Forty to fifty percent of therapeutic drugs today target a class of plasma membrane proteins called G-protein coupled receptors (GPCRs) (Beaulieu & Gainetdinov, 2011). The dopamine receptor is a type of GPCR that, when activated by dopamine, plays a role in reward, motivation, movement, and more. Imbalances in dopamine can result in neurological disorders such as ADHD, Parkinson’s, and schizophrenia. An overarching goal of the Caron lab is to understand the mechanisms of the dopamine receptor in order to formulate therapeutics targeting this receptor for treating these neurological disorders. Specifically, many investigators are working to improve antipsychotics for the treatment of schizophrenia by reducing side effects and increasing efficacy by targeting certain pathways of the dopamine receptor.
In order to begin to formulate these antipsychotics, it is necessary to first understand specifically the mechanisms of the dopamine D2 receptor, the target of most antipsychotics. The goal of my project essentially is to uncover the complexities behind the dopamine receptor by investigating the internalization of the D2 receptor under differing conditions, including the location of the receptor and the type of ligand used for activation, by investigating
The methodology my project employs is the BRET assay that investigates protein-protein interactions by measuring bioluminescence resonance energy transfer (BRET) between one protein tagged with a light producing enzyme, a luciferase, and another protein tagged with a fluorescing substrate acceptor, in this case a YFP. Specifically, my project investigates the interaction between the D2 receptor and beta-arrestin 2, a protein involved in receptor internalization. We are currently working on manipulating the type of GRKs and drugs used and measuring the effect this has on internalization. By the end of the summer, we hope to be one step closer to understanding the complexities of internalization and the elusive dopamine receptor.
Beaulieu, J. M., & Gainetdinov, R. R. (2011). The physiology, signaling, and pharmacology of dopamine receptors. Pharmacological reviews, 63(1), 182-217.