Interaction of protein phosphatase 2A with the serotonin-1A receptor

Serotonin-specific reuptake inhibitor (SSRI) treatment of depressed patients displays a three week latency in amelioration of symptoms. Delayed desensitization of 5-hydroxytryptamine 1A (5-HT1A) autoreceptors is believed to be in part responsible for this latency and may involve receptor dephosphorylation. We hypothesized the 5-HT1A secondary intracellular (i2) loop interacts with receptor regulatory molecules. Yeast two-hybrid screen of a human cDNA library using 5-HT1A-i2 peptide as bait identified a novel 5-HT1A-i2 effector protein phosphatase 2A catalytic subunit (PP2AC). The 5-HT1A-i2-PP2AC interaction was quantified using yeast mating/beta-galactosidase assay. Furthermore, co-immunoprecipitation of tagged recombinant 5-HT1A receptor and endogenous PP2AC verified the interaction. Treatment with 5-HT1A receptor agonist enhanced the interaction. Mutation of critical receptor residues reduced or eliminated binding of PP2AC. Our results indicate a novel interaction between the 5-HT1A receptor and PP2AC and future studies will provide new insight into the role of protein phosphatase-receptor interactions in regulating 5-HT1A receptor desensitization, and resensitization