Kavli Affiliate: Kevin Bender
| Authors: Selin Schamiloglu, Elinor Lewis, Anne C Hergarden, Kevin Bender and Jennifer L Whistler
| Summary:
ABSTRACT Second generation antipsychotics (SGAs) are front-line treatments for serious mental illness. Often, individual patients benefit only from some SGAs and not others. The mechanisms underlying this unpredictability in treatment efficacy remain unclear. All SGAs bind the D3 dopamine receptor (D3R) and are traditionally considered antagonists for dopamine receptor signaling. Here, we report that some clinically important SGAs function as arrestin-3 agonists at D3R, resulting in modulation of calcium channels localized to the site of action potential initiation in prefrontal cortex pyramidal neurons. We further show that chronic treatment with an arrestin-3 agonist-SGA, but not an antagonist-SGA, abolishes D3R function through post-endocytic receptor degradation by G-protein coupled receptor-associated sorting protein-1 (GASP1). These results implicate D3R-arrestin-3 signaling as a source of SGA variability, highlighting the importance of including arrestin-3 signaling in characterizations of drug action. Furthermore, they suggest that post-endocytic receptor trafficking that occurs during chronic SGA treatment may contribute to treatment efficacy. Competing Interest Statement KJB receives research funding from BiooMarin Pharmaceutical Inc.