The differential actions of clozapine and other antipsychotic drugs on the translocation of dopamine D2 receptors to the cell surface
Date of Original Version
Most clinically available antipsychotic drugs (APDs) bind dopamine D2 receptors (D2R) at therapeutic concentrations, and it is thought that they suppress psychotic symptoms by serving as competitive antagonists of dopamine at D2R. Here, we present data that demonstrate that APDs act independently of dopamine at an intracellular pool of D2R to enhance transport of D2R to the cell surface and suggest that APDs can act as pharmacological chaperones at D2R. Among the first- and secondgeneration APDs that we tested, clozapine exhibited the lowest efficacy for translocating D2R to the cell surface. Thus, our observations could provide a cellular explanation for some of the distinct therapeutic characteristics of clozapine in schizophrenia. They also suggest that differential intracellular actions of APDs at their common G protein coupled receptor (GPCR) target, D2R, could contribute to differences in their clinical profiles.
Journal of Biological Chemistry
Schrader, Joseph M., Craig M. Irving, J. Christopher Octeau, Joseph A. Christian, Timothy J. Aballo, Dean J. Kareemo, Joseph Conti, Jodi L. Camberg, J. Robert Lane, Jonathan A. Javitch, and Abraham Kovoor. "The differential actions of clozapine and other antipsychotic drugs on the translocation of dopamine D2 receptors to the cell surface." Journal of Biological Chemistry 294, 14 (2019): 5604-5615. doi:10.1074/jbc.RA118.004682.