A new study from the National Institute on Drug Abuse suggests that dopamine receptors in the brain and body are more complex than originally thought, allowing for a more critical understanding of them and how they work.
Researchers simulated inactive dopamine receptors and analyzed their changes when the dopamine antagonists risperidone and eticlopride were used. Different dopamine receptors had different responses to the drugs.
The study authors said the findings indicate that some proteins known as G-protein coupled receptors, of which dopamine receptors are a sub-family, can shape-shift and adopt different shapes by using different activating molecules. This shape=shifting creates a molecular cascade that changes the structure of the receptor from an inactive to active states. These changes in states may play a role in the development of addiction or other mental health conditions in a patient.
“Moreover, our simulations reveal that the extracellular loops are highly dynamic, with spontaneous transitions of extracellular loop 2 from the helical conformation in the D2R/risperidone structure to an extended conformation similar to that in the D3R/eticlopride structure. Our results reveal previously unappreciated diversity and dynamics in the inactive conformations of D2R. These findings are critical for rational drug discovery, as limiting a virtual screen to a single conformation will miss relevant ligands,” the study authors wrote.
The study was conducted by scientists at NIDA’s Intramural Research Program in collaboration with the University of Nottingham, England, and Columbia University in New York City.