads to the formation of a protein complex comprising the kinase Akt and beta arrestin 2. This complex is involved in the regulation of mood. We have identified the sequences of beta arrestin 2 that are responsible for its interaction with Akt. Furthermore disruption of this interaction, using cell permeable peptides, exert biochemical and behavioral lithium-mimetic effects in animal models of mania. This suggests that targeting beta arrestin 2 interfaces with signaling proteins may constitute a viable new strategy for drug development. We propose to resolve the structure of the beta arrestin 2/Akt protein complex and to establish if this complex is a desirable target for drug development. This information will be used in the future for the rational design of a new class of compounds selectively disrupting this modality of cell signaling.