Methods for identifying compounds that regulate beta-arrestin signaling complexes for use as antipsychotic drugs
About 35% of all drugs approved by the U.S. Food and Drug Administration target G protein-coupled receptors (GPCRs), a large and ubiquitous family of cell surface receptors with important contributions to neurological, hormonal, and many other physiological systems. For the roughly $14 billion global antipsychotics market, almost every drug currently available or in development targets dopamine and serotonin GPCRs. These are effective but targeting GPCRs runs a high risk of adverse side effects, exactly the reason first-generation antipsychotics are being rapidly phased out. There is a need for identifying novel antipsychotic drug compounds that do not affect other important GPCR signaling in order to minimize side effects.
Duke inventors have developed methods for identifying compounds with beta-arrestin signaling complex activity that do not affect other important GPCR functioning, which could be useful in developing antipsychotic drugs with fewer side effects. Looking beyond the GPCR desensitization role of beta-arrestins, the team discovered that beta-arrestin 2 is a signaling intermediate that brings together the serine/threonine kinase Akt with protein phosphatase 2A (PP2A), creating a signaling complex affecting dopaminergic synaptic transmission. Crucially, this pathway is distinct from the G protein-dependent dopamine receptor pathway. The team developed methods of anti-Akt antibody immunoprecipitation to screen compounds for effects on the activity of this novel signaling complex. This was validated by treatment of mice with known psychiatric medication lithium, which prevented the co-immunoprecipitation of PP2A with Akt thus indicating that lithium disrupts the formation of the Akt/βArr-2/PP2A signaling complex in vivo, which affects mouse behavior. In addition, lithium treatment did not induce behavioral change in beta-arrestin 2 knockout mice, highlighting the importance of the Akt/βArr-2/PP2A signaling complex.
These methods could also be useful beyond antipsychotics, since beta-arrestin signaling complexes are important in various pathologies, including fibrotic diseases, cardiovascular conditions, and cancers.
- Decouples the beta-arrestin signaling complex pathways from other GPCR pathways for more nuanced screening of drug activity and side effects
- Can be used for discovery of first-in-class drug types
- Can be used in vitro or in vivo
- Validated in mouse models